Hyperthermia in Cancer Therapy

Number: 0278

Policy

1. Aetna considers the following procedures medically necessary:

   1. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of pseudomyxoma peritonei (including disseminated peritoneal adenomucinosis (DPAM), characterized by histologically benign peritoneal tumors that are frequently associated with an appendiceal mucinous adenoma, as well as peritoneal mucinous carcinomatosis, which are defined as disseminated mucin-producing adenocarcinomas);
   2. Cytoreductive surgery combined with HIPEC for the treatment of peritoneal mesothelioma;
   3. Cytoreductive surgery combined with HIPEC for the treatment of goblet cell carcinoid tumor;
   4. HIPEC for use with cisplatin at the time of interval debulking surgery for FIGO stage III ovarian cancer;
   5. Regional hyperthermic melphalan perfusion in members with stage II, IIIA, and stage III in-transit extremity melanoma;
   6. Sequential radiation and local/regional external hyperthermia only for the treatment of primary or metastatic cutaneous or subcutaneous superficial malignancies (e.g., superficial recurrent melanoma, chest wall recurrence of breast cancers, and cervical lymph node metastases from head and neck cancer).

2. Aetna considers hyperthermia experimental and investigational for all other indications including the following applications because of insufficient evidence regarding its effectiveness in these conditions:

   1. Deep hyperthermia alone or in combination with radiation therapy;
   2. HIPEC for intrapleural mesothelioma;
   3. HIPEC for appendiceal carcinoma without pseudomyxoma, bladder cancer, clear cell carcinoma of the ovary, colon cancer, colorectal signet ring carcinoma, desmoplastic small round cell tumor, fallopian tube cancer, gastric cancer, hepatocellular carcinoma, mixed germ cell tumor, pancreatic cancer, signet ring adenocarcinoma of the appendix, small bowel adenocarcinoma, thymic carcinoma, urachal cancer, and uterine leiomyosarcoma;
   4. HIPEC for peritoneal surface malignancy (peritoneal carcinomatosis) for indications other than pseudomyxoma peritonei or peritoneal mesothelioma;
   5. Interstitial, intra-cavitary, and intraluminal hyperthermia;
   6. Pleural HIPEC for the treatment of metastatic pleural malignancies, pleural mesothelioma, and other indications;
   7. Prophylactic HIPEC for gastric cancer;
   8. Regional hyperthermic melphalan perfusion in stage I, IIIB and IIIAB extremity melanoma, as well as regional hyperthermic perfusion for extremity melanoma in conjunction with any other chemotherapy;
   9. Regional hyperthermic perfusion for indications (e.g., non-small cell lung cancer) other than extremity melanoma;
   10. Superficial hyperthermia for paranasal sinus and nasal cavity cancer;
   11. Transrectal ultrasound hyperthermia for prostate cancer;
   12. Whole body hyperthermia for testicular cancer and other indications.

Note: Stages of melanoma (0 to IV) can be found in the following link: Melanoma Skin Cancer Stages

Background

Several studies support the hypothesis that hyperthermia appears to potentiate the tumoricidal effects of radiation therapy.  Radiation therapy and hyperthermia probably act independently.  Studies have suggested a potential synergistic response to radiation therapy and hyperthermia versus radiation therapy alone.

The goal of hyperthermia in cancer therapy is to produce tumor tissue temperatures above 41 to 42 degrees centigrade.  Above this temperature, heat has a direct cytotoxic effect on both normal and tumor cells and also has a radiosensitizing effect by preventing repair of sublethal and potentially lethal radiation damage.  Heat can also potentiate the cytotoxic effect of a variety of chemotherapeutic agents. 

Local hyperthermia confines the treatment to a small area, such as a tumor. Approaches to local hyperthermia include: external approach, which is used to treat tumors that are near the body surface in which external applicators are placed to raise the temperature of the tumor; interstitial approach, used to treat tumors deep within the body (eg, brain tumors) where probes or needles are inserted into the tumor and heated to higher temperatures than external techniques; and intraluminal approach, used to treat tumors within or near body cavities (eg, esophagus, prostate) by placing probes inside the cavity to deliver energy and heat to the tumor.

Whole body hyperthermia is reportedly used to treat metastatic cancer that has spread throughout the body. It can be performed using warm-water blankets, inductive coils (like those in electric blankets) or thermal chambers (similar to large incubators).

Hyperthermia has been shown to potentiate the effect of radiation therapy in the treatment of superficial lesions (less than 3 cm in depth).  Clinical experience has largely been limited to treatment of recurrent, metastatic superficial melanomas, chest wall recurrence of breast cancer and cervical lymph node metastases from head and neck cancers.  Tumor depth is a critical factor when combining radiation therapy and hyperthermia.  Lesions less than 3 cm from the surface treated with radiation therapy and hyperthermia have been shown to have a significantly greater complete response rate compared to the complete reponse rate of lesions greater than 3 cm deep.

Guidelines on breast cancer from the National Comprehensive Cancer Network (NCCN, 2009) include consideration of the addition of hyperthermia to irradiation for localized recurrences/metastastes.  The NCCN guidelines explain that there have been several prospective randomized trials comparing radiation to radiation plus hyperthermia in the treatment of locally advanced/recurrent cancers, primarily breast cancer chest wall recurrences (Vernon et al, 1996; Jones et al, 2005).  The NCCN guidelines state that, while there is heterogeneity among the study results, a recent series with strict quality assurance demontrated a statistically significant increase in local tumor response and greater duration of local control with the addition of hyperthermia to radiation compared to radiation alone (Jones et al, 2005).  However, no differences in overall survival have been demonstrated.  The NCCN guidelines state that delivery of local hyperthermia is technically demanding and requires specialized expertise and equipment (e.g., the monitoring of temperatures and management of possible tissue burns).  The NCCN Panel thus recommended the use of hyperthermia be limited to treatment centers with appropriate training, expertise and equipment.  The NCCN guidelines noted that the addition of hyperthermia generated substantial discussion and controversy among the NCCN panel members and is a category 3 recommendation (the recommendation is based upon any level of evidence but reflects major disagreement).  The NCCN's clinical practice guideline on melanoma (version 2.2013) recommends the use of hyperthermic perfusion/infusion with melphalan for "stage III in-transit" melanoma (category 2A recommendation).

The results of clinical studies combining hyperthermia and radiotherapy in the treatment of melanoma have been complex and somewhat conflicting (e.g., Shidnia et al, 1990; Engin et al, 1993; Overgaard et al, 1995).  A randomized trial of radiotherapy with or without external hyperthermia was conducted by the European Society for Hyperthermic Oncology in 70 patients with metastatic or recurrent melanoma (Overgaard et al, 1995).  The addition of hyperthermia to radiotherapy increased the complete response rate from 35 % to 62 %, and 2-year local control rates from 28 % to 46 %.  However, only 14 % of patients received the prescribed protocol treatment because of "equipment difficulties", and survival did not differ between the 2 groups.

Hyperthermia plus chemotherapy appears to result in increased cell toxicity due to net increase in DNA damage after exposure to hyperthermia and chemotherapy.  Regional hyperthermic melphalan isolated limb perfusion for stage II and IIIA extremity melanoma has become routine practice.  Isloated hyperthermic mephalan limb perfusion of state II and IIIA extremity melanomas has been shown to be effective in prospective, randomized trials.  Surgery plus regional hyperthermic melphalan perfusion versus surgery alone decreased recurrences and improved survival significantly in several randomized studies.  Also, a comparison of responses after melphalan hyperthermic therapeutic limb perfusion versus melphalan normothermic limb perfusion for extremity melanoma showed a clear advantage in response rates.  Although hyperthermic perfusion of stage IIIB and IIIAB extremity melanoma shows a trend toward improvement in survival, well controlled trials will be necessary to document the effectiveness of this technique in node- positive patients.  Similarly, while adjuvant treatment of stage I extremity melanoma shows a trend toward improved 5-year survival, well-controlled studies needed to confirm this observation.

Local or systemic hyperthermia alone has not been shown to be an effective cancer treatment.  Although interstitial radiation-hyperthermia appears promising, well controlled trials comparing radiation therapy alone versus combined interstitial radiation-hyperthermia are needed.  Whole body heating is a complex, labor- intensive technique that is difficult to accomplish and clinically impractical.

Emami et al (1996) reported on a randomized trial that found no benefit to interstitial radiation-hyperthermia in comparison with interstitial radiotherapy alone on tumor regression or control in accessible lesions.  From January 1986 to June 1992, 184 patients with persistent or recurrent tumors after previous radiotherapy and/or surgery, which were amenable to interstitial radiotherapy, were accessioned to a protocol developed by the Radiation Therapy Oncology Group (RTOG).  A total of 173 cases were analyzed (87 patients in the interstitial radiotherapy group and 86 in the interstitial radiation-hyperthermia arm).  The investigators stated that the 2 arms were well-balanced regarding stratification criteria.  Most tumors were in the head and neck (40 % in the interstitial radiation therapy group and 46 % in the interstital radiation-hyperthermia group), and pelvis (42 % and 43 %, respectively).  Eighty-four percent of patients in both arms had prior radiation therapy (40 Gy or more); 50 % and 40 %, respectively, had prior surgery, and 34 % in each arm had prior chemotherapy.  The investigators said that the dose of radiation therapy administered was dependent on the previous radiation dose and did not exceed a total cumulative dose of 100 Gy.  Hyperthermia was delivered in 1 or 2 sessions, either before or before and after interstitial implant.  According to the investigators, the intended goal of the hyperthermia was to maintain a minimal tumor temperature of 42.5 degrees C for 30 to 60 mins.  The investigators reported that there was no difference in any of the study end points between the 2 arms.  Complete response was 53 % and 55 % in both arms.  Two-year survival was 34 % and 35 %, respectively.  Complete response rate for persistent lesions was 69 % and 63 % in the 2 treatment arms as compared with 40 % and 48 % for recurrent lesions.  The investigators reported that a set of minimal adequacy criteria for the delivery of hyperthermia was developed.  When these criteria were applied, only 1 patient had an adequate hyperthermia session.  Acute grade 3 and 4 toxicities were 12 % for interstitial radiation therapy and 22 % for insterstitial radiation-hyperthermia therapy.  The investigators reported that late grade 3 and 4 toxicities were 15 % for interstitial radiation therapy and 20 % for interstitial hyperthermia radiation therapy.  The difference was not significant.  The investigators concluded that interstitial hyperthermia, as applied in this randomized study, did not show any additional beneficial effects over interstitial radiotherapy alone.  The investigators stated that delivery of hyperthermia remains a major obstacle (since only 1 patient met the basic minimum adequacy criteria as defined in this study).  The investigators stated that the benefit of hyperthermia in addition to radiation therapy still remains to be proven in properly randomized prospective clinical trials after substantial technical improvements in heat delivery and dosimetry are achieved. 

In a multi-institutional, prospective, randomized trial sponsored by the International Atomic Energy Agency, Mitsumori et al (2007) examined if the combination of hyperthermia (HT) and radiotherapy (RT) improves the local response rate of locally advanced non-small cell lung cancer (NSCLC) compared with that obtained by RT alone.  A total of 80 patients with locally advanced NSCLC were randomized to receive either RT alone or radiation RT plus HT.  The primary endpoint was the local response rate.  The secondary endpoints were local progression-free survival (PFS) and overall survival (OS).  The median follow-up period was 204 days for all patients and 450 days for surviving patients.  There were no significant differences between the 2 arms with regard to local response rate (p = 0.49) or OS rate (p = 0.868).  However, local PFS was significantly better in the RT plus HT arm (p = 0.036).  Toxicity was generally mild and no grade 3 late toxicity was observed in either arm.  The authors concluded that although improvement of local PFS was observed in the RT plus HT arm, this prospective randomized study failed to show any substantial benefit from the addition of HT to RT in the treatment of locally advanced NSCLC.

A number of studies have evaluated the use of hyperthermia combined with chemotherapy for cervical cancer.  A multi-institutional prospective randomized controlled trial sponsored by the International Atomic Energy Agency found no benefit to radiotherapy in combination with regional hyperthermia over radiotherapy alone in rate of local control of cervical cancer (Vasanthan et al, 2005).  A total of 110 patients with biopsy-proven, locally advanced cervical carcinoma were randomized to treatment by radiotherapy with or without hyperthermia.  The patients were stratified by institution, stage, and histologic type.  Each patient received external beam radiation therapy and brachytherapy.  For the patients randomized to receive hyperthermia, a minimum  of 5 sessions (60 mins each, once per week) were administered, employing a radiofrequency (RF) capacitive heating device.  The median follow-up period was 466 days for all the patients and 512 days for the surviving patients.  The authors stated that the 2 arms were well-balanced with regard to the patient factors, tumor factors, and treatment factors.  The OS rate at 3 years was 73.2 %, and the local control rate was 68.5 %.  There were no significant differences between the patients treated with or without hyperthermia, either with regard to the survival (p = 0.1893) or the rate of local control (p = 0.58).  The authors reported that survival was significantly worse among the patients with stage IIb disease who received hyperthermia (p = 0.0162) although there was no difference in their rate of local control (p = 0.7988).  The authors explained that further analysis is necessary to determine if the difference in survival is due to a greater incidence of distant metastases or some other cause.  Acute grade 2 to 3 toxicity was seen in 10 of 55 patients (18 %) treated by hyperthermia and in 2 of 55 of the patients (4 %) treated without hyperthermia (p = 0.01).  There authors reported that there was no significant difference in the late toxicity observed in the 2 arms.  The authors concluded that this prospective randomized study failed to show any benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced cervical cancer.  The authors found that acute toxicity was significantly greater among the patients receiving hyperthermia, and the survival was significantly worse among the stage IIb patients receiving hyperthermia even though there was no difference in the local control rate.

In a phase II study, Richel et al (2004) examined the efficacy and toxicity of whole-body hyperthermia with carboplatin chemotherapy in persons with metastatic or recurrent cervical cancer.  Twenty-one of 25 participants were evaluable for response: 1 complete remission, 6 partial responses, stable disease in 9 patients and progression in 5, leading to a response rate of 33 %.  The investigators reported that 3 of 4 evaluable chemotherapy pre-treated patients progressed, while this was seen in only 2 of 17 chemotherapy-naive patients.  The median survival is 7.8 months (range of 1.3 to 43+) and no patients were lost to follow-up.  The investigators reported that grades 3/4 toxicities were common: leukopenia in 35 %, thrombopenia in 61 % and anemia in 22 % of all treatments.  The investigators stated that excessive, partly reversible renal toxicity was seen in 2 patients (grades 3 and 4).  The investigators concluded that the efficacy of whole body hyperthermia and carboplatin in recurrent and/or metastatic cervical cancer seems comparable to that of other palliative chemotherapy regimens in this disease.  The investigators stated that the considerable toxicity, though largely manageable, includes unexpected and severe unacceptable renal toxicity, and that this regimen seems less suitable for palliative care.

The Dutch Deep Hyperthermia Trial showed that combining radiotherapy with hyperthermia impoved local control rates and survival over radiotherapy alone in women with locally advanced cervical carcinoma (Van der Zee et al, 2000; Franckena et al, 2008).  It is not known, however, whether radiotherapy and hyperthermia results in superior outcomes to radiotherapy and chemotherapy, which is the current standard of care for advanced cervical carcinoma.  Franckena et al (2008) reported on the long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up.  From 1990 to 1996, a total of 114 women with locoregionally advanced cervical carcinoma were randomly assigned to RT or RT+HT.  The RT was applied to a median total dose of 68 Gy.  The HT was given once-weekly.  The primary end point was local control.  Secondary end points were OS and late toxicity.  At the 12-year follow-up, local control remained better in the RT+HT group (37 % versus 56 %; p = 0.01).  The authors reported that survival was persistently better after 12 years: 20 % (RT) and 37 % (RT+HT; p = 0.03).  Grade 3 or higher radiation-induced late toxicities were reported to be similar in both groups. 

Harima et al (2001) reported on a small (n = 40) randomized controlled clinical trial of RT versus RT+HT in persons with advanced cervical carcinoma, and found improvements in response and 3-year local relapse-free survival with the addition of HT.  A total of 40 patients with stage IIIb cervical carcinoma were treated with external beam radiotherapy to the pelvis, combined with iridium 192 high-dose-rate intracavitary brachytherapy.  Patients were randomly assigned to radiotherapy alone or radiotherapy plus 3 sessions of hyperthermia.  The investigators reported that a complete response was achieved in 50 % of patients treated with RT versus 80 % in patients receiving radiotherapy plus hyperthermia.  There was also a trend toward improvement in 3-year OS and disease-free survival (DFS) among patients who were treated with RT+HT (58.2 % and 63.6 %) versus RT alone (48.1 % and 45 %), but the differences were not statistically significant.  The authors reported that the 3-year local relapse-free suvival of the patients who were treated with RT+HT (79.7 %) was significantly better than that of the patients treated with RT (48.5 %) (p = 0.048).  The authors noted that RT+HT did not significantly add to toxicity over RT alone.

Guidelines recommend the use of chemotherapy plus radiotherapy for advanced cervical cancer (e.g., NCCN, 2009; NCI, 2008).  Although it has been noted that the addition of hyperthermia to radiotherapy appears to improve response rates and 3-year survival by a magnitude similar to that observed in chemoradiotherapy studies in cervical cancer, Westermann et al (2005) has noted that the reported randomized clinical trial experience of chemotherapy studies (n = 2,192 patients) far exceeds that for radiation therapy plus hyperthermia (n = 154 patients).  Ongoing studies are examining the potential benefits of adding hyperthermia to radiotherapy and chemotherapy in advanced cervical carcinoma (Westermann et al, 2005). 

A number of studies have examined the use of cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy as a treatment for pseudomyxoma peritonei, a rare cancer arising from low-grade adenocarcinomas of appendiceal, ovarian, or peritoneal origin.  Reported outcomes of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for this rare condition are markedly superior to that reported for cytoreduction alone and other conventional treatments for this condition (Sugarbaker and Chang, 1999; Stewart et al, 2005; Elias et al, 2008). 

Although some authorities (Esquivel et al, 2007) have recommended use of HIPEC for patients with recurrent and/or metastatic colon caner with peritoneal involvement, this recommendation is based upon uncontrolled studies.  There are a lack of phase III studies demonstrating improved outcomes with the use of hyperthermia compared to non-hyperthermic administration.  The sole randomized controlled clinical trial randomly assigned 105 patients with peritoneal carcinomatosis from appendiceal (n = 18) or colorectal (n = 87) cancer to either standard treatment with systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or aggressive cytoreduction (debulking) and hyperthermic intraperitoneal chemotherapy followed by the same systemic chemotherapy regime (Verwaal et al, 2003).  After a median follow-up period of 22 months, the median survival was 12.6 months in the standard therapy arm and 22 months in the hyperthermic intraperitoneal chemotherapy arm.  The study has been criticized because the HIPEC group differed from the standard therapy group not only in the use of intraperitoneal hyperthermic chemotherapy, but also in surgical debulking.  It is possible that the important treatment was the surgical debulking, and the HIPEC made little difference.

Guidelines from the National Comprehensive Cancer Network (2009) state that the NCCN colon cancer guidelines panel considers the treatment of disseminated carcinomatosis with cytoreductive surgery (i.e., peritoneal stripping surgery) and peri-operative HIPEC to be investigational and does not endorse such therapy outside of a clinical trial.

Minicozzi and co-workers (2008) estimated the post-operative morbidity and mortality and short-term outcome of treatment of the peritoneal carcinomatosis (PC) by CRS and HIPEC.  A total of 24 patients with PC or positive cytology at peritoneal washing were treated.  Primary tumor was ovarian carcinoma in 10 patients: 4 cases presented peritoneal surface malignancies (PSM) after any time from hysteroadnexectomy related to primary tumor, 6 cases synchronous PSM.  Primary tumor was gastric cancer in 7 patients: the peritoneal washing was positive in 4 cases and, during follow-up following gastrectomy, another 2 cases presented PSM.  One patient was previously treated with ovariectomy for ovarian mass that resulted a Krukenberg's tumor of gastric cancer.  Primary tumor was pseudomixoma peritonei (PMP) in 4 patients; CRS and HIPEC was performed as 1st-line therapy in only 1 patient.  Three patients were previously treated for colon carcinoma; HIPEC was performed via the abdomino-pelvic cavity for 60 mins using a closed abdomen technique.  The drugs used were mitomycin C (3.3 mg/m2/L) and cisplatin (25 mg/m2/L).  The intra-cavitary mean temperature was 41.8 degrees C.  The mean peritoneal cancer index was 14.  Post-operative major complications occurred in 7 cases (28 %), post-operative minor complications occurred in 8 cases (32 %).  No patients died in the post-operative period.  Mean hospital stay was 11.5 days (6 to 35 days).  After a median follow-up of 8 months (range of 2 to 34), 14 (58 %) patients were alive and 13 were disease-free.  The authors concluded that these findings are consistent with other studies for the high rate of post-operative morbidity associated with treatment, but they achieved best results on mortality and post-operative hospital stay.  The authors concluded that CRS associated with HIPEC is a good therapeutic option especially in ovarian-related carcinosis and PMP.

Scaringi et al (2008) evaluated the role of HIPEC, associated or not to CRS in the treatment of different stages of advanced gastric cancer (AGC).  A total of 37 patients with AGC who underwent 43 HIPEC were included in this study.  Hyperthermic intraperitoneal chemotherapy used mitomycin-C and cisplatin for 60 to 90 mins at 41 to 43 degrees C intra-abdominal temperature.  The main endpoints were long-term survivals, morbidity and mortality rates.  Eleven patients had no demonstrable sign of PC and constituted the prophylactic-group, while 26 patients had macroscopic PC (PC-group).  Five patients were Gilly 1 or 2 (nodules less than 0.5 cm) and 21 Gilly 3 or 4 (nodules greater than or equal to 0.5 cm).  In the PC-group a complete curative CRS was achieved before HIPEC in 8 (PC-curative subgroup) and a palliative HIPEC in 18 patients (PC-palliative subgroup).  The overall 30-days mortality was 5 % (2 patients).  Two patients in the prophylactic group died within 6 months after hospital discharge (overall mortality 11 %).  The estimated risk of death per procedure was 9 %.  Ten patients (27 %) presented 1 or more complications.  The median survival was 23.4 months in the prophylactic group, and 6.6 months in the PC-group (p < 0.05).  The median survival in the PC-curative subgroup was 15 versus 3.9 months in the PC-palliative subgroup (p = 0.007).  The median survival according to Gilly classification was significantly different (Gilly 1 and 2 versus Gilly 3 and 4, 15 versus 4 months, respectively, p = 0.014).  The global recurrence rates between the prophylactic group and the PC-curative subgroup at 2 years were 36 % versus 50 %, respectively.  The median delay to recurrence was 18.5 versus 9.7 months, respectively.  The authors concluded that HIPEC might be useful to improve the survival in selected patients with AGC only when a complete CRS can be achieved.  Despite encouraging data, prospective studies, based on larger cohorts of patients are needed to evaluate the role of this procedure as a prophylactic treatment in patients with AGC.

Spiliotis et al (2008) reported their experience in the combined treatment of PC using CRS plus HIPEC.  This prospective study included patients with PC from gynecological, gastric and colon cancer, treated in 2 centers.  Cytoreductive surgery included the peritonectomy procedures described by Jacquet and Sugarbaker as well as multi-visceral resections in order to achieve a complete macroscopical cancer eradication.  The HIPEC that followed was performed via the open abdomen technique.  A total of 24 patients (3 men and 21 women, mean age of 60 years) were treated.  Twelve patients had PC from ovarian cancer, 7 from colon, 3 from gastric and 2 from uterine cancer.  The mean duration of the procedure was 7.83 hours (range of 5  to 12.30).  Macroscopically, complete cytoreduction (CC) was achieved in 18 (75 %) patients.  Two (8.3 %) patients died in the first 30 days.  The overall morbidity was 42 % and 2 patients were re-operated.  The mean follow-up was 22 months (range of 3 to 36).  The overall 1-year survival was 59.1 %; concerning the gynecological cancers it was 53.8 % (mean survival of 11.7 months) and for gastrointestinal cancers it was 44.4 % (mean survival of 9.5 months).  The authors concluded that their findings suggested that the combined treatment of CRS plus HIPEC for PC is associated with acceptable mortality and morbidity and offers an improved survival in these patients.

Di Giorgio et al (2008) examined the use of CRS (peritonectomy procedures) combined with HIPEC in the treatment of diffuse PC from ovarian cancer.  A total of 47 patients with primary advanced or recurrent ovarian cancer and diffuse PC were enrolled; 22 underwent primary and 25 secondary CRS plus immediate HIPEC followed by systemic chemotherapy.  The overall mean Sugarbaker peritoneal cancer index was 14.9 (range of 6 to 28).  A mean of 6 surgical procedures were required per patient (range of 4 to 10).  In 87.3 % of the patients debulking achieved optimal cytoreduction (Sugarbaker completeness of cytoreduction [CC] score 0 to 1), whereas in 12.7 % it left macroscopic residual disease (CC-2 or CC-3).  Major complications developed in 21.3 % of the patients and the in-hospital mortality rate was 4.2 %.  The mean OS was 30.4 months, median survival was 24 months, and mean DFS was 27.4 months.  Five-year survival was 16.7 %.  Uni-variate (log-rank test and analysis of variance) and multi-variate analyses (Cox proportional-hazard model) identified the CC score as the main factor capable of independently influencing survival.  The authors concluded that peritonectomy procedures combined with HIPEC offer promising long-term survival in patients with diffuse peritoneal ovarian carcinomatosis.  They achieved high adequate primary and secondary surgical cytoreduction rates with acceptable morbidity and mortality.

Verwaal et al (2008) noted that the treatment of PC is based on CRS followed by HIPEC and combined with adjuvant chemotherapy.  In 2003, a randomized trial was finished comparing systemic chemotherapy alone with CRS followed by HIPEC and systemic chemotherapy.  This trial showed a positive result favoring the studied treatment; and has now been updated to a minimal follow-up of 6 years to show long-term results.  For all patients still alive, the follow-up was updated until 2007.  In the original study, 4 patients were excluded -- 2 because of no eligible histology/pathology and 2 because of major protocol violations.  After randomization, 4 patients in the HIPEC arm and 6 in the control arm were not treated using the intended therapy, 1 patient because of withdrawal, 1 because of a life-threatening other malignant disease and the others because of progressive disease before initiation of the treatment.  During the follow-up, 1 patient was crossed-over from the control arm and underwent CRS and HIPEC for recurrent disease, after the assigned treatment was completed.  The data from these patients were censored at the moment of the cross-over.  Progression-free and disease-specific survival were analyzed using the Kaplan Meyer test and compared using the log rank method.  The long-term results were studied in more detail to evaluate efficacy and toxicity.  At the time of this update, the median follow-up was almost 8 years (range of 72 to 115 months).  In the standard arm, 4 patients were still alive, 2 with and 2 without disease; in the HIPEC arm, 5 patients were still alive, 2 with and 3 without disease.  The median PFS was 7.7 months in the control arm and 12.6 months in the HIPEC arm (p = 0.020).  The median disease-specific survival was 12.6 months in the control arm and 22.2 months in the HIPEC arm (p = 0.028).  The 5-year survival was 45 % for those patients in whom a R1 resection was achieved.  The authors concluded that with 90 % of all events having taken place up to this time, this randomized trial shows that CRS followed by HIPEC does significantly add survival time to patients affected by PC of colorectal origin.  For a selected group, there is a possibility of long-term survival.

Elias and colleagues (2009) compared the long-term survival of patients with isolated and resectable PC in comparable groups of patients treated with systemic chemotherapy containing oxaliplatin or irinotecan or by CRS plus HIPEC.  All patients with gross PC from colorectal adenocarcinoma who had undergone CRS plus HIPEC were evaluated.  The standard group was constituted by selecting patients with colorectal PC treated with palliative chemotherapy during the same period, but who had not benefited from HIPEC because the technique was unavailable in the center at that time.  A total of 48 patients were retrospectively included in the standard group and were compared with 48 patients who had undergone HIPEC and were evaluated prospectively.  All characteristics were comparable except age and tumor differentiation.  There was no difference in systemic chemotherapy, with a mean of 2.3 lines per patient.  Median follow-up was 95.7 months in the standard group versus 63 months in the HIPEC group.  Two-year and 5-year overall survival rates were 81 % and 51 % for the HIPEC group, respectively, and 65 % and 13 % for the standard group, respectively.  Median survival was 23.9 months in the standard group versus 62.7 months in the HIPEC group (p < 0.05, log-rank test).  The authors concluded that patients with isolated, resectable PC achieve a median survival of 24 months with modern chemotherapies, but only CRS plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51 %.

In a phase II clinical study, Lim et al (2009) evaluated the toxicities and treatment response of intra-operative HIPEC in patients with advanced epithelial ovarian cancer.  Intra-operative HIPEC (cisplatin 75 mg/m(2), 41.5 degrees C, 90 mins) was performed in 30 patients with residual tumor of less than 1 cm after CRS between January 2007 and February 2008.  All the patients received adjuvant chemotherapy with combination platinum and taxane.  Adverse events and responses to primary treatment were evaluated and scored as follows: grade I, observation; grade II, medical treatment; grade III, intervention; and grade IV, re-operation or admission to the intensive care unit.  No deaths or grade IV morbidities were observed.  A total of 107 adverse events were identified in 30 patients (grade I, 40; grade II, 46; grade III, 21).  The most common adverse events affected the hematological system (n = 26), followed by the gastro-intestinal system (n = 23).  Most adverse events were anemias requiring transfusion and nausea/vomiting requiring medication.  Twenty-eight patients (93 %) experienced complete remission, and 2 patients (7 %) had progressive disease.  The authors concluded that HIPEC after extensive CRS for ovarian cancer is a procedure with acceptable morbidity that patients can tolerate.  They stated that more follow-up is needed to determine the effect of HIPEC on survival.

There is some evidence that cytoreductive surgery with intra-operative chemotherapy and hyperthermia may be of help in some individuals with peritoneal mesothelioma, which is a rare disease, but increasing in frequency.  The incidence is about 1 per 1,000,000 and approximately 1/5 to 1/3 of all mesotheliomas are peritoneal.  Because of its unusual nature, the disease has not been clearly defined either in terms of its natural history, diagnosis, or management.

Sebbag et al (2000) discussed results of treatment of 33 patients (10 women and 23 men) with peritoneal mesothelioma.  Patients were treated by a uniform strategy involving CRS with peritonectomy procedures and peri-operative intraperitoneal chemotherapy (cisplatin, doxorubicin).  Median survival was 31.0 months; overall projected survival at 3 years was 56 %.  The most significant positive predictive factors of survival were: female sex (p = 0.003), low prior surgical score (p = 0.002), completeness of cytoreduction (p = 0.0002) and second-look surgery (p = 0.019).  The morbidity rate for this combined treatment was 33 % and the peri-operative mortality rate was 3 %.  These investigators concluded that although peritoneal mesothelioma is rare, progress in its management has occurred.  Survival has been extended and selection factors by which patients may be allocated to aggressive management strategies have been defined.

Sethna et al (2003) described their experience with 5 cases (4 females and 1 male) of cystic peritoneal mesothelioma.  All of these patients were treated with CRS with peritonectomy procedures and HIIC.  The authors concluded that cystic peritoneal mesothelioma should no longer be referred to as "benign" cystic mesothelioma.  An aggressive approach with complete disease eradication is the correct goal of treatment.  From the authors' experience, CRS to remove all visible tumor and intraperitoneal chemotherapy to control microscopic residual disease will help patients with peritoneal cystic mesothelioma to remain symptom- and disease-free over an extended time period with a single surgical intervention.  Disease eradication may prevent the transition to an aggressive and fatal disease process.

Diffuse malignant peritoneal mesothelioma (DMPM) is a subset of peritoneal mesothelioma with a poor clinical outcome.  Deraco et al (2006) performed a prognostic analysis in a cohort of DMPM patients treated homogeneously by CRS and intraperitoneal hyperthermic perfusion (IPHP).  A total of 49 DMPM patients who underwent 52 consecutive procedures were enrolled onto the study.  Cytoreductive surgery was performed according to the peritonectomy technique, and the IPHP was performed with cisplatin plus doxorubicin or cisplatin plus mitomycin C.  These investigators evaluated the correlation of the clinicopathologic variables (previous surgical score, age, sex, performance status, previous systemic chemotherapy, carcinomatosis extension, completeness of cytoreduction, IPHP drug schedule, mitotic count [MC], nuclear grade, and biological markers [epidermal growth factor receptor, p16, matrix metalloproteinase 2 and matrix metalloproteinase 9]) with overall and progression-free survival.  The mean age was 52 years (range of 22 to 74 years).  The mean follow-up was 20.3 months (range of 1 to 89 months).  Regarding the biological markers, the rates of immunoreactivity of epidermal growth factor receptor, p16, matrix metalloproteinase 2, and matrix metalloproteinase 9 were 94 %, 60 %, 100 %, and 85 %, respectively.  The strongest factors influencing OS were completeness of cytoreduction and MC, whereas those for PFS were performance status and MC.  No biological markers were shown to be of prognostic value. The authors concluded that completeness of cytoreduction, performance status, and MC seem to be the best determinants of outcome.  These data warrant confirmation by a further prospective formal trial.  No biological markers presented a significant correlation with the outcome.  The over-expression of epidermal growth factor receptor, matrix metalloproteinase 2, and matrix metalloproteinase 9 and absent or reduced expression of p16 might be related to the underlining tumor kinetics of DMPM and warrant further investigation with other methods.

Kusamura et al (2006) analyzed morbidity and mortality of CRS and IPHP in the treatment of peritoneal surface malignancies.  A total of 205 patients (50 with peritoneal mesothelioma, 49 with pseudomyxoma peritonei, 41 with ovarian cancer, 32 with abdominal sarcomatosis, 13 with colon cancer, 12 with gastric cancer, and 8 with carcinomatosis from other origins) underwent 209 consecutive procedures.  Four patients underwent the intervention twice because of disease relapse.  There were 70 men and 135 women.  Mean age was 52 years (range of 22 to 76 years).  Cytoreductive surgery was performed by using peritonectomy procedures; IPHP through the closed abdomen technique was conducted with a pre-heated (42.5 degrees C) perfusate containing cisplatin + mitomycin C or cisplatin + doxorubicin.  Major morbidity rate was 12 %.  The most significant complications were 23 anastomotic leaks or bowel perforations, 4 abdominal bleeds, and 4 sepses.  Operative mortality rate was 0.9 %.  On logistic regression model multi-variate analysis, extent of cytoreduction (odds ratio [OR], 2.88; 95 % confidence interval [CI]: 1.29 to 6.40) and dose of cisplatin for IPHP greater than or equal to 240 mg (OR, 3.13; 95 % CI: 1.24 to 7.90) were independent risk factors for major morbidity.  Ten patients presented with grade 3 to 4 toxicity.  The authors concluded that CRS + IPHP presented acceptable morbidity, toxicity, and mortality rates, all of which support prospective phase III clinical trials.

According to the National Cancer Institute's guideline on the treatment of malignant mesothelioma (2009), "[i]ntrapleural or intraperitoneal administration of chemotherapeutic agents (e.g., cisplatin, mitomycin, and cytarabine) has been reported to produce transient reduction in the size of tumor masses and temporary control of effusions in small clinical studies.  Additional studies are needed to define the role of intracavitary therapy".  Furthermore, although the NCCN guidelines on malignant pleural mesothelioma (2011) recommend cisplatin as a 1st-line drug for inoperable mesothelioma, there is no recommendation for either hyperthermic or intrapleural administration.

Baratti et al (2010) noted that unlike novel molecular-targeted therapies for metastatic gastrointestinal stromal tumors (GIST), conventional treatments for peritoneal sarcomatosis (PS) are mostly ineffective.  As with carcinomatosis of epithelial origin, a rationale base supports an aggressive loco-regional treatment of PS, but the use of CRS and HIPEC in this setting is still controversial.  These researchers assessed the outcome of clinically and pathologically homogeneous subsets of patients with PS uniformly treated by CRS and HIPEC.  A prospective database of 37 patients who underwent CRS and close-abdomen HIPEC with cisplatin and doxorubicin or mitomycin-C was reviewed.  PS originated from GIST (pre-imatinib era) in 8 patients, uterine leiomyosarcoma (ULS) in 11, retroperitoneal liposarcoma (RPLP) in 13, and other sarcoma in 5.  Cytoreductive surgery was macroscopically complete in 28 patients (75.7 %).  Operative mortality was 3.7 % and morbidity 21.6 %.  After median follow-up of 104 (range of 1 to 131) months, peritoneal disease progression occurred in 16 patients, distant metastases in 5, and both in 13.  For all patients, median OS was 26.2 months; 7 patients were alive at 46 to 130 months (ULS, n = 4; RPLP, n = 2; GIST, n = 1).  Retroperitoneal liposarcoma had the best OS (median of 34 months) but 100 % peritoneal relapse; GIST had dismal overall, local-regional-free and distant-free survival; ULS had the higher proportion of long survivors and best local-regional-free survival.  The authors concluded that overall, results of CRS and HIPEC did not compare favorably to those of conventional therapy.  In a subgroup analysis, the combined approach did not change GIST and RPLS natural history.  The interesting results with ULS may warrant further investigations.

Esquivel et al (2011) noted that CRS and HIPEC are being widely used in the treatment of patients with peritoneal surface malignancies.  The open procedure has been associated with high grade III and IV morbidity and prolonged hospitalization. In this study, these researchers evaluated laparoscopic CRS and HIPEC in patients with limited peritoneal surface malignancies.  Patients with peritoneal surface malignancies and no gross evidence of carcinomatosis on the computed tomographic scan were enrolled to undergo laparoscopic CRS and HIPEC.  They aimed to assess the feasibility, safety, and outcome of this procedure.  Post-operative complications were reported according to the National Cancer Institute Common Toxicity Criteria.  From October 2008 to January 2010, a total of 14 patients were enrolled into the protocol.  Of the 14 patients, 1 patient was found with extensive carcinomatosis at the time of laparoscopy and had no surgical procedure; 13 patients had a complete cytoreduction and HIPEC, 10 (77 %) laparoscopically and 3 (23 %) were converted to an open procedure.  There was 1 grade 3 morbidity (10 %) and 1 patient (10 %) in the laparoscopy group experienced a grade 4 complication, needing a re-operation for an internal hernia.  Mean length of hospital stay was 6 days for those completed laparoscopically, 8 days for those converted to an open procedure and 8 days for a matched cohort of patients with an upfront open procedure.  The authors concluded that this initial investigative stage demonstrated the feasibility and safety of CRS and HIPEC via the laparoscopic route in selected patients with low-tumor volume and no small bowel involvement mainly from appendiceal malignancies.  They stated that longer follow-up and additional studies are needed to evaluate its long-term effectiveness.

In a systematic review, Lammers et al (2011) evaluate the effectiveness of chemohyperthermia (C-HT) as a treatment for non-muscle-invasive bladder cancer (NMIBC).  The review process followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.  An electronic search of the Medline, Embase, Cochrane Library, CancerLit, and ClinicalTrials.gov databases was undertaken.  Relevant conference abstracts and urology journals were also searched manually.  Two reviewers independently reviewed candidate studies for eligibility and abstracted data from studies that met inclusion criteria.  The primary end-point was time to recurrence.  Secondary end-points included time to progression, bladder preservation rate, and adverse event (AE) rate.  A total of 22 studies met inclusion criteria and underwent data extraction.  When possible, data were combined using random effects meta-analytic techniques.  Recurrence was seen 59 % less after C-HT than after mitomycin C (MMC) alone.  Due to short follow-up, no conclusions can be drawn about time to recurrence and progression.  The overall bladder preservation rate after C-HT was 87.6 %.  This rate appeared higher than after MMC alone, but valid comparison studies were lacking.  Adverse events were higher with C-HT than with MMC alone, but this difference was not statistically significant.  The authors concluded that published data suggested a 59 % relative reduction in NMIBC recurrence when C-HT is compared with MMC alone.  Chemohyperthermia also appears to improve bladder preservation rate.  However, due to a limited number of randomized trials and to heterogeneity in study design, definitive conclusions can not be drawn.  In the future, C-HT may become standard therapy for high-risk patients with recurrent tumors, for patients who are unsuitable for radical cystectomy, and in cases for which bacillus Calmette-Guérin treatment is contraindicated.

Hurwitz et al (2011) presented long-term results from a phase II study that evaluated the effectiveness of transrectal ultrasound hyperthermia plus radiation with or without androgen suppression for the treatment of locally advanced prostate cancer.  Patients with clinical T2b-T3bN0M0 disease (according to 1992 American Joint Committee on Cancer [AJCC] criteria) received radiation plus 2 transrectal ultrasound hyperthermia treatments.  After the first 4 patients, 6 months of androgen suppression were allowed.  The study was designed to assess absolute improvement in the 2-year disease-free survival rate compared with the short-term androgen suppression arm in Radiation Therapy Oncology Group (RTOG) study 92-02.  A total of 37 patients received a total of 72 hyperthermia treatments.  The mean cumulative equivalent minutes (CEM) Temp = 43^°C was 8.4 minutes.  According to the 1992 AJCC classification, there were 19 patients with T2b tumors, 8 patients with T2c tumors, 5 patients with T3a tumors, and 5 patients with T3b tumors.  The median Gleason score was 7 (range of 6 to 9), and the median prostate-specific antigen (PSA) level was 13.3 ng/ml (range of 2 to 65 ng/ml).  Thirty-three patients received androgen suppression.  At a median follow-up of 70 months (range of 18 to 110 months), the 7-year OS rate was 94 %, and 61 % of patients remained failure free (according to the American Society for Therapeutic Radiology and Oncology definition for failure free survival).  The absolute rate of DFS at 2 years, which was the primary study end-point, improved significantly (84 %) compared with a rate of 64 % for similar patients on the 4-month androgen suppression arm of RTOG 92-02.  When Phoenix criteria (PSA nadir + 2 ng/ml) were used to define biochemical failure, 89 % of patients were failure-free at 2 years.  The authors concluded that hyperthermia combined with radiation for the treatment of locally advanced prostate cancer appeared to be promising.  The current results indicated that further study of hyperthermia for the treatment of prostate cancer with optimal radiation and systemic therapy is warranted.

Suzuki et al (2000) noted that since clear cell carcinoma of the ovary does not respond to conventional platinum-based chemotherapy, the prognosis of recurrent tumors is especially poor.  In a 51-year old female who underwent surgery for clear cell carcinoma of the ovary, a solitary metastatic carcinoma developed in the pelvic cavity 7 months after the initial surgery.  The patient underwent a whole pelvic irradiation at a total dose of 65 Gy combined with hyperthermia.  Complete remission was achieved 46 months after treatment.  A study using gynecologic carcinoma cell lines showed that the mean 50 % growth inhibitory dose of radiation was 1.2 +/- 0.4 Gy in several clear cell carcinoma cell lines.  The value did not significantly differ from those for serous carcinoma cell lines (2.3 +/- 1.2 Gy) and uterine cervical carcinoma cell lines (1.6 +/- 0.4 Gy).  The authors stated that currently, no anti-cancer agents are effective for clear cell carcinoma; radiotherapy combined with hyperthermia may be effective for localized tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal mesenchymal tissue neoplasm in young patients and spreads through the abdominal cavity.  Desmoplastic small round cell tumor usually presents with diffuse abdominal metastatic disease similar in gross appearance to carcinomatosis.  To date, very aggressive treatment programs have yielded dismal outcomes. 

Msika et al (2010) stated that prognosis of DSRCT is poor despite a multi-modal therapy including chemotherapy, radiotherapy, and surgical cytoreduction.  Hyperthermic intra-peritoneal chemotherapy is considered as an additional strategy in the treatment of peritoneal carcinomatosis; for this reason, these investigators planned to treat selected cases of children with DRSCT using surgical cytoreduction and HIPEC.  Peritoneal disease extension was evaluated according to Gilly classification.  Surgical cytoreduction was considered as completeness of cytoreduction -- stage 0 of Gilly classification (no macroscopic disease); HIPEC was performed according to the open technique.  These researchers described 3 cases: the 2 first cases were realized for palliative conditions and the last one was operated on with curative intent.  There was no post-operative mortality.  One patient was re-operated for a gallbladder perforation.  There was no other complication related to HIPEC procedure.  The authors concluded that surgical cytoreduction and HIPEC provide a local alternative approach to systemic chemotherapy in the control of microscopic peritoneal disease in DRSCT, with an acceptable morbidity, and may be considered as a potential beneficial adjuvant waiting for a more specific targeted therapy against the fusion protein.

In a review on “Desmoplastic small round cell tumor: Current management and recent findings”, Dufrense et al (2012) states that “Overall, data supporting the use of HIPEC in patients with DSRCT is limited and this technique is not recommended for the management of patients with DSRCT outside clinical trials”.

National Comprehensive Cancer Network clinical practice guideline on “Non-small cell lung cancer” (NCCN, 2013) does not mention the use of hyperthermia as a therapeutic option.

Mi and colleagues (2013) stated that adjuvant intraoperative hyperthermic intraperitoneal chemotherapy (IHIC) is a therapy that combines thermotherapy and intraperitoneal chemotherapy.  It is theoretically powerful for patients with advanced gastric cancer (AGC), but is there no evident advantage in clinical practice.  These researchers performed a meta-analysis to evaluate the safety and effectiveness of adjuvant IHIC inpatients with resectable locally AGC, and provided the reference for clinical practice and study.  These investigators searched the Cochrane Library, PubMed, Embase, Web of Science and Chinese databases (Chinese BioMedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and Wanfang) electronically and also retrieved papers from other sources (tracing related references and communication with other authors).  All relevant randomized controlled trials (RCTs) were collected to compare surgery combined with IHIC to surgery without IHIC for AGC.  There were no language restrictions.  After independent quality assessment and data extraction by 2 reviewers, meta-analysis was conducted by RevMan 5.1 software.  A total of 16 RCTs involving 1,906 patients were included.  Compared with surgery alone, combination therapy (surgery plus IHIC) was associated with a significant improvement in survival rate at 1 year (hazard ratio (HR) = 2.99; 95 % CI: 2.21 to 4.05; p < 0.00001), 2 years (HR = 2.43; 95 % CI: 1.81 to 3.26; p < 0.00001), 3 years (HR = 2.63; 95 % CI: 2.17 to 3.20; p < 0.00001), 5 years (HR = 2.49; 95 % CI: 1.97 to 3.14; p < 0.00001), and 9 years (HR = 2.14; 95 % CI: 1.38 to 3.32; p = 0.0007).  Compared with surgery alone, combination therapy was associated with a significant reduction in recurrence rate at 2 years (RR = 0.42; 95 % CI:  0.29 to 0.61; p < 0.00001), 3 years (RR = 0.35; 95 % CI: 0.24 to 0.51; p < 0.00001) and 5 years (RR = 0.47; 95 % CI: 0.39 to 0.56; p < 0.00001).  Intraoperative hyperthermic intraperitoneal chemotherapy was not found to be associated with higher risks of anastomotic leakage, ileus, bowel perforation, myelosuppression, GI reaction and hypohepatia, but it increased the incidence of abdominal pain (RR = 21.46; 95 % CI: 5.24 to 87.78; p < 0.00001).  The authors concluded that compared with surgery alone, surgery combined with IHIC can improve survival rate and reduce the recurrence rate, with acceptable safety.  However, they stated that safety outcomes should be further evaluated by larger samples and high quality studies.  Furthermore, these investigators stated that hyperthermia for intraperitoneal chemotherapy needs more clinical research.

Furthermore, the NCCN clinical practice guideline on “Gastric cancer” (Version 2.2013) does not mention the use of hyperthermic intraperitoneal chemotherapy as a therapeutic option.

National Comprehensive Cancer Network's clinical practice guideline on “Pancreatic adenocarcinoma” (Version 1.2014) does not mention the use of hyperthermic intraperitoneal chemotherapy as a therapeutic option.

Tejani et al (2014) stated that treatment of advanced appendiceal adenocarcinoma at NCCN’s member institutions commonly incorporates agents used for colorectal cancer.  Guidelines from the NCCN stated that small bowel and appendiceal carcinoma may be treated with systemic chemotherapy according to the NCCN guidelines for colon cancer (Version 2.2015), which states that "the panel considers the treatment of disseminated carcinomatosis with cytoreductive surgery and HIPEC to be investigational and does not endorse this therapy outside of a clinical trial". 

Furthermore, NCCN’s clinical practice guideline on “Gastric cancer” (Version 1.2015) does not mention HIPEC as a therapeutic option.

A recent review by Elias et al (2014a) stated that HIPEC for neuroendocrine tumors (NETs) is in the investigational stage.  Furthermore, Elias et al (2014b) compared the results of complete cytoreductive surgery (CCRS) of peritoneal metastases from NET with and without HIPEC and reported that they were not able to determine whether HIPEC had a positive or negative impact on outcomes.

Guidelines from the National Cancer Institute on “Gastrointestinal Carcinoid Tumors Treatment (PDQ^®)” (2014) have no recommendation for HIPEC.  Also, NCCN’s guideline on NETs (Version 1.2015) has no recommendations for the use of HIPEC for carcinoid tumors. 

Tabrizian et al (2014) presented a series of patients with peritoneal hepatocellular carcinoma (HCC) treated with CRS +/- HIPEC and evaluated their clinicopathologic characteristics and outcomes.  Between 07/2007 to 08/2012, 14 patients with limited disease to the peritoneum underwent CRS; 7 of these patients received additional HIPEC treatment.  Primary end-point was OS.  Operative treatment was directed for metachronous peritoneal disease in the majority (92.8 %) of patients.  Mean intra-operative PCI was 9.9 (± 8.3) and complete mascroscopic cyto-reduction (CCR 0-1) was achieved in all but 1 case.  Overall major morbidity rate (Clavien-Dindo III-IV) at 30 days was 7.1 %.  One post-operative death occurred in a patient with extensive tumor burden (PCI = 33, CCR2).  Median follow-up after initial surgery was 43.8 months and the median time to metachronous peritoneal recurrence was 23 months.  Three-year recurrence rate after peritoneal resection was 100 %.  Median survival of the cohort CCR0-1 was 35.6 months.  The authors concluded that treatment of peritoneal HCC remains challenging and survival is poor.  In well-selected candidates, however, CRS +/- HIPEC may prolong survival compared to systemic therapy alone in patients with peritoneal HCC.

However, NCCN’s clinical practice guideline on “Hepatobiliary cancers” (Version 1.2015) does not mention HIPEC as a therapeutic option.

A recently published review of small intestine neoplasms (Reynolds et al, 2014) stated that the evidence for HIPEC in small bowel adenocarcinoma is anecdotal.  The review stated that "The role of more radical resections or metastasectomy for small bowel adenocarcinoma is unclear but anecdotal reports indicate a possible role for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy".

An UpToDate review on “Treatment of small bowel neoplasm” (Cusack and Overman, 2014) stated that “Long-term survival has been reported after aggressive cytoreduction surgery and intraperitoneal hyperthermic chemotherapy in a handful of highly selected patients with peritoneal carcinomatosis from a small bowel adenocarcinoma.  Experience with this approach, which is more commonly applied to patients with pseudomyxoma peritonei or malignant peritoneal mesothelioma, is very limited.  Patients being considered for this approach should be referred to a center with expertise in the management of peritoneal surface malignancies".  The authors recommended systemic chemotherapy for patients with locally advanced unresectable or metastatic small bowel adenocarcinoma.

Also, guidelines from the NCCN stated that small bowel and appendiceal carcinoma may be treated with systemic chemotherapy according to the NCCN guidelines for colon cancer (Version 2.2015); which states that "the panel considers the treatment of disseminated carcinomatosis with cytoreductive surgery and HIPEC to be investigational and does not endorse this therapy outside of a clinical trial".

An UpToDate review on “Clinical presentation and management of thymoma and thymic carcinoma” (Bezjak et al, 2014) does not mention the use of hyperthermic administration of intraperitoneal chemotherapy as a therapeutic option.  Furthermore, the NCCN’s clinical practice guideline on “Thymomas and thymic carcinoma” (version 1.2014) does not mention the use of hyperthermic administration of intraperitoneal chemotherapy as a therapeutic option.

Desmoplastic Small Round Cell Tumor

Hayes-Jordan et al (2010) noted that less than 200 cases have been reported in the world literature since DSRCT was first described in 1989.  To date, chemotherapy, radiation therapy, and surgery have resulted in a poor survival of 30 % to 5 5%.  These researchers used HIPEC at the time of complete tumor resection as an adjunct to treatment of pediatric and adolescent patients with DSRCT.  These investigators evaluated survival as a function of disease burden and response to HIPEC in patients with DSRCT.  A total of 24 patients with DSRCT from 1995 to 2008 were evaluated; 8 patients undergoing CRS and HIPEC were compared with 16 historical controls that had chemotherapy +/- radiation therapy or surgery alone.  Median age was 12 years in 8 patients who underwent HIPEC. Significant morbidity after HIPEC included renal insufficiency and gastroparesis.  There were no operative mortalities.  The estimated median overall 3-year survival for patients not undergoing surgery or HIPEC was 26 % compared with 71 % in patients who underwent HIPEC.  Extra-abdominal metastasis correlated with poor survival (p = 0.021).  The authors concluded that HIPEC is safe in children with DSRCT.  It may prolong disease-free survival in selected cases of DSRCT.  It may have a limited role as an adjunct to local control in patients with DSRCT.  Moreover, they stated that “our results demonstrate that surgery, with or without HIPEC, has a significantly better OS compared with medical therapy alone.  The fact that different chemotherapy regimens were used could confound the results.  The study was also limited by the small sample size …. Many more patients are needed to validate these proposed criteria.  It is our hope that all patients with DSRCT not be considered stage 4 and the aforementioned criteria would be used to predict appropriate candidates for HIPEC or other aggressive medical or surgical treatments.  Further prospective data are needed to validate these proposed staging criteria”.

Hayes-Jordan et al (2014) stated that DSRCT is a rare tumor of adolescents and young adults.  Less than 100 cases per year are reported in North America.  Extensive peritoneal metastases are characteristic of this disease.  These investigators performed CRS and HIPEC using cisplatin (CDDP) for DSRCT.  A retrospective cohort study was performed on 26 pediatric and adult patients who underwent cytoreduction/HIPEC using CDDP for DSRCT at a single cancer center.  Neoadjuvant chemotherapy, adjuvant chemotherapy, and post-operative enteral nutrition were given to all patients.  Post-operative radiation therapy was given to most patients.  Follow-up was from 6 months to 6 years.  Outcome variables were evaluated for disease-free survival (DFS) and overall survival (OS).  Five patients (19 %) were less than 12 years of age at surgery.  Patients who had disease outside the abdomen at surgery had a larger risk of recurrence or death than those who did not (p = 0.0158, p = 0.0393 time from surgery to death respectively).  Age, liver metastasis, and peritoneal cancer index level did not significantly predict DFS or OS.  Patients who had CR0 or CR1 and HIPEC had significantly longer median survival compared with patients who had HIPEC and CR2 cytoreduction (63.4 versus 26.7 months).  The authors concluded that HIPEC may be an effective therapy for children and young adults with DSRCT.  Patients with DSRCT require complete cytoreduction before HIPEC to optimize outcome.  Patients with DSRCT and disease outside the abdomen at the time of surgery do not benefit from HIPEC.  There may have been overlapping patients in this study and that of the 2010 study.  These investigators also noted that “We are presently continuing to enroll patients on a phase 2 trial, understanding that HIPEC in DSRCT has not been established as superior to surgery alone.  A prospective, randomized trial is needed …. We continue CRS and HIPEC in DSRCT in the setting of a clinical trial”.

Hayes-Jordan et al (2015) began a pediatric HIPEC program, and this report described their initial results from the first 50 pediatric, adolescent, and young adult patients.  A single-institution, retrospective study investigated the first 50 CRS and HIPEC by 1 surgeon for patients 3 to 21 years of age.  The HIPEC was added to chemotherapy and radiotherapy treatment.  Demographics, outcome, and complications were recorded.  The median follow-up period for the surviving patients was 21.9 months.  The most common diagnoses were DSRCT (n = 21), rhabdomyosarcoma (n = 7), mesothelioma (n = 4), and other carcinoma (n = 17).  Multi-variate analysis showed that patients treated with HIPEC and an incomplete cytoreduction had a greater risk for recurrence than those who had a complete cytoreduction (p = 0.0002).  The patients with a higher peritoneal cancer index (PCI) (i.e., a large tumor burden) had a median OS of 19.9 months relative to the patients with a lower PCI score, who had a median OS of 34 months (p = 0.049).  The patients without complete cytoreduction had a median OS of 7.1 months compared with 31.4 months for the patients with complete cytoreduction (p = 0.012).  No peri-operative mortalities occurred.  The incidence of major complications was 28 %.  The authors concluded that CRS and HIPEC with a programmatic approach for patients 3 to 21 years of age is unique.  The best outcome was experienced by patients with DSRCT and those with complete cytoreduction.  Complete cytoreduction for patients without disease outside the abdominal cavity at the time of surgery affords the best outcome.  Moreover, these researchers stated that “This study suffers from its small sample size and diverse histologies.  Therefore, further study is necessary for definitive conclusions”.  Furthermore, there may have been overlapping DSRCT patients in this study with those of the 2010 and 2014 studies.

Hayes-Jordan (2015) stated that CRS and HIPEC is an approach for local control of DSRCT.  Because of the poor prognosis of DSRCT, novel treatment strategies were necessary.  Cytoreductive surgery and HIPEC has been recently trialed as part of multi-modality therapy in DSRCT.  CRS and HIPEC allows complete resection of the sometimes hundreds of intra-abdominal tumor implants, followed by the delivery of hyperthermic cisplatin for 90 mins at approximately 41 ^°C.  HIPEC is thought to enhance microscopic control of abdominal DSRCT, after surgical resection, and prevent or prolong recurrence.   The author noted that “A phase 2 trial of cytoreductive surgery and HIPEC in DSRCT and other sarcomas was just completed.  The results have not been published, awaiting long-term follow-up data …. Novel therapeutics are needed in this recently described sarcoma”.

Hayes-Jordan et al (2016) stated that “Presently, the question of whether the effects of HIPEC and complete resection are additive remains unresolved and the use of HIPEC should be protocol based.  Use of HIPEC in the case of disease outside the peritoneal cavity, presence of liver metastases, and extensive retroperitoneal or portal lymphadenopathy is probably not indicated”.  A recently published series by Honore et al (2017) found no significant benefit to HIPEC in patients with DSRCT without extra-peritoneal metastasis, concluding that “The benefit of HIPEC is still unknown and should be evaluated in a prospective trial”.  National Cancer Institute guidelines (NCI PDQ, 2017) have no recommendation for HIPEC in desmoplastic round cell tumor.  

HIPEC for Goblet Cell Carcinoid Tumor

Van Sweringen et al (2012) stated that peritoneal metastases in patients with high-grade adenocarcinoma have been typically associated with a poor outcome.  Recent literature has suggested that CRS and HIPEC may improve survival.  These researchers examined this subset of patients in an effort to better delineate those factors which contribute to improved survival.  They performed a retrospective review looking at patients who had undergone CRS/HIPEC.  Patients were identified as high-grade histology on the basis of pathology reports indicating their lesion as high grade, moderately, or poorly differentiated and/or associated with signet ring or goblet cell carcinoid features.  Peritoneal cancer index and completeness of cytoreduction (CC) were used to define disease burden.  Survival analysis was performed by the method of Kaplan-Meier with the log-rank test used to determine significance.  Of the 250 patients who underwent CRS/HIPEC between 1999 and 2011, 36 (14 %) were identified as having peritoneal metastases from a high-grade gastro-intestinal primary.  Actual overall survival (OS) from the time of diagnosis was 11.1 % at 5 years.  Median survival from time of surgery was 21.6 months.  Survival advantage was conferred to those patients who underwent a CC0/CC1 resection, had a peritoneal cancer index score at time of surgery less than or equal to 20, appendiceal primary, or moderately differentiated histopathology.  Receipt of neoadjuvant chemotherapy and nodal status was not significantly predictive of improved survival.  Patients with signet ring cell histology had a particularly poor prognosis.  The authors concluded that for those patients with high-grade peritoneal metastases and historically a poor prognosis, prolonged survival may be achieved through CRS/HIPEC, optimally with a CC0/CC1 resection.

McConnell et al (2014) noted that the debate remains whether appendiceal goblet cell cancers behave as classical carcinoid or adenocarcinoma.  Treatment options are unclear and reports of outcomes are scarce; CRS+HIPEC is considered optimal treatment for peritoneal involvement of other epithelial appendiceal tumors.  Prospective cohorts of patients treated for advanced appendiceal tumors from 3 peritoneal malignancy centers were collected (1994 to 2011).  All patients underwent complete CRS+HIPEC, when possible, or tumor debulking.  Demographic and outcome data for patients with goblet cell cancers were compared to patients with low- or high-grade epithelial appendiceal tumors treated during the same time period.  Details on 45 goblet cell cancer patients were compared to 708 patients with epithelial appendix lesions.  In the goblet cell group, 57.8 % were female, median age was 53 years, median peritoneal cancer index (PCI) was 24, and CRS+HIPEC was achieved in 71.1 %.  These details were similar in patients with low- or high-grade epithelial tumors.  Lymph nodes were involved in 52 % of goblet cell patients, similar to rates in high-grade cancers, but significantly higher than in low-grade lesions (6.4 %; p < 0.001).  At 3 years, OS was 63.4 % for goblet cell patients, intermediate between that for high-grade (40.4 to 52.2 %) and low-grade (80.6 %) tumors.  On multi-variate analysis, tumor histology, PCI, and achievement of CRS+HIPEC were independently associated with OS.  The authors concluded that these data supported the concept that appendiceal goblet cell cancers behave more as high-grade adenocarcinomas than as low-grade lesions.  These patients have reasonable long-term survival when treated using CRS+HIPEC, and this strategy should be considered.

Randle et al (2015) stated that CRS/HIPEC is a treatment commonly applied to peritoneal surface disease from low-grade mucinous tumors of the appendix.  Some centers have extended this therapy to carcinomatosis from more aggressive malignancies.  These investigators reviewed their experience with CRS/HIPEC for patients with goblet cell carcinomatosis.  Patients were identified in a prospectively maintained database of 1,198 CRS/HIPEC procedures performed between 1991 and 2014.  Patient demographics, disease characteristics, morbidity, mortality, and survival were reviewed.  A total of 31 patients with carcinomatosis originating from appendiceal goblet cell tumors underwent CRS/HIPEC during the study period.  Patients were generally young (mean age of 53 years) and otherwise healthy (84 % without co-morbidities) with good performance status (94 % Eastern Cooperative Oncology Group [ECOG] 0 or 1).  The mean number of visceral resections was 3.5, and complete cyto-reduction of macroscopic disease was accomplished in 36 %.  Major 90-d morbidity and mortality rates were 38.7 % and 9.7 %, respectively.  Median overall survival (OS) for all patients was 18.4 months.  Patients with negative nodes had better survival than those with positive nodes (median OS, 29.2 versus 10.2 months), respectively (p = 0.002).  Although complete cyto-reduction was associated with longer median OS after CRS/HIPEC (R0/R1 28.6 versus R2 17.2 months, p = 0.47), the observed difference did not reach statistical significance.  The authors concluded that CRS/HIPEC may improve survival in patients with node-negative goblet cell carcinomatosis when a complete cyto-reduction was achieved.  Patients with disease not amenable to complete cyto-reduction should not be offered CRS/HIPEC. 

The major drawback of this study were:

1. its small sample size (n = 31); even though it was a relatively large cohort of patients with a rare disease treated at a single institution,
2. the study cohort reflected a cautiously selected patient population and could not be considered a reflection of all patients presenting with goblet cell appendiceal carcinomatosis, and
3. this study was not designed to determine any benefit or risk HIPEC added to meticulous cyto-reduction.

Lamarca et al (2016) stated that appendix goblet cell carcinoids are known to share histological features of adenocarcinoma and neuroendocrine tumors.  Due to their low incidence, quality evidence is lacking for the management of these patients.  These investigators performed a single-center retrospective study of patients with a confirmed diagnosis of appendiceal goblet cell carcinoid (GCC; 1996 to 2014).  Patients were divided into curative intent (CI) and palliative intent (PI) cohorts.  The primary end-point was OS.  A total of 74 patients were eligible; 76 % were treated with CI [surgery only (36 %), CRS and HIPEC (36 %), adjuvant chemotherapy (20 %) and a combination of CRS and HIPEC followed by adjuvant chemotherapy (9 %)], and 23 % had advanced-stage disease amenable to palliative treatment (chemotherapy or supportive care) only.  Completion right hemi-colectomy, performed in 64 % of the CI cohort, did not impact on the relapse rate or disease-free survival (DFS).  FOLFOX chemotherapy was used in both the adjuvant and palliative settings; safety was as expected, and these researchers observed a high rate (60 %) of disease control in the palliative cohort.  The estimated median OS (all patients), DFS (CI patients) and progression-free survival (PFS) (PI patients) were 52.1 (95 % confidence interval [CI]: 29.4 to 90.3), 75.9 (26.6 to not reached) and 5.3 (0.6 to 5.7) months, respectively.  Age and stage were independent factors associated with OS in the multi-variable analysis.  Tang classification showed a trend for impact on OS.  No benefit from specific adjuvant approach was identified; however, selection bias for treatment approach was observed.  The authors concluded that prospective trials are needed to define optimal approaches in GCC.  All GCC patients should be managed by specialized centers due to their esoteric behavior; the authors provided management considerations based on their experience and conclusions.

Yu et al (2017) stated that goblet cell carcinomas (GCCs) of the appendix are rare and aggressive malignancies with early peritoneal dissemination. The aim of the present article is to describe the authors’ experience in the management of GCCs with peritoneal carcinomatosis (PC) through cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) and to determine the impact of multiple clinical characteristics on the prognosis. From a prospectively maintained database of patients receiving CRS and HIPEC for peritoneal surface malignancy, the data of 15 patients with GCC and PC were collected. Neo-adjuvant laparoscopic HIPEC was performed if indicated. CRS and HIPEC with mitomycin-C or 5-fluorouracil plus oxaliplatin were performed. Adjuvant chemotherapy was also arranged if suitable for the patient's condition. Nine males and six females with a mean age of 52.4 years were enrolled. The estimated median survival after the diagnosis of GCC with PC and after definitive CRS-HIPEC was 28 and 17 months, respectively. The 1-, 2-, 3-, 4-year survival rates were 86%, 69%, 57%, and 24%, respectively. Log-rank test revealed that the significant independent risk factors for more favorable outcomes were age >50 years, peritoneal cancer index (PCI) <27, postoperative PCI <20, administration of HIPEC, and adjuvant chemotherapy. Multivariate analyses confirmed that administration of HIPEC played a crucial role in providing prognostic benefit. The authors concluded that the management of GCC with PC remains challenging. The authors recommend CRS and HIPEC, followed by adjuvant systemic chemotherapy, as a promising strategy to improve survival, especially in selected patients with low PCI and possibility to achieve complete cytoreduction.

Madsen et al (2018) stated goblet cell carcinoma (GCC) of the appendix is a rare disease. Treatment options vary according to disease staging. Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) may improve survival in patients with peritoneal spreading. The aim of this study was to examine the prognosis of patients with appendiceal GCC treated per protocol, and to evaluate the results of CRS+HIPEC in cases of peritoneal spreading. From 2009 to 2016, a total of 48 GCC patients were referred to the European Neuroendocrine Tumour Center of Excellence, Aarhus University Hospital. All patients received treatment per protocol according to disease staging. In patients with localized disease, the treatment was a right hemicolectomy. Patients with peritoneal spread who met the inclusion criteria for CRS + HIPEC, as well as patients with high-risk features of developing peritoneal spread, received CRS + HIPEC. If too-extensive disease was found, palliative chemotherapy was offered. Overall survival for patients with localized disease (n = 6) or deemed at risk of peritoneal spread (n = 8) was 100% after a median follow-up of 3.5 years. In patients with peritoneal spread and eligible for CRS+HIPEC(n = 27), the median survival was 3.2 years [95% confidence interval (CI) 2.3-4.1] and the 5-year survival rate was 57%. In contrast, the median survival for patients with too-extensive intraperitoneal disease (n = 7) was 1.3 years (95% CI 0.6-2.0), with a 3-year survival rate of 20%. The authors concluded that long-term survival can be achieved in patients with peritoneal spread treated with CRS + HIPEC. CRS+HIPEC was associated with a favorable outcome in GCC patients at high-risk of developing peritoneal spread.

Tsang et al (2018) stated goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. Prognostic clinical and treatment factors in a population-based cohort. Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). The authors concluded that this population-based cohort study demonstrates excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.

Furthermore, National Comprehensive Cancer network's clinical practice guideline on "Neuroendocrine tumors" (Version 2.2016) (this guideline include carcinoid tumors) does not mention HIPEC/ hyperthermic intraperitoneal chemotherapy as a management tool.

HIPEC for Ovarian Cancer

Helm et al (2010) performed an analysis of experience of surgical and gynecologic oncologists in the United States with the use of HIPEC for women with invasive epithelial ovarian cancer (EOC).  An Internet-based registry (HYPER-O) collected data from collaborating institutions.  Eligibility included women with EOC treated with HIPEC.  Borderline and non-epithelial cancers were excluded.  As of July 1, 2008, 141 women were eligible for analysis treated at the following time points: front-line (n = 26), interval debulking (n = 19), consolidation (n = 12), and recurrence (n = 83).  The mean perfusion temperatures were 38.5 to 43.6 degrees C (median of 41.9 degrees C) for inflow and 36.9 to 42.9 degrees C (median of 41 degrees C) for outflow for 30 to 120 minutes.  Treatment was with a platinum agent (n = 72), mitomycin (n = 53), or a combination (n = 14).  Median follow-up was 18 months (range of 0.3 to 140.5 months) and median overall survival (OS) of 30.3 months (95 % confidence interval [CI]: 23.0 to 37.6) with 2-, 5-, and 10-year OS probabilities of 49.1 %, 25.4 %, and 14.3 %, respectively.  Of the 141 patients, 110 (78% ) experienced recurrence of ovarian cancer and 87 died, 3 (0.5 %) dying within 30 days of surgery.  In the multivariable analysis, the factors significant for increased survival were sensitivity to platinum response (p = 0.048), completeness of cytoreduction scores of 1 or 0 (p = 0.025), carboplatin alone or a combination of 2 or more chemotherapy agents used (p = 0.011), and duration of hospital stays of 10 days or less (p = 0.021).  The authors concluded that HIPEC is a viable additional treatment option for patients with invasive EOC and may extend life in selected groups; it warrants further study in randomized controlled trials (RCTs).

Huo et al (2015) stated that emerging evidence suggests that HIPEC with CRS showed a survival benefit over CRS alone for patients with epithelial ovarian carcinoma (EOC).  This systematic review and meta-analysis evaluated the safety and effectiveness of HIPEC with CRS for EOC.  Searches of 5 databases from inception to February 17, 2015 was performed.  Clinical outcomes were synthesized, with full tabulation of results.  A total of 9 comparative studies and 28 studies examining HIPEC + CRS for primary and/or recurrent EOC were included.  Meta-analysis of the comparative studies showed HIPEC + CRS + chemotherapy had significantly better 1-year survival compared with CRS + chemotherapy alone (odds ratio [OR]: 3.76, 95 % confidence intervals [CI]: 1.81 to 7.82).  The benefit of HIPEC + CRS continued for 2-, 3-, 4-, 5- and 8-year survival compared to CRS alone (OR: 2.76, 95 % CI: 1.71 to 4.26; OR: 5.04, 95 % CI: 3.24 to 7.85; OR: 3.51, 95 % CI: 2.00 to 6.17; OR: 3.46 95 % CI: 2.19 to 5.48; OR: 2.42, 95 % CI: 1.38 to 4.24, respectively).  Morbidity and mortality rates were similar.  Pooled analysis of all studies showed that among patients with primary EOC, the median, 1-, 3-, and 5-year overall survival (OS) rates were 46.1 months, 88.2 %, 62.7 % and 51 %.  For recurrent EOC, the median, 1-, 3-, and 5-year OS rates were 34.9 months, 88.6 %, 64.8 % and 46.3 %.  A step-wise positive correlation between completeness of cytoreduction and survival was found.  The authors concluded that the addition of HIPEC to CRS and chemotherapy improved OS rates for both primary and recurrent EOC.  Moreover, the authors stated that the findings in this review should be interpreted in view of certain limitations.  Firstly, the eligibility criteria (tumor stage, age, follow-up, extent of disease, previous chemotherapy and surgery, etc.) of patients with EOC were not identical between studies included.  This might influence the consistency of effects across these included studies and lead to differences the patient baseline characteristics.  However, this study has attempted to minimize these differences by stratification of the results.  Secondly, the total number of patients in each study was small.  However, our pooled results reached statistical significance when analyzing the benefit in OS with HIPEC + CRS + chemotherapy compared to CRS + chemotherapy alone.  Thirdly, disease-free survival (DFS) was often poorly reported in studies, especially within the comparative studies.  Without DFS, it makes it difficult to quantitate the benefit of HIPEC.  Finally, there was only 1 study that was a RCT.  Although the RCT was of high quality in having described the generation of randomization, by having only 1 RCT, it makes it difficult to conclude that HIPEC + CRS + chemotherapy is superior to CRS + chemotherapy alone for EOC.  The results of the ongoing RCTs will be essential in determining whether HIPEC + CRS + chemotherapy is appropriate for EOC. 

Hotouras et al (2016) noted that despite advances in surgical oncology, most patients with primary ovarian cancer develop a recurrence that is associated with a poor prognosis.  These researchers examined the impact of HIPEC in the OS  of patients with recurrent ovarian cancer.  A search of PubMed/Medline databases was performed in February 2015 using the terms "recurrent ovarian cancer", "cytoreductive surgery/cytoreduction" and "heated/hyperthermic intraperitoneal chemotherapy".  Only English articles with available abstracts assessing the impact of HIPEC in patients with recurrent ovarian cancer were examined.  The primary outcome measure was OS, whereas secondary outcomes included disease-free survival (DFS) and HIPEC-related morbidity.  A total of 16 studies with 1,168 patients were analyzed.  Most studies were Level IV, with 4 studies graded as Level III and 1 Level II.  Cisplatin was the main chemotherapeutic agent used, but variations were observed in the actual technique, temperature of perfusate, and duration of treatment.  In patients undergoing CRS and HIPEC, the OS ranged between 26.7 and 35 months, with DFS varying between 8.5 and 48 months; HIPEC appeared to confer survival benefits to patients with recurrent disease, with a RCT reporting that the OS is doubled when CRS is compared with CRS and chemotherapy (13. 4 versus 26.7 months [Spiliotis et al, 2015); HIPEC-related morbidity ranged between 13.6 % and 100 %, but it was mainly minor and not significantly different from that experienced by patients who only underwent CRS.  The authors concluded that CRS and HIPEC appeared to be associated with promising results in patients with recurrent ovarian cancer.  They stated that large international prospective studies are needed to further quantify the true efficacy of HIPEC and identify the optimal treatment protocol for a maximum survival benefit.

D'Hondt et al (2016) conducted a phase II clinical trial to examine the feasibility of interval cytoreductive surgery (CS) and HIPEC with cisplatin in patients with stage III and IV pleural ovarian carcinoma in first-line treatment with no macroscopic residual disease after surgery.  Patients could be treated either with primary CS with HIPEC followed by 6 conventional cycles of chemotherapy or with 3 or 4 cycles of neoadjuvant chemotherapy before CS with HIPEC and 3 post-operative chemotherapy cycles; HIPEC was performed with cisplatin (50 mg/m) for 60 minutes, only in case of complete CR.  A total of 19 patients were included in the study, and they all underwent neoadjuvant chemotherapy before CS; 16 patients underwent complete CS with HIPEC.  There was no mortality, and morbidity of CS with HIPEC was acceptable.  The HIPEC procedure did not prevent the administration of the standard first-line treatment.  In the 16 patients who underwent CS with HIPEC, the outcomes were very good.  The authors concluded that the findings of this study showed an acceptable toxicity of adding HIPEC to the standard first-line treatment in patients with stage III ovarian carcinoma treated with interval CS.  They stated that further studies are needed to confirm the role of HIPEC in the treatment of ovarian carcinoma.

Polom et al (2016) stated that HIPEC, a strategy combining maximal CRS and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients.  However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed.  These investigators discussed treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting.  They noted that HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer.  The authors concluded that  due to the lack of randomized trials, the evidence of HIPEC is very limited.  They stated that future randomized studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer.

Boisen et al (2016) stated that HIPEC is often used to treat gastrointestinal malignancies and is of interest in EOC given the propensity for intraperitoneal spread.  The role of HIPEC in the treatment of gynecologic malignancies is not well defined.  These researchers described clinical characteristics and outcomes of their patient population treated with HIPEC; IRB approval was obtained.  Patients diagnosed with EOC and treated with HIPEC from January 2007 until December 2013 were identified using a prospectively maintained HIPEC database.  Patient charts were abstracted to identify patient demographic information, treatment characteristics, and outcome data.  Statistical analysis was descriptive.  A total of 34 patients were identified; mean age at diagnosis was 56.5 years.  The majority of cases (28, 82 %) were of serous histology.  The indications for HIPEC administration were as follows: 9 % primary treatment, 41 % first recurrence, 26 % second recurrence, and 24 % consolidative therapy in the setting of primary or recurrent disease.  The majority of patients (21, 62 %) received mitomycin C.  The other drugs administered include cisplatin (10, 29 %), oxaliplatin (2, 6 %), and carboplatin (1, 3% ).  Mean length of hospital stay was 9 days (range of 3 to 39 days).  The rates of post-operative bacteremia and hematologic toxicity were 6 % and 54 %, respectively; 7 (21 %) patients developed transient renal dysfunction, and this was seen almost exclusively in the patients who received cisplatin; 1 (3 %) additional patient had renal dysfunction that persisted longer than 30 days post-operative but did not go on to require dialysis.  There were no peri-operative deaths in this cohort; 11 (32 %) patients received additional chemotherapy following HIPEC administration.  At a median follow-up of 20 months (range of 3 to 87 months), 8 patients were alive with disease, 7 had no evidence of disease, 14 have died of their disease, and 5 patients have been lost to follow-up.  The authors concluded that these data supported a reasonable side effect profile of treatment of EOC with HIPEC.  Moreover, they stated that prospective studies are needed to elucidate the optimal drug and patient population that would derive the most benefit from treatment with HIPEC.

An UpToDate review on “Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease” (Birrer and Fujiwara, 2016) states that “The administration of heated intraperitoneal chemotherapy (HIPEC) is used in select conditions, such as appendiceal carcinoma and pseudomyxoma peritonei.  Given the tendency of recurrent ovarian cancer to present as abdominal disease, there is growing interest in the use of HIPEC for women with recurrent EOC following surgical cytoreduction.  However, we consider HIPEC an investigational modality for the treatment of patients with platinum-resistant EOC”.

An UpToDate review on “First-line chemotherapy for advanced (stage III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer” (Herzog and Armstrong, 2016) states that “Outside of a clinical trial, we suggest not using hyperthermic intraoperative IP chemotherapy (HIPEC) as first-line treatment.  HIPEC refers to the instillation of heated chemotherapy at the time of surgery.  There is growing interest in the use of HIPEC for EOC, and early data on HIPEC as a component of front-line therapy of advanced EOC are encouraging.  However, major concerns about this approach include its inherent potential morbidity, the lack of randomized trials confirming the theoretical advantage of hyperthermia, and that longer postoperative recovery time may result in delay, decreased dose intensity, or even withdrawal from subsequent systemic chemotherapy, thereby worsening prognosis”.

Also, a statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria and AGO Switzerland (Harter et al, 2016) concluded that HIPEC remains experimental; its use is not recommended and should be rejected outside of prospective controlled trials.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Ovarian cancer including fallopian tube cancer and primary peritoneal cancer” (Version 1.2016) does not mention proton beam radiotherapy as a therapeutic option.

HIPEC for Peritoneal Carcinomatosis

Levine et al (2014) stated that peritoneal dissemination of abdominal malignancy (carcinomatosis) has a clinical course marked by bowel and death; it traditionally does not respond well to systemic therapy and has been approached with nihilism.  To treat carcinomatosis, these researchers used CS with hyperthermic intraperitoneal chemotherapy (HIPEC).  A prospective database of patients has been maintained since 1992.  Patients with biopsy-proven peritoneal surface disease were uniformly evaluated for, and treated with, CS and HIPEC.  Patient demographics, performance status (Eastern Cooperative Oncology Group), resection status, and peritoneal surface disease were classified according to primary site.  Univariate and multivariate analyses were performed.  The experience was divided into quintiles and outcomes compared.  Between 1991 and 2013, a total of 1,000 patients underwent 1,097 HIPEC procedures.  Mean age was 52.9 years and 53.1 % were female.  Primary tumor site was appendix in 472 (47.2 %), colorectal in 248 (24.8 %), mesothelioma in 72 (7.2 %), ovary in 69 (6.9 %), gastric in 46 (4.6 %), and other in 97 (9.7 %).  Thirty-day mortality rate was 3.8 % and median hospital stay was 8 days.  Median overall survival (OS) was 29.4 months, with a 5-year and 10-year survival rates of 32.5 % and 18 %, respectively.  Factors correlating with improved survival on univariate and multivariate analysis (p ≤ 0.0001 for each) were pre-operative performance status, primary tumor type, resection status, and experience quintile (p = 0.04).  For the 5 quintiles, the 1- and 5-year survival rates, as well as the complete cytoreduction score (R0, R1, R2a) have increased, and transfusions, stoma creations, and complications have all decreased significantly (p < 0.001 for all).  The  authors concluded that this largest reported single-center experience with CS and HIPEC demonstrated that prognostic factors include primary site, performance status, completeness of resection, and institutional experience.  The data showed that outcomes have improved over time, with more complete cytoreduction and fewer serious complications, transfusions, and stomas.  This was due to better patient selection and increased operative experience. They stated that cytoreductive surgery with HIPEC represented a substantial improvement in outcomes compared with historical series, and showed that meaningful long-term survival is possible for selected carcinomatosis patients.  They stated that multi-institutional cooperative trials are needed to refine the use of CS and HIPEC.

Di Vita et al (2015) noted that gastric cancer is one of the most dreadful neoplastic diseases and remains the 2nd cause of cancer death worldwide.  Patients who develop peritoneal metastasis have a poor prognosis, with a median survival of less than 6 months.  Despite being the cause of 60 % of deaths from gastric cancer, peritoneal metastasis can still be considered a local disease and a local multi-disciplinary approach can improve the prognosis even in this end-stage disease.  At present, HIPEC is the most widely accepted treatment for peritoneal surface diseases and can be performed in patients with different stages of cancer and with various anti-tumoral drugs.  These investigators performed a systematic review of the current status of HIPEC in the treatment of gastric peritoneal metastasis in an attempt to obtain answers to the questions that still remain: Do results differ with these different methods?  Does HIPEC exert a significant effect on the intra-cavitary delivery of drugs?  Which patients should be treated and which should not?  What can we expect from this approach in terms of survival, morbidity, and mortality?  On reviewing the literature, despite the lack of trials comparing the different methods, the authors found that HIPEC has been shown to be an effective tool whenever a complete or an almost complete resection of the peritoneal implants can be performed.  Therefore, it is advisable to refer all at-risk patients to specialized centers to be enrolled in randomized trials to achieve truly reliable results.

An UpToDate review on “Locoregional methods for management and palliation in patients who present with stage IV colorectal cancer” (Rodriguez-Bigas, 2016) states that “Patients who undergo complete cytoreduction followed by heated (hyperthermic) intraperitoneal chemotherapy (HIPEC) seem to have a more favorable prognosis than can be achieved with systemic chemotherapy alone.  However, in our view, there remains insufficient evidence to conclude whether the survival advantage is due to treatment or to biologic features that allow these patients to undergo complete cytoreductive surgery.  Furthermore, the quality of the cytoreductive surgery is dependent upon the skills and level of experience of the surgeon.  The favorable results (particularly with regard to treatment-related toxicity) achieved by international experts in the field may not be replicated in routine clinical practice.  Finally, the independent contribution of HIPEC to the success of this approach has not been proven.  Randomized trials are needed.  Based upon all of these issues, in our view (and that of the National Comprehensive Cancer Network [NCCN] ), this approach should not be considered standard at present and should only be pursued in centers with demonstrated expertise, preferably in the context of a clinical trial.  Such a trial, USMCI 8214/ACOSOG Z6091, in which patients with peritoneal carcinomatosis from colorectal cancer (CRC) were randomized to standard systemic chemotherapy or surgical cytoreduction with HIPEC followed by systemic chemotherapy, was closed for lack of accrual.  Another trial, Prodige 7, in which patients with isolated intraperitoneal metastases from CRC are randomly assigned to cytoreductive surgery with or without HIPEC, is underway in France.  An international list of centers with expertise in treatment of peritoneal surface malignancies is available online”.

Seshadri and Glehen (2016) stated that peritoneal metastasis, either synchronous or metachronous, is commonly seen in gastric cancer.  It is associated with a poor prognosis, with a median survival of less than 1 year.  The outcomes are not significantly improved by the use of systemic chemotherapy.  These investigators reviewed the relevant literature on the role of HIPEC in gastric cancer.  Cytoreductive surgery (CRS) and HIPEC has been used in 3 situations in gastric cancer.  Besides its role as a definitive treatment in patients with established peritoneal metastasis (PM), it has been used as a prophylaxis against peritoneal recurrence after curative surgery and also as a palliative treatment in advanced peritoneal metastasis with intractable ascites.  While prophylactic HIPEC has been shown to reduce peritoneal recurrence and improve survival in many randomized trials, palliative HIPEC can reduce the need for frequent paracentesis.  The authors concluded that although CRS with HIPEC has shown promise in increasing the survival of selected patients with established PM from gastric cancer, larger studies are needed before this can be accepted as a standard of care.  Key words of this study included peritoneal carcinomatosis.

In a pilot study, Sanchez-Garcia et al (2016) reported the findings of 21 patients with peritoneal carcinomatosis (PC) from ovarian cancer who underwent CRS and HIPEC by means of PRS-1.0 Combat^®, a new model for closed abdomen HIPEC aimed at improving fluid distribution with assistance from a CO2 recirculation system.  This new technology has been previously shown to be successful in an experimental study (pig model) performed by these investigators, and has been approved for use in their hospital.  Patients with PC of ovarian cancer origin were included in the study.  Cytoreductive surgery and HIPEC were performed by a closed abdomen fluid and CO2 recirculation technique using the PRS-1.0 Combat^® model.  These researchers analyzed the intra-operative safety tolerance and post-operative morbidity and mortality during the first 30 days.  Between November 2011 and March 2014, a total of 21 patients with epithelial ovarian cancer, International Federation of Gynecology and Obstetrics stage II-IV, were included in the study.  During the procedure there were no significant hemodynamic or analytical disturbances.  Complication rates were 38.1 % and 57.14 % for grade III/IV and minor (grade I/II) complications, respectively.  Post-operative mortality was 4.76 % (1 patient).  Complete CRS and intraperitoneal chemotherapy improved OS and disease-free survival (DFS) in women with advanced ovarian cancer.  The association of HIPEC increased the therapeutic benefit.  The authors concluded that the findings of this study has shown that closed abdomen intraperitoneal chemohyperthermia by a fluid and CO2 recirculation system (PRS-1.0 Combat^®) can be a safe and feasible model for the treatment of PC of ovarian cancer origin.  This pilot study did not address the effectiveness of HIPEC.

HIPEC for Fallopian Tube Cancer

A statement by the Kommission OVAR of the AGO Study Group on the use of HIPEC (Hyperthermic Intraperitoneal Chemotherapy) to treat primary and recurrent ovarian cancer (Harter et al, 2013) noted that “HIPEC is offered to patients with ovarian, fallopian tube or primary peritoneal cancer at some hospitals.  Altogether, there is still no evidence that HIPEC leads to an improvement of prognosis in any gynecologic tumor, neither in primary therapy nor in treatment of relapse.  The available data indicate an increased complication rate which might negatively impact the benefit-risk balance of this procedure.  In addition, standard treatment with proven efficacy might be withheld due to application of unproven methods.  The use of HIPEC outside of well designed, prospective and controlled clinical trials is therefore disregarded”.  An update of the 2013 Statement by the Kommission OVAR of the AGO Study Group on the use of HIPEC (Harter et al, 2016) concluded that HIPEC remains experimental.  Its use is not recommended and should be rejected outside of prospective controlled trials.

Cripe and colleagues (2015) evaluated morbidity and mortality associated with HIPEC in patients with ovarian, fallopian tube, and primary peritoneal cancer.  A retrospective review of patients undergoing cyto-reductive surgery (CRS) plus HIPEC from January 1, 2007 to July 29, 2013 at 2 academic medical centers was performed.  Grade 3/4 complications (National Cancer Institute's Common Toxicity Criteria version 4.0) from day of surgery until 30 days post-operatively were recorded.  A total of 32 patients were identified, with 27 cases of ovarian cancer, 3 primary peritoneal cancers, and 2 fallopian tube cancers.  Indications included 24 at the time of cancer recurrence, 6 at interval surgical resection, and 2 in the consolidative setting.  Hyperthermic chemotherapeutic regimens included carboplatin (n = 21), cisplatin (n = 4), oxaliplatin (n = 2), oxaliplatin + intravenous 5-fluorouracil (n = 1), doxorubicin (n = 1), and cisplatin + doxorubicin (n = 1).  Infusion time ranged from 30 to 90 mins, with a maximum temperature range of 41 to 43 ^°C.  The combined grade 3/4 morbidity rate was 65.6 %, and the most frequent morbidities included grade 3 anemia (40.6 %), infection (15.6 %), and pleural effusion (12.5 %); 6 patients required re-admission (18.8 %), and 2 patients required re-operation (6.2 %).  Full-thickness diaphragm resection/peritoneal stripping had a significant association with grade 3/4 pleural effusions (p = 0.0007).  The authors concluded that CRS plus HIPEC was feasible in patients with ovarian cancer with 65.6 % grade 3/4 morbidity and no deaths.  They stated that balancing these complications with potential survival benefits is important in centers considering implementing HIPEC protocols.  This appeared to be a “feasibility” study; only 2 patients had fallopian tube cancer and the effectiveness of HIPEC was not addressed.

An UpToDate review on “Overview of epithelial carcinoma of the ovary, fallopian tube, and peritoneum” (Chen and Berek, 2016) does not mention HIPEC as a therapeutic option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Ovarian cancer including fallopian tube cancer and primary peritoneal cancer” (Version 1.2016) does not mention HIPEC/hyperthermic intraperitoneal chemotherapy as a therapeutic option.

HIPEC for Mixed Germ Cell Tumor

Hayes-Jordan and colleagues (2016) stated that CRS and HIPEC have been used in adults with ovarian carcinoma proving overall survival benefit in randomized trials, but measured in months.  Diffuse peritoneal disease from pediatric type ovarian tumors is rare.  These researchers applied CRS and HIPEC to pediatric girls with diffuse peritoneal disease as part of a clinical trial.  In all patients complete CRS was followed by HIPEC using 100 mg/m2 of cisplatin for 90 mins in a closed technique.  All received neoadjuvant chemotherapy.  Patients with disease outside of the abdominal cavity were excluded.  Of 101 pediatric CRS and HIPEC operations, 8 had ovarian primary tumors and multi-focal peritoneal disease.  There were 3 yolk sac tumors (germ cell, mixed teratoma), 1 Sertoli-Leydig, 1 PNET of the ovary, 1 choriocarcinoma, 1 juvenile granulosa cell tumor and 1 adenocarcinoma; age ranged from 4 to 18 years; 3 of the 8 (37 %) recurred and died.  The remaining 63 % are disease free 2 to 6 years post-HIPEC.  Overall survival and relapse-free survival in this cohort were 64 % and 62 %, respectively [confidence interval [CI]:  0.64 (0.34, 1); 0.62 (0.37, 1)].  The authors noted that this was the first report of CRS and HIPEC in pediatric ovarian tumors.  They stated that HIPEC may be effective in pediatric-type ovarian tumors; however, more study is needed in a larger cohort.

Pleural HIPEC

de Beer et al (2002) stated that no established curative treatment is available for pleural thymoma metastases and malignant pleural mesothelioma (MPM).  Recently, peritoneal malignancies have been treated by cyto-reductive surgery (CRS) and intra-operative hyperthermic intra-cavitary perfusion chemotherapy (HIPEC).  These researchers investigated the feasibility and safety of this multimodality treatment in the thoracic cavity.  Patients with pleural thymoma metastases or early-stage MPM were enrolled in a feasibility study.  Morbidity, recurrence, and survival rates were recorded.  A total of 3 patients with pleural thymoma metastases and 11 patients with pleural mesothelioma were treated.  Cyto-reductive surgery and intraoperative HIPEC (HITHOC) with cisplatin and adriamycin were performed.  The mesothelioma patients received adjuvant radiotherapy on the thoracotomy wound and drainage tracts.  Morbidity and mortality rates were 47 % and 0 %, respectively.  Re-operation was necessary in 4 cases.  Severe chemotherapy-related complications were not observed.  A solitary mediastinal and a contralateral pleural thymoma recurrence were successfully treated by radiotherapy and a contralateral HITHOC procedure.  All thymoma patients were alive and free of disease after a mean follow-up period of 18 months.  After a mean follow-up period of 7.4 months, 9 mesothelioma patients were alive; 2 mesothelioma patients died of contralateral pleural and peritoneal recurrent disease, while 1 patient was alive with loco-regional recurrence.  The authors concluded that CRS and HITHOC with cisplatin and adriamycin was feasible in patients with pleural thymoma metastases and early-stage MPM, and was associated with acceptable morbidity rates.  They stated that early data on loco-regional disease control were encouraging, and a phase II study will be conducted.

Isık et al (2013) noted that malignant pleural effusion (MPE) means poor prognosis in the majority of cases.  Intra-pleural HIPEC appeared to be a promising approach for these patients.  These researchers examined if CRS followed by HIPEC provides any survival benefit in cases with metastatic MPEs.  Between January 2009 and December 2011, a total of 19 patients with metastatic MPEs were treated with HIPEC following surgical interventions such as pleurectomy/decortication and/or lung resection (group 1).  Comparison was done with historical control groups consisted of patients who received either talc pleurodesis or pleurectomy/decortication followed by systemic treatment for the management of metastatic MPEs between June 2007 and June 2008 (group 2 and 3).  Statistical analyses including overall survival (OS), disease free interval were done for the group comparisons.  Median survival in group 1, 2 and 3 were 15.4, 6, 8 months, respectively; 1-year survival was 54.7 % in group 1 where it was 0.6 % and 0.8 % in group 2 and 3, respectively.  There was no operative mortality; morbidity occurred in 1 patient in group 1 (5.3 %).  The authors concluded that HIPEC combined with CRS appeared to be a promising therapeutic option for subjects with metastatic MPEs.  They stated that further studies are needed for the optimization of HIPEC method, drug of choice, and the best combination therapy for the multi-modal treatment.

In a prospective study, Migliore et al (2015) examined if pleurectomy/decortication (P/D) and hyperthermic intra-operative intra-pleural chemotherapy (HITHOC) could be successfully performed in a low volume center.  Criteria of inclusion were a proven diagnosis of malignant pleural mesothelioma (MPM), early-stage disease and good performance status.  A total of 6 consecutive patients were enrolled.  Following P/D, intra-pleural cisplatin was administered for 60 mins at 42.5 ^°C.  Wedge resections and diaphragmatic reconstruction were added in 2 patients and 1 patient, respectively.  Morbidity was 16.6 %; mortality was nil.  Hospital stay was 7.8 days.  Mean survival was 21.5 months (range of 6 to 30).  The authors concluded that this small experience confirmed that P/D and HITHOC were a good therapeutic option in the multi-modality treatment of MPM; moreover, they stated that a randomized controlled trial is needed.

Ishibashi et al (2015) noted that surgical procedure for MPM remains controversial.  These investigators reviewed their protocol including P/D for patients with malignant pleural mesothelioma who were intolerable to extra-pleural pneumonectomy (EPP).  From June 2010 to April 2014, a total of 14 patients with MPM were intended to treat with multi-modality therapy including surgery; 4 patients who were intolerable to EPP received a protocol consisting of P/D and intra-operative intra-pleural hyperthermic cisplatin perfusion, followed by systemic chemotherapy; 10 patients received tri-modality treatment of EPP, systemic chemotherapy, and intensity modulated radiation therapy (IMRT) for hemi-thorax.  Surgical outcomes of acute operative results and interim survivals were examined and compared between the groups.  All patients obtained macroscopic complete resection and received multi-modality treatment in P/D and EPP groups.  Operation time was longer in P/D group; however, there were no differences in ICU stays or hospitalizations.  Four patients in P/D group and 7 patients in EPP group experienced post-operative complications; however, there was no operative morality; EPP group suffered from cardiac complications and P/D group had prolonged air-leak.  Full walk recovery was obtained earlier in P/D group; 1 patient in P/D group had a local recurrence 11 months after surgery, while the other 3 patients survived 23 to 41 months with no evidence of diseases.  The authors concluded that P/D and intra-operative intra-pleural cisplatin perfusion achieved a favorable macroscopic resection in patients with MPM who were intolerable to EPP; post-operative complications were manageable and survival could be promising.  Moreover, they stated that further study warrants with a larger number of patients.

Liu et al (2016) analyzed the safety of the bedside hyperthermic intra-pleural or intra-peritoneal chemotherapy (HIPEC) from September 2007 to July 2015.  A total of 5,759 times of bedside HIPEC in 985 cases of malignant pleural or peritoneal carcinomatosis were analyzed.  Of them, 1,510 times was given to 315 cases of malignant pleural effusion, while 4,249 times was performed in 402 patients with malignant ascites and 268 patients without ascites (total 670 patients for peritoneal carcinomatosis).  In average, patients with pleural effusion was given 5 times bedside HIPEC and stayed in the hospital for 6.7 days; while patients with peritoneal carcinomatosis was given 6 times of HIPEC and stayed in the hospital for 6.5 days.  Overall HIPEC-associated mortality was zero.  Overall HIPEC-associated incidence of side effect in the intra-pleural HIPEC was 2.0 %.  Specifically, 0.6 % was pneumothorax, 0.3 % was cytotoxic agent-induced pleural inflammation, 0.5 % was pain at puncture location, and 0.3 % was failure of HIPEC procedure.  Overall HIPEC-associated incidence of side effect in the intra-peritoneal HIPEC was 2.4 %, i.e., failure of HIPEC procedure in 1.3 %, pain at puncture location was 0.5 %, cytotoxic agent-induced peritoneal inflammation was 0.1 %, intestinal obstruction was 0.1 % and intestinal perforation was 0.07 %.  These findings indicated that bedside HIPEC applied in the current study was safe to be performed by a physician or oncologist under local anesthesia at a patient's bedside.  The procedure is easy to perform and well-tolerated by the patients with late stage cancer or post-surgery recurrent cancer.  This was a safety study.

Sugarbaker et al (2013) noted that local recurrence limits long-term survival in patients with malignant pleural mesothelioma (MPM).  These researcher s examined if hyperthermic intraoperative cisplatin chemotherapy lavage affects the interval to recurrence and overall survival (OS) among patients with favorable prognostic factors.  Using a pre-operative risk assessment algorithm these investigators had previously developed and validated, they retrospectively identified a cohort of patients treated with cyto-reductive surgery (CRS) from 2001 to 2009.  The patients had epithelial histologic findings on biopsy and were characterized as having a low risk of early recurrence and death (i.e., tumor volume less than or equal to 500 cm(3) and were either men with a hemoglobin level of greater than or equal to 13 g/dL or were women).  Those patients who had received hyperthermic intraoperative cisplatin chemotherapy were compared with a comparison group of those who had not.  Fisher's exact test was used to determine the balance of prognostic factors.  The Kaplan-Meier method and log-rank tests were used to estimate and compare the interval to recurrence and OS.  Cox proportional hazards regression was used for multi-variate analysis.  The cohort criteria identified 103 patients: 72 who received hyperthermic intraoperative cisplatin chemotherapy and 31 who did not.  The groups were balanced for prognostic factors, except for the use of neoadjuvant chemotherapy (more common in the comparison group).  The hyperthermic intraoperative cisplatin chemotherapy group exhibited a significantly longer interval to recurrence (27.1 versus 12.8 months) and OS (35.3 versus 22.8 months) than the comparison group.  The improved interval to recurrence and OS for the hyperthermic intraoperative cisplatin chemotherapy group were particularly evident among the subgroups of patients who had not received hemi-thoracic radiotherapy and who had pathologic stage N1 or N2 lymph node metastases.  The authors concluded that a favorable outcome and minimal incremental morbidity supported the incorporation of hyperthermic intraoperative cisplatin chemotherapy into multi-modality treatment strategies for patients with low-risk epithelial malignant pleural mesothelioma.

The authors stated that the present study was limited by its retrospective nature and small sample size, particularly for the comparison group.  The low-risk cohort represented a highly selected group of patients and inherent bias was present in using the group of patients who did not receive HIOC as a comparison group.  Moreover, the comparison group included significantly more patients who had received neoadjuvant chemotherapy, limiting the comparability of this cohort to the patients who had received HIOC.  The HIOC group included patients treated on and off various protocols during the study period.  Patients were able to complete adjuvant therapy with variable consistency, frequently at outside institutions.  The inclusion of adjuvant therapy as a co-variate in the multi-variate analysis was subject to guarantee time bias, which might have resulted in an over-estimation of its relative influence on OS.  These issues introduced some variability and bias into the analysis that could be overcome with a randomized prospective trial.  However, a prospective randomized trial is unlikely to be performed.  Overall, in evaluating their experience with cisplatin-only HIOC, these researchers have found that their data suggested (but do not prove) that HIOC improves the outcomes of low-risk patients with MPM.

Zhou et al (2017) stated that although HIPEC has been widely used to treat malignant ascites or as a preventive strategy for microscopic carcinomatosis following surgical resection of abdominal tumors, application of hyperthermic intrathoracic chemotherapy (HITHOC) in the treatment of malignant pleural effusion is limited.  These researchers performed a systematic review and meta-analysis on the application of HITHOC in the palliative treatment of malignant pleural effusion.  After thorough searching of online databases, a total of 27 articles were included into qualitative systematic review and 5 of them were used to conduct qualitative meta-analysis.  It was found that most of HITHOC was used in combination of CRS including pleurectomy/decortication or after surgical resection of primary tumors, which mainly were lung cancer, thymoma or thymic carcinoma, breast cancer, and ovarian cancer.  Patients who received HITHOC had significantly longer median survival length compared to the patients without HITHOC (Hedges g = 0.763, p < 0.001).  In addition, HITHOC therapy was favored (Hedges g = 0.848, p < 0.001) in terms of median survival length, tumor-free survival rate, with tumor survival rate or Karnofsky performance status (KPS) scale.  The authors concluded that HITHOC is a safe and effective therapy in controlling pleural effusion and increasing patient's survival rate.

The authors noted that the major limitation of the current review was that only 5 studies were eligible for the meta-analysis and case numbers included in each study was small.  In addition, techniques of HITHOC used in the 27 articles were heterogeneous including difference of cytotoxic drug and their concentration, equipment used for HITHOC, volume and temperature of the perfusion solution, and circulation duration, etc.  Thus, it is urgent to standardize the method of HITHOC in the clinical application.  They stated that although a large number of randomized and controlled clinical trials are necessary to further confirm the therapeutic advantage of HITHOC in the treatment of malignant pleural effusion, findings of the current systematic review and meta-analysis indicated that HITHOC is an effective and safe therapeutic procedure for extending patient's life and controlling disease progress.

Also, an UpToDate review on “Systemic treatment for unresectable malignant pleural mesothelioma” (Tsao and Vogelzang, 2018) does not mention HIPEC as an therapeutic option.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Malignant pleural mesothelioma” (Version 2.2017) states that “Intraoperative adjuvant therapies – such as hyperthermic pleural lavage, photodynamic therapy or heated chemotherapy – are under investigation”.

HIPEC for the Treatment of Cervical Cancer

Harima and colleagues (2016) evaluated the effectiveness of whole-pelvic HT added to standard chemoradiotherapy (CRT) in locally advanced cervical cancer (CC), by investigating the clinical response and survival of patients treated with cisplatin-based CRT versus CRT with HT (CRT + HT).  This study was conducted at 5 hospitals in Japan between September 2001 and March 2015 in patients with the International Federation of Gynecology and Obstetrics stage IB (bulky)-IVA CC undergoing definitive CRT.  After giving a written informed consent, patients were randomly allocated to 2 treatment groups:

1. CRT and
2. CRT + HT group; OS, disease-free survival (DFS), local relapse-free survival (LRFS), complete response (CR) rate and tolerability were evaluated. 

In total, 101 patients were treated.  Patient characteristics, total dose of cisplatin and radiotherapy were similar for both groups.  Although not statistically significant, the 5-year OS, DFS and LRFS in the CRT + HT group (77.8 %, 70.8 % and 80.1 %, respectively) were better than those in the CRT group (64.8 %, 60.6 % and 71.0 %, respectively).  CR was significantly more likely to be achieved in patients in the CRT + HT group than in the CRT group (88 % versus 77.6 %; adjusted odds ratio [OR], 3.993; 95 % confidence interval [CI]: 1.018 to 15.67; p = 0.047).  CRT + HT was well-tolerated and caused no additional acute or long-term toxicity compared with CRT alone.  The authors concluded that HT combined with CRT improved the CR rate of CRT in patients with locally advanced CC, however, could not improve survival outcomes.  They stated that these findings need to be validated in future phase III studies or meta-analyses consisting of larger sample sizes.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Cervical cancer” (Version 1.2018) does not mention hyperthermia as a therapeutic option.

HIPEC for the Treatment of Colon Cancer

Verwaal et al (2003) attempted to confirm the findings from uncontrolled studies that aggressive cytoreduction in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) is superior to standard treatment in patients with peritoneal carcinomatosis of colorectal cancer (CRC) origin.  Between February 1998 and August 2001, a total of 105 patients were randomly assigned to receive either standard treatment consisting of systemic chemotherapy (fluorouracil-leucovorin) with or without palliative surgery, or experimental therapy consisting of aggressive cytoreduction with HIPEC, followed by the same systemic chemotherapy regime.  The primary endpoint was survival.  After a median follow-up period of 21.6 months, the median survival was 12.6 months in the standard therapy arm and 22.3 months in the experimental therapy arm (log-rank test, p = 0.032).  The treatment-related mortality in the aggressive therapy group was 8 %.  Most complications from HIPEC were related to bowel leakage.  Subgroup analysis of the HIPEC group showed that patients with 0 to 5 of the 7 regions of the abdominal cavity involved by tumor at the time of the cytoreduction had a significantly better survival than patients with 6 or 7 affected regions (log-rank test, p < 0.0001).  If the cytoreduction was macroscopically complete (R-1), the median survival was also significantly better than in patients with limited (R-2a), or extensive residual disease (R-2b; log-rank test, p < 0.0001).  The authors concluded that cytoreduction followed by HIPEC improved survival in patients with peritoneal carcinomatosis of colorectal origin; however, patients with involvement of 6 or more regions of the abdominal cavity, or grossly incomplete cytoreduction, had still a grave prognosis.  It should be noted that this study has been criticized because the HIPEC group differed from the standard therapy group not only in the use of intraperitoneal hyperthermic chemotherapy, but also in surgical debulking.  It is possible that the important treatment was the surgical debulking, and the HIPEC made little difference.

Furthermore, in discussing the study by Verwaal et al (2003), the National Comprehensive Cancer Network’s clinical practice guideline on “Colon cancer” (Version 3.2021) notes that “long-term survival does not seem to be improved by this treatment as seen in follow-up results.  Importantly, this trial was performed without oxaliplatin, irinotecan, or molecularly targeted agents.  Some experts have argued that the OS difference seen might have been much smaller if these agents had been used (i.e., the control group would have had better outcomes)”.  It also states that “the individual components of the HIPEC approach have not been well studied … The panel currently believes that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for who R0 resection can be achieved.  However, the significant morbidity and mortality associated with HIPEC, as well as the conflicting data on clinical efficacy make this approach very controversial”.

Franko et al (2010) noted that survival benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion was demonstrated by a prospective randomized trial for colorectal peritoneal carcinomatosis.  Because of a recent substantial improvement in chemotherapy, the authors analyzed therapeutic options of colorectal carcinomatosis in the current era.  Consecutive patients with colorectal carcinomatosis treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion from 2001 to 2007 were included.  The control group patients with carcinomatosis received contemporary chemotherapy alone.  Overall survival (OS) was the primary end-point.  All patients underwent systemic chemotherapy.  The cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion group (n = 67) was similar to the control group (n = 38) in sex, tumor grade, site of tumor origin, T status, and N status.  The control group was, however, older (59 versus 51 years; p < 0.001).  Median survival measured from the diagnosis of peritoneal disease was longer with cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion (34.7 months versus 16.8 months; p < 0.001).  Presence of liver metastasis was a significant negative predictor of survival (hazard ratio [HR], 2.13).  The authors concluded that (i) contemporary chemotherapy is associated with prolonged survival among patients with carcinomatosis as compared with historical controls, and (ii) addition of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion to modern chemotherapy regimens may significantly prolong survival.  Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion and systemic chemotherapy are not competitive therapies, and they both have a role in a multidisciplinary approach to patients with carcinomatosis.

The authors recognized several inherent limitations to this type of study and have attempted to limit bias in the analysis.  They excluded patients with poor performance status and supportive care only.  They required presence of initially asymptomatic carcinomatosis and at least 4 cycles of chemotherapy for inclusion in the control arm.  Because performance status affects survival, this approach limited selection bias toward poor-performance patients entering the control group.  To avoid lead-in bias, these researchers elected to report survival measured from diagnosis of peritoneal carcinomatosis for the purpose of comparison between the groups.  Because selection of control group in retrospective studies always has to be presumed as biased, these investigators took special precautions to limit the selection bias.  This resulted in a relatively limited number of control cases.  Similarly, Elias et al collected a limited number of their control cases among 5 large cancer centers.  The unique setup of the authors’ institution (a network of cancer centers) allowed for analysis of data from many cancer centers and allowed them to construct their control group in a similar fashion to that of Elias et al … future studies will explain the interaction of tumor grade, other clinical variables, and role of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion in the treatment of peritoneal carcinomatosis from colorectal cancer”.

Huang et al (2017) stated that the therapeutic efficacy of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is still under debate.  These researchers performed a meta-analysis and systematic review of published literature on this comprehensive strategy to evaluate its effectiveness on CRC patients with PC.  A systemic review with meta-analysis of published literatures on treatment of CRS plus HIPEC for patients with PC from CRC was performed.  In addition, a summary of study results of published literatures concerning CRS plus HIPEC treating patients with PC from CRC was also conducted.  A total of 76 studies were selected, including 1 randomized controlled trial (RCT), 14 non-randomized controlled studies, and 61 non-controlled studies.  The pooled HRs for OS in the 15 researches for meta-analysis was 2.67 (95 % CI: 2.21 to 3.23, I2 = 0 %, p < 0.00001), and no significant evidence of publication bias was found.  The difference of chemotherapy regimens of HIPEC was not associated with OS and DFS (disease-free survival) after CRS and HIPEC, with no significant difference of heterogeneity (p = 0.27, I2 = 24.1 %).  In both groups of mitomycin C-based HIPEC group and oxaliplatin group, patients received HIPEC had significant better survival (p < 0.00001).  The mean mortality and morbidity for HIPEC program were 2.8 % and 33.0 %, respectively.  The authors stated that with the summary of 76 studies, it is found that although HIPEC is now widely accepted and performed in most institutions, details of performing HIPEC varies among different institutions.  As they noted, there are several mainly different techniques concerning HIPEC including “open” or “closed” technique, using MMC and/or L-OHP,  mono-chemotherapy or combination of chemotherapy regimens, and temperature and duration of HIPEC.  These can be further studied in future studies.  The authors concluded that this meta-analysis showed that CRS+HIPEC comprehensive therapeutic strategy was associated with improvement of OS in CRC PC patients, and the results of the meta-analysis were proved of good reliability by low heterogeneous and robust sensitivity.  Meanwhile, CRS and HIPEC can be performed with acceptable safety according to summary results of all 76 studies.

Behrenbruch et al (2017) stated that the peritoneum is the 2nd most common site of metastasis after the liver and the only site of metastatic disease in approximately 25 % of patients with CRC.  In the past, peritoneal carcinomatosis in CRC was thought to be equivalent to distant metastasis; however, the trans-coelomic spread of malignant cells is an acknowledged alternative pathway.  Metastasectomy with curative intent is well accepted in patients with liver metastasis in CRC despite the paucity of randomized trials.  Thus, there is rationale for local treatment with peritonectomy to eliminate macroscopic disease, followed by hyperthermic intraperitoneal chemotherapy to destroy any residual free tumor cells within the peritoneal cavity.  These researchers summarized the current evidence for cytoreduction and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis in CRC.  The authors concluded that “Few randomized trials assess the benefits of CRS and HIPEC in the treatment of PC from CRC … The results of randomized trials and future molecular studies will serve to guide future management, including refinements of patient selection”.

Klaver and colleagues (2017) presented long-term oncological outcomes of a pilot study on adjuvant HIPEC to reduce development of peritoneal metastases of colorectal cancer (PMCRC), with systematic review of literature.  Long-term oncological outcomes of 10 patients who underwent laparoscopic HIPEC within 8 weeks after resection of primary CRC in the pilot study were retrospectively collected.  A systematic search of literature was performed on studies describing the use of HIPEC in patients with CRC at high risk of developing PM.  The median follow-up was 54 months (range of 49 to 63).  All patients were alive at the last follow-up moment and none of them had developed PM; 2 patients had developed pulmonary metastases.  Systematic review revealed 5 small cohort studies, including 2 matched comparisons.  Peritoneal recurrences were found in 0 % to 9 % after adjuvant HIPEC, which was 28 % and 43 % in the 2 control groups, respectively; DFS and OS were significantly higher in favor of HIPEC.  The authors concluded that long-term follow-up of 10 patients included in a pilot study on adjuvant HIPEC revealed no peritoneal recurrences.  This finding was in line with other published pilot studies, a promising observation.  Moreover, they stated that the outcomes of the Dutch randomized COLOPEC trial and similar trials worldwide should be awaited for definitive conclusions on the effectiveness of adjuvant HIPEC.

Barratti et al (2017) noted that CRS and HIPEC are maximally effective in early-stage colorectal cancer peritoneal metastases (CRC-PM); however, the use of HIPEC to treat subclinical-stage PM remains controversial.  In a prospective, 2-center study, these researchers examined adjuvant HIPEC in CRC patients at high risk for metachronous PM.  During 2006 to 2012, a total of 22 patients without systemic metastases were prospectively enrolled to receive HIPEC simultaneously with curative surgery, plus adjuvant systemic chemotherapy (oxaliplatin/irinotecan-containing ± biologics), based on primary tumor-associated criteria: resected synchronous ovarian (n = 2) or minimal peritoneal (n = 6) metastases, primaries directly invading other organs (n = 4) or penetrating the visceral peritoneum (n = 10).  A control group retrospectively included 44 matched (1:2) patients undergoing standard treatments and no HIPEC during the same period.  The cumulative PM incidence was calculated in a competing-risks framework.  Patient characteristics were comparable for all groups.  Median follow-up was 65.2 months [95 % confidence interval (CI): 50.9 to 79.5] in the HIPEC group and 34.5 months (95 % CI: 21.1 to 47.9) in the control group . The 5-year cumulative PM incidence was 9.3 % in the HIPEC group and 42.5 % in the control group (p = 0.004).  Kaplan-Meier estimated 5-year overall survival (OS) was 81.3 % in the HIPEC group versus 70.0 % in the control group (p = 0.047).  No operative death occurred.  Grade 3 to 4 [National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4] morbidity rates were 18.2 % in the HIPEC group and 25 % in controls (p = 0.75).  At multi-variate analysis, HIPEC correlated to lower PM cumulative incidence [hazard ratio (HR) 0.04, 95 % CI: 0.01 to 0.31; p = 0.002], and better OS (HR 0.25, 95 % CI: 0.07 to 0.89; p = 0.039) and PFS (HR 0.31, 95 % CI: 0.11 to 0.85; p = 0.028).  The authors concluded that adjuvant HIPEC may benefit CRC patients at high-risk for peritoneal failure; these results warrant confirmation in phase-III clinical trials.

National Comprehensive Cancer Network’s clinical practice guideline on “Colon cancer” (Version 1.2018) states that “The panel currently believes that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for whom R0 resection can be achieved.  The panel recognizes the need for randomized clinical trials that will address the risks and benefits associated with each of these modalities”.

National Comprehensive Cancer Network’s clinical practice guideline on “Colon cancer” (Version 2.2021) does not mention the use of HIPEC for the treatment of stage IV colon cancer.  It states that “the individual components of the HIPEC approach have not been well studied … The panel currently believes that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for who R0 resection can be achieved.  However, the significant morbidity and mortality associated with HIPEC, as well as the conflicting data on clinical efficacy make this approach very controversial”.

HIPEC for the Treatment of Ovarian Cancer

Kim and colleagues (2019) noted that the use of HIPEC after CRS has been extensively studied in patients with peritoneal carcinomatosis from various malignancies.  However, the effectiveness of HIPEC for ovarian cancer is still controversial.  In a meta-analysis, these researchers identified patients with ovarian cancer who could obtain survival benefit from HIPEC.  Articles regarding HIPEC in the Medline, Embase, and Cochrane Library were searched till December 2018.  A total of 13 case-control studies and 2 RCTs were included in this meta-analysis.  These investigators examined the effect of HIPEC on DFS and OS, and performed subgroup analyses based on the study design, adjustment of confounding variables, and quality of the study.  HIPEC improved both DFS (HR, 0.603; 95 % CI: 0.513 to 0.709) and OS (HR, 0.640; 95 % CI: 0.519 to 0.789).  In cases of primary disease, HIPEC improved DFS (HR, 0.580; 95 % CI: 0.476 to 0.706) and OS (HR, 0.611; 95 % CI: 0.376 to 0.992).  Sub-group analyses revealed that HIPEC did not improve OS but improved DFS of patients with residual tumors of less than or equal to 1 cm or no visible tumors.  In cases of recurrent disease, HIPEC was associated with better OS (HR, 0.566; 95 % CI: 0.379 to 0.844) but not with DFS.  Sub-group analyses also revealed similar tendencies.  However, HIPEC improved DFS of patients with residual tumors of less than or equal to 1 cm or no visible tumors, while it improved OS of only those with residual tumors of less than or equal to 1 cm.  The authors concluded that HIPEC may improve DFS of patients with ovarian cancer when residual tumors were less than or equal to 1 cm or not visible.  It may also improve OS of only patients with recurrent disease whose residual tumors were less than or equal to 1 cm.  Moreover, these researchers stated that additional relevant clinical trials are needed to select the appropriate patients and to demonstrate the effect of HIPEC on their prognosis in the near future.

The French Clinical Practice Guidelines on “Management of epithelial cancer of the ovary, fallopian tube, and primary peritoneum” (Lavoue et al, 2019) noted that “After complete interval surgery for FIGO stage III disease, hyperthermic intraperitoneal chemotherapy (HIPEC) can be proposed, in accordance with the modalities of the OV-HIPEC trial (grade B)”.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Ovarian cancer including fallopian tube cancer and primary peritoneal cancer” (Version 3.2019) stated that “HIPEC with cisplatin (100 mg/m2) can be considered at the time of interval debulking surgery [IDS] for stage III disease”.

Prophylactic Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Gastric Cancer

Chen and associates (2018) stated that advanced gastric cancer (AGC) has a high recurrence rate (especially peritoneal relapse) and a poor prognosis.  Systematic chemotherapy or targeted therapy have not been able to significantly reduce the major cause of an unfavorable prognosis, namely the high peritoneal AGC recurrence rate post-surgery.  Further studies concerning the application of HIPEC following curative surgery for AGC patients, namely the prophylactic HIPEC (P-HIPEC), have involved a prophylactic approach to prevent peritoneal relapse following curative gastrectomy in high-risk patients.  Theoretically, breaking the "plasma-peritoneal barrier" increases cytotoxic chemotherapy activity via a synergistic hyperthermic effect; thus, HIPEC can eradicate free cancer cells and micro-metastasis within the peritoneal cavity intra-operatively or soon after curative gastrectomy to reduce peritoneal recurrence.  Many clinical trials have shown that P-HIPEC can reduce peritoneal recurrence and improve prognosis of AGC patients.  However, some studies applying HIPEC at an early stage have revealed a high rate of complications that limited generalizability.  This procedure has been increasingly adopted, given the complication rate has now been reduced and safety has been proven.  Recently, for assessing the important role of HIPEC, many high-quality prospective RCTs have been conducted to further examine the best guidance for P-HIPEC and to demonstrate its safety and effectiveness with a higher grade of evidence.  With theory development, the technique, equipment, and management of HIPEC and the role of P-HIPEC for AGC continues to evolve.

Brenkman and colleagues (2019) noted that survival after potentially curative treatment of GC remains low, mostly due to peritoneal recurrence.  This descriptive review gave an overview of available comparative studies concerning prophylactic HIPEC for patients with GC with neither clinically evident metastases nor positive peritoneal cytology who undergo potentially curative gastrectomy.  After searching the PubMed, Embase, CDSR, CENTRAL and ASCO meeting library, a total of 11 studies were included comparing surgery plus prophylactic HIPEC versus surgery alone (SA): 3 RCTs and 8 non-randomized comparative studies, involving 1,145 patients.  Risk of bias was high in most of the studies.  Morbidity after prophylactic HIPEC was 17 to 60 % compared to 25 to 43 % after SA; OS was 32 to 35 months after prophylactic HIPEC and 22 to 28 months after SA.  The 5-year survival rates were 39 to 87 % after prophylactic HIPEC and 17 to 61 % after SA, which was statistically significant in 3 studies.  Peritoneal recurrence occurred in 7 to 27 % in the HIPEC group, compared to 14 to 45 % after SA.  This review tended to demonstrate that prophylactic HIPEC for GC could be performed safely, may prevent peritoneal recurrence and may prolong survival.  However, studies were heterogeneous and outdated, which emphasized the need for well-designed trials conducted according to current standards.

HIPEC for the Treatment of Gastric Cancer

Desiderio et al (2017) stated that hyperthermic intraperitoneal chemotherapy (HIPEC) has been used within various multi-modality strategies for the prevention and treatment of gastric cancer (GC) peritoneal carcinomatosis (PC).  In a meta-analysis, these researchers examined the role of HIPEC in GC and clarified its effectiveness at different stages of peritoneal disease progression.  Data sources were Medline and Embase databases between January 1, 1985 and June 1, 2016.  Randomized control trials (RCTs) and high-quality non-RCTs selected on a validated tool (methodological index for non-randomized studies) comparing HIPEC and standard oncological management for the treatment of advanced stage GC with and without peritoneal carcinomatosis were considered.  The primary outcomes were overall survival (OS) and disease recurrence; secondary outcomes were overall complications, type of complications, and sites of recurrence.  A total of 11 RCTs and 21 non-RCTs (2,520 patients) were included.  For patients without the presence of PC, the OS rates between the HIPEC and control groups at 3 or 5 years resulted in favor of the HIPEC group (risk ratio [RR] = 0.82, p = 0.01).  No difference in the 3-year OS (RR = 0.99, p = 0.85) in but a prolonged median survival of 4 months in favor of the HIPEC group (weighed mean difference [WMD] = 4.04, p < 0.001) was observed in patients with PC.  HIPEC was associated with significantly higher risk of complications for both patients with PC (RR = 2.15, p < 0.01) and without (RR = 2.17, p < 0.01).  This increased risk in the HIPEC group was related to systemic drugs toxicity.  Anastomotic leakage rates were found to be similar between groups.  The authors concluded that this study demonstrated a survival advantage of the use of HIPEC as a prophylactic strategy and suggested that patients whose disease burden was limited to positive cytology and limited nodal involvement may benefit the most from HIPEC.  For patients with extensive carcinomatosis, the completeness of cytoreductive surgery (CRS) is a critical prognostic factor for survival.  Moreover, these researchers stated that future RCTs should better define patient selection criteria.

The authors stated that there were limitations to this meta-analysis that help direct future investigations of HIPEC in GC.  First, most of the RCTs and non-RCTs to-date were studies, which have been carried out by Asian institutions, limiting the interpretation of their findings for Western populations.  This reflected the difficulty of planning this type of studies in Western centers.  However, among the ongoing trials, significant contribution to this field is expected from the completion of 2 relevant European randomized and multi-center phase-III studies.  The GASTRICHIP Trial is currently enrolling patients with resectable T3 or T4 gastric adenocarcinoma with or without lymph node metastases (determined by endoscopic ultrasound [US] and computed tomography [CT] scan) plus or minus positive peritoneal cytology (at the time of pre-operative laparoscopy), for which a curative gastrectomy is scheduled.  This large trial with an estimated enrollment of 322 patients started in May 2013 with a planned evaluation of its primary and secondary outcomes in May 2023.  Its primary outcome is OS at 5-years follow-up and the secondary outcomes are the recurrence free survival (RFS; at 3 and 5 years), morbidity and mortality during the 2 post-treatment months and quality of life with EORTC questionnaire OLQ-C30 and QLQ-STO 22.  The GASTRIPEC Trial is recruiting patients with GC and synchronous PC.  The CRS+HIPEC is compared with CRS alone.  This study started in March 2014 with an expected enrollment of 180 subjects and aims to evaluate the OS through a 2.5-year maximum follow-up per patient.  Complication rate, time to disease progression, and QOL are among the secondary outcomes.  The GASTRIPEC Trial is anticipated to be completed by September 2020,

Second limitation was that the studies thus far have not specifically addressed the role and timing of adjuvant chemotherapy and its impact within a multi-modality treatment pathway.  HIPEC did not demonstrate efficacy in preventing local or lymph nodal recurrence and no benefit can be attributable to preventing liver metastasis or the systemic spread of the disease.  These findings were consistent with the evidence that HIPEC could not kill cancer cells that have penetrated deeply into the sub-peritoneal layers.  The decreased OS of patients who have involvement of more than 10 lymph node in the HIPEC group versus the control group suggested that delay in adjuvant systemic chemotherapy may have an adverse effect on the patient outcome and timely systemic chemotherapy remains the best therapeutic option for these patients.  A relevant issue is to verify if HIPEC associated complications may retard adjuvant chemotherapy.  This represents a major point for future investigations.  In summary, this study highlighted the need to find a balance between locally and peritoneally directed treatment of the disease with systemic therapies.

Third, comprehensive molecular profiling studies, such as that conducted by the Asian Cancer Research Group (ACRG), may provide insight into selecting patients with the optimal disease biology for HIPEC.  The ACRG observed that GC defined as a microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT) molecular classification exhibited peritoneal seeding as the preferential pattern of disease recurrence with a very low proportion of liver metastases.  Future clinical studies evaluating the impact of HIPEC will greatly be enhanced with correlative molecular analyses of tumor to examine if this MSS/EMT subset derives the greatest benefit from HIPEC.  At the same time, evaluation that focuses on specific treatment protocols for patients with positive cytology after peritoneal lavage may provide a category of patients for whom HIPEC may have the greatest potential benefit, since they are classified as stage IV with serious risk of peritoneal progression.

Hotopp (2019) noted that GC with the presence of peritoneal metastases (PMGC) is associated with a very poor prognosis.  Despite the widespread use and promising results of the multi-modal treatment regimens including CRS and a subsequent HIPEC, it is still not fully understood which patient group is suitable for this treatment.  A total of 26 patients (median age of 53 years, range of 39 to 71) were scheduled for 3 cycles of neoadjuvant systemic chemotherapy using bi-weekly FLOT-protocol followed by CRS + HIPEC.  After this treatment 3 additional cycles of FLOT were given.  During HIPEC, oxaliplatin was applied in a dosage of 200 mg/m2 and docetaxel in a dosage of 80 mg/m2.  All patients underwent the standardized multi-modal treatment including FLOT, CRS and HIPEC.  This treatment resulted in an OS of 17 months in comparison to 6 months as the outcome of the classic treatments.  Regression analysis demonstrated a Peritoneal Cancer Index (PCI) of greater than or equal to 12 as a negative factor for survival.  Furthermore, these investigators observed a worse prognosis by a higher temperature (greater than 41,4 °C) of the chemotherapy used for the HIPEC.  In consideration of the gender, the histomorphology and the Lauren-classification, these researchers could develop a precise score to define the patient group that would benefit from this multi-modal treatment with a prognosis improvement of 24 months.  The authors concluded that neoadjuvant chemotherapy using the FLOT-protocol followed by CRS + HIPEC appeared to be associated with prolonged OS in patients with PC from GC.  This treatment needs a critical evaluation for patients with a PCI of greater than or equal to 12.  Furthermore, the accurate selection of patients suffering of PMGC by using the developed score could improve the OS of up to 24 months for a suitable group and it could avoid the extensive treatment for unsuitable patients.  The authors noted that based on these findings, a pre-therapeutic score was developed that included parameters such as the sex and histomorphology of the primary tumor and may contribute to the profound selection of patients who benefit from multi-modal therapy.  The findings of this study were confounded by the use of the multi-modal therapy.

Manzanedo et al (2019) stated that GC with PC is traditionally considered a terminal stage of the disease.  The use of a multi-modal treatment, including CRS and HIPEC, could benefit these patients.  In a retrospective, multi-center study, these researchers examined the morbidity and survival outcomes of these patients.  Data were derived from a prospective national database of patients diagnosed with PC secondary to GC treated with CRS and HIPEC from June 2006 to October 2017.  A total of 88 patients from 7 specialized Spanish institutions were treated with CRS and HIPEC, with median age of 53 years; 51 % were women.  Median PCI was 6, and complete cytoreduction was achieved in 80 patients (90.9 %).  HIPEC was administered in 85 cases with 4 different regimens (cisplatin + doxorubicin, mitomycin-C + cisplatin, mitomycin-C and oxaliplatin); 27 cases (31 %) had severe morbidity (grade III to IV) and 3 patients died in the post-operative period (3.4 %).  Median follow-up was 32 months.  Median OS was 21.2 months, with 1-year OS of 79.9 % and 3-year OS of 30.9 %.  Median disease-free survival (DFS) was 11.6 months, with 1-year DFS of 46.1 % and 3-year DFS of 21.7 %.  After multi-variate analysis, the extent of peritoneal disease (PCI greater than or equal to 7) was identified as the only independent factor that influenced OS (hazard ratio [HR] 2.37, 95 % confidence interval [CI]: 1.26 to 4.46, p = 0.007).  The authors concluded that the multi-modal treatment, including CRS and HIPEC, for GC with PC could improve the survival results in selected patients (PCI less than 7) and in referral centers.

The authors stated that this study had several drawbacks.  First, it was a retrospective, observational study, not experimental, so the conclusions may have the biases inherent to this type of studies.  Second, although the selection of patients has improved greatly since the publication of the French registry (which referred up to 44 % of CCS [0), the incomplete cytoreduction rate of this study (9 % of CCS [0) was very striking.  This could suggest a bias of communication, on the part of some centers, of possible cases in which the procedure had to be aborted when finding unexpectedly in the laparotomy unresectable peritoneal disease; thus, over-estimating the effect by ‘‘intention to treat’’ of the CRS and HIPEC.  Third, there was a great variability of HIPEC drugs used, and this could confound the results, although these investigators found no differences when they analyzed the influence of HIPEC drug in OS.  This heterogeneity was due to the participation of multiple centers in the study.  Nonetheless, this was one of the most important National Registries published so far.  As these researchers noted previously, there was only 1 clinical trial published.  Currently, there are several Asiatic trials recruiting patients, and there is one ongoing German phase-III trial (GASTRIPEC) examining the role of HIPEC for PC of GC origin.  In a few years, clinicians will have more information from these trials that are currently underway.

Bonnot et al (2019) stated that gastric cancer (GC) with peritoneal metastases (PMs) is a poor prognostic evolution.  Cytoreductive surgery (CRS) yields promising results, but the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains controversial.  These researchers compared outcomes between CRS-HIPEC versus CRS alone (CRSa) among patients with PMs from GC.  From prospective databases, these investigators identified 277 patients with PMs from GC who were treated with complete CRS with curative intent (no residual nodules greater than 2.5 mm) at 19 French centers from 1989 to 2014.  Of these patients, 180 underwent CRS-HIPEC and 97 CRSa.  Tumor burden was evaluated using the peritoneal cancer index.  A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to examine the effect of HIPEC and account for confounding factors.  After IPTW adjustment, the groups were similar, except that median peritoneal cancer index remained higher in the CRS-HIPEC group (6 versus 2; p = 0.003).  CRS-HIPEC improved overall survival (OS) in both crude and IPTW models.  Upon IPTW analysis, in CRS-HIPEC and CRSa groups, median OS was 18.8 versus 12.1 months, 3- and 5-year OS rates were 26.21 % and 19.87 % versus 10.82 % and 6.43 % (adjusted hazard ratio [HR], 0.60; 95 % confidence interval [CI]: 0.42 to 0.86; p = 0.005), and 3- and 5-year recurrence-free survival (RFS) rates were 20.40 % and 17.05 % versus 5.87 % and 3.76 % (p = 0.001), respectively; the groups did not differ regarding 90-day mortality (7.4 % versus 10.1 %, respectively; p = 0.820) or major complication rate (53.7 % versus 55.3 %, respectively; p = 0.496).  The authors concluded that compared with CRSa, CRS-HIPEC improved OS and RFS, without additional morbidity or mortality.  When complete CRS was possible, CRS-HIPEC may be considered a valuable therapy for strictly selected patients with limited PMs from GC.  Moreover, these researchers stated that this study provided a rationale for additional randomized clinical trials.

The authors stated that the main drawback of this study was the lack of homogeneity of the selection criteria and management between institutions performing CRSa and CRS-HIPEC, especially between those specialized in peritoneal surface malignancy management from the BIG-RENAPE group and those involved in gastric surgery only from the FREGAT group.  This explained the principal imbalances between groups, especially the reduced neoadjuvant therapy in the CRSa group and the higher peritoneal tumor burden in the HIPEC group.  The high rate of upfront surgery was mainly linked to the high proportion of signet ring cell adenocarcinoma.  This histologic subtype was considered chemotherapy resistant by many centers in the FREGAT group, such that upfront surgery was commonly chosen at centers practicing CRSa, despite European recommendations.  Furthermore, because PMs usually represent a contraindication to resection at those centers, most patients in the CRSa group had localized and limited metastases that were intra-operatively discovered and were selected for curative-intent surgery.  Surgeons from the CRS-HIPEC group might have influenced the results because of their expertise in the management of PMs from other origins.  However, patients in that group had more diffuse PMs, with a mean PCI 3 times higher and almost 25 % having a PCI of 10 or greater, which is currently a potential contraindication for CRS-HIPEC in GC.  Finally, the low number of patients included over the study period reflected the necessarily strict selection process and may constitute another bias.

Newhook et al (2019) noted that laparoscopic HIPEC (LS-HIPEC) is a novel strategy for patients with gastric adenocarcinoma (GA) metastatic to the peritoneum.  These researchers examined the safety profile of LS-HIPEC for patients with positive peritoneal cytology (PPC) or carcinomatosis from GA.  Outcomes were reviewed of patients with stage IV GA with peritoneal involvement who received LS-HIPEC from June 2014 to January 2017.  LS-HIPEC included a 60-min perfusion of mitomycin-C (30-mg) and cisplatin (200-mg) with in-flow temperatures of 41 to 42 °C and out-flow temperatures of 39 to 40 °C.  A total of 71 LS-HIPEC procedures were performed in 44 patients.  At diagnosis, 68 % (n = 30) had carcinomatosis and 32 % (n = 14) had isolated PPC; 3 patients (7 %) underwent LS-HIPEC for intractable ascites.  All patients initially received systemic chemotherapy, and 20 patients (45 %) received pre-procedural chemo-radiotherapy.  The median number of LS-HIPEC procedures performed per patient was 1 (range of 1 to 5 procedures).  There were no conversions to laparotomy, 2 out-flow catheter obstructions, and 1 major (Clavien-Dindo grade-III) surgical complication within 30 days.  A total of 7 post-operative adverse hematologic events (greater than CTCAE 2) were observed in 5 patients (11 %), without any major renal or gastro-intestinal (GI) adverse events (AEs) within 30 days.  The median overall length of hospital stay (LOS)  after LS-HIPEC was 2 (range of 2 to 11) days; 11 patients (25 %) underwent secondary gastrectomy following resolution of peritoneal cytology.  The authors concluded that laparoscopic HIPEC was a safe procedure and may be repeated in patients with peritoneal metastases from gastric cancer.   Moreover, these researchers stated that future studies are needed to determine the optimal HIPEC regimen and timing relative to systemic therapy to best minimize morbidity.

The authors stated that this study had several drawbacks.  This patient cohort was heterogeneous, with patients with both gastric and gastro-esophageal junction tumors, a varying range of tumor sizes, and patients with positive peritoneal cytology, low-volume carcinomatosis, or both.  Moreover, there was no standardized, pre-operative therapy regimen, and thus it was reasonable to submit that local and occult systemic disease control was heterogeneous.  However, as a referral center many patients received 1st-line systemic therapy at outside institutions before presenting to M.D. Anderson Cancer Center.  The retrospective nature of this work was another drawback; however, prospective data collection and clinical trials incorporating LS-HIPEC into the treatment paradigm of patients with gastric cancer are ongoing.

Mielko et al (2019) stated that PMs of GC are characterized by a particularly poor prognosis, with median survival time of 6 months, and virtually no 5-year survival reported.  Conversion therapy for GC is defined as a surgical treatment aiming at an R0 resection after systemic chemotherapy for tumors that were originally unresectable (or marginally resectable) for technical and/or oncological reasons.  These researchers examined early and late outcomes in GC patients with PM who underwent the CRS with HIPEC after neoadjuvant (conversion) chemotherapy.  A total of 30 patients with stage-IV GC underwent CRS plus HIPEC.  Severe grade-III/IV (Clavien-Dindo classification) complications occurred in 13 (43 %) patients.  The Comprehensive Complication Index (CCI) ranged from 8.7 to 100 (median of 42.4).  In the multi-variate survival analysis, ypT2 and P3 (according to the Japanese classification of the PM severity) were favorable and adverse prognostic factors p = 0.031 and o = 0.035, respectively.  Estimated 1- and 3-year survival was 73.9 % and 36.6 %, respectively.  The median survival was 19.3 months.  The authors concluded that conversion surgery, including extended gastrectomy and multi-organ resections followed by HIPEC performed after systemic chemotherapy therapy for GC with PM was justified in down-staged patients with ypT2 and limited (less than P3) PM.

The authors stated that this study had 2 main drawbacks.  Due to its retrospective nature, it could not identify causation.  Furthermore, due to the relatively small sample size (n = 30), subgroup stratification analysis might be biased.

Yu et al (2020) noted that there is no currently available treatment for PMs of GC.  In a phase-II clinical trial, these researchers examined the safety and effectiveness of neoadjuvant systemic chemotherapy and HIPEC combined with CRS for the treatment of these patients.  Neoadjuvant chemotherapy comprised 2 cycles of HIPEC and 4 cycles of S-1 plus paclitaxel.  HIPEC was administered intra-peritoneally with paclitaxel (75 mg/m2).  For systemic chemotherapy, paclitaxel was administered intravenously(150 mg/m2) on day 1, and S-1 was administered orally (80 mg/m2/day)on days 1 to 14 of a 3-week cycle.  Another 2 cycles of HIPEC and 4 cycles of S-1 plus paclitaxel were administered after 2nd diagnostic staging laparoscopy or CRS.  The primary endpoints were treatment safety and effectiveness; the secondary endpoint was 3-year OS.  A total of 40 patients were enrolled and 38 patients have been analyzed.  Of these, 18 (47.4 %) patients received neoadjuvant systemic chemotherapy, HIPEC and CRS (conversion therapy group), while 20 patients received only chemotherapy and HIPEC (palliative chemotherapy group).  Median OS was markedly improved in the conversion therapy group (21.1 months, 95 % CI: 16.7 to 25.6 months) in comparison with the palliative chemotherapy group(10.8 months, 95 % CI: 7.3 to 14.2 months, p = 0.002).  After neoadjuvant systemic chemotherapy and HIPEC, a 2nd laparoscopic exploration was carried out, and the prognosis of patients with low PCI (PCI of less than 6) was significantly better than that of patients with high PCI (PCI of greater than or equal to 6) (20.1 versus 11.3 months, p = 0.006).  The authors concluded that neoadjuvant systemic chemotherapy and HIPEC combined with CRS was safe and feasible; and could potentially improve the prognosis of GC patients with limited PMs; however, prospective, randomized, multi-center clinical studies with a large sample size are needed to validate the findings of this study.  The drawbacks of this study included a relatively small sample size, a single-center design, and short follow-up.

Beeharry et al (2020) noted that even though treatment modalities such as adjuvant systemic radio-chemotherapy and neoadjuvant chemotherapy (NAC) had individually improved OS and progression-free survival (PFS) rates in advanced GC (AGC), the peritoneum still presides as a common site of treatment failure and disease recurrence.  The role of HIPEC has been acknowledged as prophylaxis for PC in AGC patients.  In a multi-center, phase-III RCT, these investigators will examine the safety and effectiveness of the combination of neoadjuvant laparoscopic HIPEC (NLHIPEC) with NAC in the neoadjuvant phase followed by surgery of curative intent with intra-operative HIPEC followed by adjuvant chemotherapy (AC).  A total of 326 patients will be randomly separated into 2 groups into a 1:1 ratio after laparoscopic exploration.  The experiment arm will receive the proposed comprehensive Dragon II regimen while the control group will undergo standard R0 D2 followed by 8 cycles of AC with oxaliplatin with S-1 (SOX) regimen.  The Dragon II regimen comprises of 1 cycle of NLHIPEC for 60 mins at 43 ± 0.5 °C with 80 mg/m2 of paclitaxel followed by 3 cycles of NAC with SOX regimen and after assessment, standard R0 D2 gastrectomy with intra-operative HIPEC followed by 5 cycles of SOX regimen chemotherapy.  The endpoints for the study are 5-year PFS, 5-year OS, PM rate (PMR) and morbidity rate.  The authors stated that this study is one of the first to combine NLHIPEC with NAC in the pre-operative phase, which is speculated to provide local management of occult PC or peritoneal free cancer cells while NAC will promote tumor down-sizing and down-staging.  The addition of the intra-operative HIPEC is speculated to manage dissemination due to surgical trauma.  Where the roles of intra-operative HIPEC and NAC have individually been examined, this study provides innovative insight on a more comprehensive approach to management of AGC at high risk of peritoneal recurrence.  It is expected that the combination of NLHIPEC with NAC and HIPEC will increase PFS by 15 % and decrease PMR after gastrectomy of curative intent.

Chicago Consensus Working Group (CCWG, 2020) provided multi-disciplinary recommendations for the management of gastric cancer (GC) specifically as it relates to the management of peritoneal surface malignancy.  These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists.  These guidelines recognize and address the emerging need for increased awareness of the appropriate management of peritoneal surface disease.  They are not intended to replace the quest for higher levels of evidence.  The CCWG stated that the role of CRS and peri-operative chemotherapy in the management of GC with peritoneal metastases (PM) is evolving.  CRS and HIPEC have demonstrated a significant survival benefit in a variety of cancers.  Only 1 phase-III randomized clinical trial comparing CRS/HIPEC with CRS alone has been completed.  In this trial, which was performed in China, CRS/HIPEC was associated with a median survival of 11.0 months in contrast to 6.5 months in the CRS-alone group.  However, no phase-III clinical trials have been completed in a Western population of patients with GC and PM, and biologic differences in GC between Eastern and Western populations of patients are known.  The consensus panel recognizes the need for multi-institutional and randomized trials within the U.S.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Gastric cancer” (Version 1.2021; Version 2.2022) states that “Hyperthermic intraperitoneal chemotherapy (HIPEC) or laparoscopic HIPEC may be a therapeutic alternative for carefully selected stage IV patients in the setting or ongoing clinical trials and is under further clinical investigation”.

HIPEC for the Treatment of Urachal Cancer

Mertens and colleagues (2019) noted that urachal adenocarcinoma (UrAC) is a rare malignancy arising from persistent urachal remnants, which can cause peritoneal metastases (PM).  Currently, patients with this stage UrAC are considered beyond cure.  These researchers reported long-term oncological outcome after CRS plus HIPEC for patients with PM of urachal adenocarcinoma (UrAC).  They identified 55 patients with UrAC treated at their hospital between 1994 and 2017.  Patients were staged with CT, bone scintigraphy and/or PET/CT.  From 2001 on, cN0M0 patients underwent staging laparoscopy; 10 patients had PM and were treated with CRS/HIPEC; 35 showed no metastases and underwent local treatment; 10 had distant metastases and received palliative chemotherapy.  Disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method and log-rank tests.  Post-operative complications represent a secondary outcome.  The median follow-up was 96.8 months.  Of the CRS/HIPEC patients, 5 (50 %) developed a recurrence; 4 (40 %) died of disease.  The 2-year and 5-year DSS after CRS/HIPEC were 66.7 % and 55.6 %, respectively.  DSS of the CRS/HIPEC patients did not significantly differ from DSS of patients without metastases who only underwent curative local treatment and was superior to patients with distant metastases (p = 0.012).  The overall complication rate after CRS/HIPEC was 60 %.  Major complications (Clavien 3) constituted 20 %.  The authors concluded that CRS/HIPEC demonstrated satisfactory long-term oncological outcome for patients with PM of UrAC.  These researchers stated that this approach may be offered as a potentially curative therapeutic option for this group of patients.  Moreover, they stated that this study was limited by its retrospective nature and the small sample size (n = 10 who received CRS/HIPEC).

A consensus statement by the Canadian Urological Association and Genitourinary Medical Oncologists of Canada on “Management of urachal cancer” (Hamilou et al, 2020) had no recommendations for use of HIPEC.

Furthermore, an UpToDate review on “Non-urothelial bladder cancer” (Quinn, 2021) does not mention HIPEC as a management / therapeutic option.

HIPEC for Signet Ring Cell Adenocarcinoma of the Appendix

Signet ring cell carcinoma (SRCC) is a diffuse type of adenocarcinoma found most often in the glandular cells of the stomach.  van Oudheusden et al (2015) noted that SRCC patients have a poor oncologic outcome.  These researchers examined if the potential drawbacks of HIPEC outweigh the benefits in patients with peritoneally metastasized SRCC.  Patients with PC of colorectal origin referred to 2 tertiary centers between April 2005 and December 2013 were identified and retrospectively analyzed.  Data were compared between SRCC histology and other differentiations.  A total of 351 patients were referred for CRS + HIPEC among which 20 (5.7 %) patients were identified with SRCC histology.  CRS + HIPEC was performed in 16 of these 20 (80 %) and 252 out of the 331 remaining patients (76.1 %).  A higher proportion of patients in the SRCC-group were diagnosed with N2 stage (62.5 % versus 36.1 %, p = 0.04).  A macroscopic complete resection was achieved in 87.5 % and 97.2 %, respectively (p = 0.04).  Median survival was 14.1 months compared to 35.1 months (p < 0.01).  Recurrence occurred in 68.8 % of the SRCC patients and in 43.7 % of the other histology patients (p = 0.05).  The authors concluded that patients with SRCC and PC treated with CRS + HIPEC have a poor median survival only slightly reaching over 1 year.  In the presence of other relative contraindications, SRCC histology should refrain a surgeon from performing CRS and HIPEC.

Grotz et al (2017) stated that moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death.  These researchers examined the effects of cytoreductive surgery (CRS) and HIPEC in patients with moderately and poorly differentiated appendiceal adenocarcinoma.  A total of 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database.  Clinical, pathologic, and treatment factors were analyzed for outcomes.  Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42 %) patients.  These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease; 27 (41%) patients were excluded from CRS because of findings on DL, while 116 (65 %) patients underwent CRS and HIPEC, with a median disease-free survival (DFS) of 23 months.  Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS.  The median OS following CRS and HIPEC was 48 months.  Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with  OS.; 85 (73.3 %) patients received neoadjuvant chemotherapy, and 40 (47.1 %) patients achieved a radiographic response; 36 (42.3 %) had stable disease (SD), while 9 (10.6 %) had progressive disease (PD). Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011).  The authors concluded that in selected patients, long-term survival could be obtained.  Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI of less than or equal to 20, and response/stable disease after neoadjuvant chemotherapy were important selection criteria for CRS and HIPEC.

Munoz-Zuluaga et al (2019) noted that CRS/HIPEC is standard treatment for peritoneal dissemination from appendiceal cancer (AC); however, its role in high-grade histopathologic subtypes (high-grade mucinous carcinoma peritonei [HGMCP] and HGMCP with signet ring cells [HGMCP-S]) is controversial due to their aggressive behavior.  This study analyzed clinical outcomes of high-grade AC after CRS/HIPEC.  These investigators reviewed a prospective database of CRS/HIPEC procedures for HGMCP performed from 1998 to 2017; peri-operative variables and survival were analyzed.  A total of 86 HGMCP and 65 HGMCP-S were identified.  HGMCP had more positive tumor markers (TM) (CEA/CA-125/CA-19-9) than HGMCP-S (63 % versus 40 %, p = 0.005).  HGMCP had higher PCI (32 versus 26, p = 0.097) and was less likely to have positive lymph nodes (LN) than HGMCP-S (28 % versus 69 %, p = < 0.001).  Complete cytoreduction was achieved in 84 % and 83 %, respectively.  Progression-free survival (PFS) at 3- and 5-years was 5 9% and 48 % for HGMCP versus 31 % and 14 % for HGMCP-S.  Median PFS was 4.3 and 1.6 years, respectively (p < 0.001); OS at 3- and 5-years was 84 % and 64 % in HGMCP versus 38 % and 25 % in HGMCP-S.  Median OS was 7.5 and 2.2 years, respectively (p < 0.001).  LN negative HGMCP-S had longer median PFS and OS than LN positive HGMCP-S (PFS: 3.4 versus 1.5 years, p = 0.03; OS: 5.6 versus 2.1 months, p = 0.021).  The authors concluded that the aggressive histology of HGMCP-S was associated with poor OS, had fewer abnormal TM, and was more likely to have positive LN; however, CRS/HIPEC could achieve a 5-year survival of 25 %, which may improve to 51 % with negative LN.

In a retrospective, cohort study, Shamavonian et al (2021) examined the effect of signet ring cell (SRC) histopathology in AC with peritoneal dissemination on OS in patients undergoing CRS/HIPEC.  A total of 255 patients were identified; 174 had high-grade disease with no SRC component, 35 with a low count of SRC and 46 with a high count of SRC.  Median OS without SRC was 93.8 months versus 58.2 months for low count SRC and 23.7 months for high count SRC (p < 0.001); 5-year OS was 60 % for patients with no SRC, 35.5 % and 10 % in those with low count and high count SRC, respectively.  On multi-variate analysis, presence of SRC and complete cytoreduction score were identified as independent factors that affect OS.  The authors concluded that the presence of SRC in appendix cancer with peritoneal dissemination was associated with worse OS when compared to an absence of SRC in patients undergoing CRS/HIPEC.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Colon cancer” (Version 3.2021) notes that “long-term survival does not seem to be improved by this treatment as seen in follow-up results.  Importantly, this trial was performed without oxaliplatin, irinotecan, or molecularly targeted agents.  Some experts have argued that the OS difference seen might have been much smaller if these agents had been used (i.e., the control group would have had better outcomes)”.  It also states that “the individual components of the HIPEC approach have not been well studied … The panel currently believes that complete cytoreductive surgery and/or intraperitoneal chemotherapy can be considered in experienced centers for selected patients with limited peritoneal metastases for who R0 resection can be achieved.  However, the significant morbidity and mortality associated with HIPEC, as well as the conflicting data on clinical efficacy make this approach very controversial”.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Hyperthermia:
CPT codes covered if selection criteria are met:
77600	Hyperthermia, externally generated; superficial (i.e., heating to a depth of 4 cm or less)
CPT codes not covered for indications listed in the CPB:
77605	Hyperthermia, externally generated; deep (i.e., heating to depths greater than 4 cm)
77610	Hyperthermia generated by interstitial probe(s); 5 or fewer interstitial applicators
77615	more than 5 interstitial applicators
77620	Hyperthermia generated by intracavitary probe(s)
Others CPT codes related to the CPB:
96446	Chemotherapy administration into the peritoneal cavity via indwelling port or catheter
Other HCPCS codes related to the CPB:
J8600	Melphalan, oral 2 mg
J9245	Injection, melphalan HCI, 50 mg
ICD-10 codes covered if selection criteria are met:
C43.0 - C44.99	Malignant melanoma of skin
C50.011 - C50.929	Malignant neoplasm of breast
C76.0	Malignant neoplasm of head, face, and neck
C77.0	Secondary and unspecified malignant neoplasm of lymph nodes of head, face, and neck
C79.81	Secondary malignant neoplasm of breast
D03.0 - D03.9	Melanoma in situ
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C17.0 - C17.9	Malignant neoplasm of small intestine, including duodenum [small bowel adenocarcinoma]
C18.1	Malignant neoplasm of appendix [without pseudomyxoma]
C22.0	Liver cell carcinoma [hepatocellular carcinoma]
C31.0 - C31.9	Malignant neoplasm of accessory sinuses
C34.00 - C34.92	Malignant neoplasm of lung
C37	Malignant neoplasm of thymus [thymic carcinoma]
C45.1, C48.1, C48.8	Malignant neoplasm of specified parts of peritoneum
C49.0 - C49.9	Malignant neoplasm of connective and other soft tissue [desmoplastic small round cell tumor]
C56.1 - C56.9	Malignant neoplasm of ovary [clear cell carcinoma]
C57.10 - C57.12	Malignant neoplasm of broad ligament of uterus (mesovarium; parovarian region)
C57.4	Malignant neoplasm of uterine adnexa, unspecified
C62.00 - C62.92	Malignant neoplasm of testis
C67.7	Malignant neoplasm of urachus
C78.5	Secondary malignant neoplasm of large intestine and rectum [colorectal signet ring carcinoma]
C78.6	Secondary malignant neoplasm of retroperitoneum and peritoneum
C79.60 - C79.62	Secondary malignant neoplasm of ovary
C7A.00, C7A.090 - C7A.098	Malignant carcinoid tumors of other and unspecified sites [goblet carcinoid tumor]
C7A.010 - C7A.019	Malignant carcinoid tumors of the small intestine [goblet carcinoid tumor]
C7A.020 - C7A.029	Malignant carcinoid tumors of the appendix, large intestine, and rectum [goblet carcinoid tumor]
D3A.00, D3A.090 - D3A.8	Benign carcinoid tumors of other and unspecified sites [goblet carcinoid tumor]
D3A.010 - D3A.019	Benign carcinoid tumors of the small intestine [goblet carcinoid tumor]
D3A.020 - D3A.029	Benign carcinoid tumors of the appendix, large intestine, and rectum [goblet carcinoid tumor]
Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy, HIPEC:
CPT codes covered if selection criteria are met:
77605	Hyperthermia externally generated; deep (ie, heating to depths greater than 4 cm) [allowed when combined with cytoreductive surgery]
77620	Hyperthermia generated by intracavitary probe(s) [allowed when combined with cytoreductive surgery]
96446	Chemotherapy administration into the peritoneal cavity via indwelling port or catheter
CPT codes not covered for indications listed in the CPB:
96440	Chemotherapy administrations into pleural cavity, requiring and including thoracentesis
Other HCPCS codes related to the CPB:
J9060	Injection, cisplatin, powder or solution, 10 mg
ICD-10 codes covered if selection criteria are met:
C18.1	Malignant neoplasm of appendix [without pseudomyxoma] [not covered for signet ring cell adenocarcinoma]
C45.1	Mesothelioma of peritoneum
C48.0 - C48.8	Malignant neoplasm of retroperitoneum and peritoneum
C56.1 - C56.9	Malignant neoplasm of ovary [stage III ovarian cancer]
C78.6	Secondary malignant neoplasm of retroperitoneum and peritoneum [pseudomyxoma peritonei]
C7A.020 - C7A.029	Malignant carcinoid tumors of the appendix, large intestine, and rectum [goblet cell carcinoid tumor]
C7A.098	Malignant carcinoid tumors of other sites [goblet cell carcinoid tumor]
D12.1	Benign neoplasm of appendix
D20.1	Benign neoplasm of soft tissue of peritoneum
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C16.0 - C16.9	Malignant neoplasm of stomach
C18.0, C18.2 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectum, rectosigmoid junction, anus and anal canal
C25.0 - C25.9	Malignant neoplasm of pancreas
C45.0	Mesothelioma of pleura
C54.0 - C54.9	Malignant neoplasm of corpus uteri [leiomyosarcoma]
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C62.00 - C62.92	Malignant neoplasm of testis
C67.0 - C67.9	Malignant neoplasm of bladder
C78.2	Secondary malignant neoplasm of pleura
Intraluminal hyperthermia:
No specific code
Transrectal ultrasound hyperthermia:
No specific code
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C61	Malignant neoplasm of prostate

The above policy is based on the following references: