Clinical Policy Bulletin: High Dose Chemotherapy with Bone Marrow or Peripheral Stem Cell Transplant for Ovarian Cancer
Aetna considers high-dose chemotherapy (HDC) with autologous bone marrow or peripheral stem cell transplant medically necessary for the treatment of persons with relapsed germ cell tumors of the ovary that were responsive to standard chemotherapy.
Aetna considers HDC with autologous bone marrow or peripheral stem cell transplant medically necessary as consolidation therapy for persons with germ cell tumors of the ovary that is in complete remission.
Aetna considers HDC with tandem autologous bone marrow or peripheral stem cell transplant medically necessary for persons with germ cell tumors of the ovary that is in relapse.
Aetna considers HDC with autologous bone marrow or peripheral stem cell transplant experimental and investigational when used as initial treatment (i.e., instead of an initial course of standard-dose chemotherapy with Food and Drug Administration (FDA)-approved drugs) of persons with germ cell tumors of the ovary because its effectiveness for this indication has not been estanlished.
Aetna considers HDC with allogeneic bone marrow or peripheral stem cell transplant experimental and investigational for the treatment of persons with germ cell tumors of the ovary because its effectiveness for this indication has not been estanlished.
Aetna considers HDC with bone marrow or peripheral stem cell transplant (autologous or allogeneic) experimental and investigational for the treatment of persons with epithelial ovarian cancers because its effectiveness for this indication has not been estanlished.
Ovarian cancer is the leading cause of death among gynecological malignancies and the 4th leading cause of cancer death in American women. Each year about 25,400 new cases of ovarian cancer are diagnosed and 14,500 women die from the disease. Approximately 90 % of all ovarian cancers are epithelial ovarian carcinomas arising from the germinal epithelium of the ovary. The remaining 10 % of ovarian malignancies consist of germ cell origin, stromal and sex cord tumors. Epithelial ovarian cancer accounts for 4 % of all cancers in women. Germ cell tumors of the ovary are uncommon but aggressive tumors seen most often in young women or adolescent girls. About 50 % of germ cell malignancies are pure dysgerminomas; and about 70 % of dysgerminomas are confined to the ovary at diagnosis.
The most important risk factor for ovarian cancer is a family history of a 1st-degree relative with the disease. Approximately 5 to 10 % of ovarian cancers are familial and there is increasing evidence that there are a small number of families at particularly high-risk for developing epithelial ovarian cancer. Three distinct hereditary syndromes associated with the occurrence of familial ovarian cancer have been identified: (i) ovarian cancer syndrome, (ii) hereditary breast-ovarian cancer syndrome, and (iii) Lynch II syndrome, which includes a predisposition to ovarian, endometrial, and colon cancers. All 3 syndromes exhibit an autosomal dominant pattern of transmission with variable penetrance.
Since early stage ovarian cancer has no major associated symptoms and there are no reliable screening tests, the majority of patients present with metastatic disease throughout the peritoneal cavity. In the United States, nearly 70 % of the 23,000 patients diagnosed annually with epithelial ovarian cancer present with advanced disease -- International Federation of Gynecology and Obstetrics (FIGO) stages III to IV. The FIGO staging for primary ovarian carcinoma is as follows:
Growth limited to the ovaries
Growth involving 1 or both ovaries with pelvic extension
Tumor involving 1 or both ovaries with peritoneal implants outside the pelvis and/or retroperitoneal or inguinal nodes. Superficial liver metastasis equals stage III. Tumor is limited to the true pelvis, but with histologically proven malignant extension to small bowel or omentum
Tumor involving 1 or both ovaries with distant metastasis. If pleural effusion is present, there must be positive cytologic test results to allot a case to stage IV. Parenchymal liver metastasis equals stage IV
The prognosis of ovarian cancer is influenced by several factors including stage at presentation, size of residual tumor following initial surgery, histologic grade, patient performance status and age. The 5-year survival rate for patients with advanced ovarian cancer treated with conventional therapy were only 15 to 25 % for stage III disease and less than 5 % for stage IV disease.
All stages of ovarian cancer are first treated with cytoreductive surgery, including oophorectomy and total abdominal hysterectomy. Unilateral oophorectomy is adequate treatment for most patients with stage I and stage II diseases. The objective of surgery in disease stages later than stage I is to reduce the bulk of the largest residual tumor deposit to less than 1 or 2 cm for optimal disease prognosis. While this may be sufficient treatment for cases confined to the ovary, typically intra-peritoneal spread is identified; thus, surgery is commonly followed by chemotherapy. Paclitaxel/platinum combinations are the standard 1st-line chemotherapy. The extent of chemotherapy treatment varies with the stage of disease. Ovarian cancers are responsive to chemotherapy in 80 to 90 % of cases, and the success of chemotherapy is dependent on the volume of disease that remains after cytoreductive surgery. Salvage chemotherapy with several single agents has only modest activity and does not extend survival of patients with relapsed ovarian carcinoma. Sex cord-stromal tumors can occur at any point in a woman's life. Because of the rarity of sex cord-stromal tumors, there is no established chemotherapeutic regimen.
Multiple uncontrolled studies have examined the effectiveness of single and multiple cycles of high-dose chemotherapy (HDC) with stem cell support (peripheral stem cells or autologous bone marrow transplantation) in patients with advanced and chemo-resistant epithelial ovarian cancer. High-dose chemotherapy with autologous stem cell transplantation is still investigational for patients with epithelial ovarian cancer.
In a review on HDC for the management of patients with ovarian cancer, McGuire (2000) noted that the effect of HDC (including stem cell-supported HDC) on the survival of women with ovarian cancer has been examined in numerous clinical studies. The data demonstrated increased response rates with high-dose regimens, but any survival advantages observed have been limited. Patients with the most favorable outcome were those with low tumor burden and chemotherapy-sensitive tumors. An attempt to study this group of patients in a randomized trial in the United States (Gynecologic Oncology Group Protocol 164) was unsuccessful because of low accrual. European randomized trials are under way to evaluate HDC and stem cell transplantation as part of initial therapy or as consolidation after initial response to therapy and to compare HDC with standard-dose chemotherapy. Until results from these studies become available, HDC remains limited to the clinical trial setting.
In a phase I clinical trial, Donato and associates (2001) examined the effectiveness of HDC with autologous stem cell support for the treatment of women with advanced ovarian cancer (n = 53). All patients had refractory and/or recurrent ovarian cancer and had been previously treated with paclitaxel and platinum. The overall response rate in the 30 patients with measurable or evaluable disease was 93 %. It was reported that toxicity was acceptable and there were no treatment-related deaths. The authors concluded that in the setting of ovarian cancer, high-dose regimens should be administered only as part of a well-designed clinical trial.
In a retrospective study, Ledermann and colleagues (2001) analyzed the outcome of patients with advanced or recurrent epithelial ovarian cancer (n = 254) treated with HDC -- 105 received HDC in complete or very good partial remission, 27 in second remission and 122 in the presence of residual disease. Most received melphalan or carboplatin, or a combination (86 %) supported by autologous bone marrow or peripheral blood stem cells. The survival of patients treated in remission was significantly better than in other groups (median 33 versus 14 months). The durability of remission was longer after transplantation in first remission than in second remission (median disease-free survival 18 versus 9 months). With a median follow-up of 76 months from diagnosis, the median disease-free and overall survival (OS) in stage III disease transplanted in remission is 42 and 59 months and for stage IV disease 26 and 40 months, respectively. The authors concluded that HDC has a potential benefit for patients in remission. The results support the conduct of randomized studies to determine whether there is a real value from this treatment.
In a review on 2nd-line and subsequent therapy for ovarian carcinoma, Peethambaram and Long (2002) stated that HDC with autologous stem cell transplantation is still investigational. Women with advanced ovarian carcinoma should continue to be encouraged to participate in well-designed clinical trials.
The European Group for Blood and Marrow Transplantation (Urbano-Ispizua et al, 2002) recently stated that for ovarian cancer with minimal residue disease, allogeneic transplantation is not generally recommended; while autologous transplantation may be undertaken in approved clinical protocols -- the value of transplants for patients included in this category needs further investigation. For refractory ovarian cancer, allogeneic transplantation using sibling donor is developmental (there is very little experience with this particular type of transplant); while allogeneic transplantation using alternative donor or autologous transplantation is not generally recommended. For relapsed germ cell tumors that were sensitive to chemotherapy, allogeneic transplantation is not generally recommended, while autologous transplantation is standard use in selected patients. For refractory germ cell tumors, allogeneic transplantation is not generally recommended; while autologous transplantation may be undertaken in approved clinical protocols.
Schilder et al (2003) stated that HDC (supported by hematopoietic stem cells) as 1st-line treatment for epithelial ovarian cancer remains experimental and should be restricted to clinical trials.
Bengala et al (2005) reported that HDC with autologous hemopoietic support does not benefit patients with advanced epithelial ovarian cancer in first complete remission.
In a phase II multi-center study, Goncalves and colleagues (2006) assessed the feasibility, toxicity and effectiveness of post-operative front-line sequential HDC with hematopoietic stem cell (HSC) support in patients with advanced ovarian cancer (AOC). A total of 34 patients with stage IIIC/IV epithelial ovarian cancer received a post-operative sequential combination of high-dose cyclophosphamide/epirubicin (D1, D21) with HSC harvesting, high-dose carboplatin (D42, D98) followed by HSC infusion, and dose-dense paclitaxel (D63, D77, D119, D133). Rh-G-CSF (filgrastim) was administered following all cycles. Primary endpoint was pathological complete response rate (pCR). A total of 30 patients received at least 7 of the scheduled 8 cycles. Hematological toxicity was significant but manageable. Grade 3/4 extra-hematopoietic toxicities were relatively uncommon and reversible. No toxicity-related death was observed. The observed pCR was 37 % and did not reach the initial endpoint. Post-operative front-line sequential HDC in AOC is feasible and safe in a multi-center setting. The observed pCR does not support a clear advantage over conventional treatment. The authors concluded that regarding the high level of toxicity encountered, this approach should not be performed outside clinical trials, and remains an experimental strategy to further optimize and validate.
In a multi-center phase I/II clinical study, Frickhofen and colleagues (2006) assessed the effectiveness of multi-cycle (also known as sequential) HDC with autologous peripheral blood stem cell support for the treatment of patients with advanced ovarian cancer. A total of 48 subjects with untreated ovarian cancer were enrolled in this trial. Median age was 46 (19 to 59 years); International FIGO-stage was III in 79 % and IV in 21 %; 31 % had residual disease greater than 1 cm after surgery. Two courses of induction/mobilization therapy with cyclophosphamide (250 mg/m2) and paclitaxel (250 mg/m2) were used to collect peripheral blood stem cells. High-dose chemotherapy consisted of 2 courses of carboplatin (area under curve (AUC) 18-22) and paclitaxel followed by 1 course of carboplatin and melphalan (140 mg/m2) with or without etoposide (1,600 mg/m2). Main toxicity was gastrointestinal. Limiting carboplatin to AUC 20 and eliminating etoposide resulted in manageable toxicity (69 % without grade 3/4 toxicity). One patient died from treatment-related pneumonitis. At 8 years median follow-up, median progression-free-survival (PFS) and OS is 13.3 and 37.0 months. Five-years PFS and OS are 18 and 33 %, respectively. The authors noted that multi-cycle HDC is feasible in a multi-center setting, and a European phase III trial based on this regimen examining the effectiveness of multi-cycle HDC has been completed. Preliminary findings do not suggest an improvement of OS or PFS with multi-cycle HDC compared to standard dose chemotherapy. They stated that multi-cycle HDC should thus be considered experimental in ovarian cancer.
Mobus and colleagues (2007) compared sequential HDC with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy to ascertain if dose-intensification improves outcome. A total of 149 patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential HDC with 2 cycles of cyclophosphamide and paclitaxel followed by 3 cycles of high-dose carboplatin and paclitaxel with PBSC support. High-dose melphalan was added to the final cycle. The median age was 50 years (range of 20 to 65) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4 %, III in 78 %, and IV in 17 %. Seventy-six percent of patients received all 5 cycles in the high-dose arm and the main toxicities were neurotoxicity/ototoxicity, gastrointestinal toxicity, and infection and 1 death from hemorrhagic shock. After a median follow-up of 38 months, the PFS was 20.5 months in the standard arm and 29.6 months in the high-dose arm (hazard ratio [HR], 0.84; 95 % confidence interval [CI]: 0.56 to 1.26; p, 0.40). Median OS was 62.8 months in the standard-arm and 54.4 months in the HD-arm (HR, 1.17; 95 % CI: 0.71 to 1.94; p, 0.54). The authors stated that this is the first randomized trial comparing sequential HDC versus standard-dose chemotherapy in 1st-line treatment of patients with advanced ovarian cancer. They observed no statistically significant difference in PFS or OS and concluded that HDC does not appear to be superior to conventional dose chemotherapy.
Bay and colleagues (2010) stated that although preliminary results suggested that allogeneic hematopoietic stem cell transplantation (allo HCT) for ovarian cancer (OC) is a feasible procedure, the low patient number in previous studies had limited ability to evaluate the true benefit of allo HCT in OC. This retrospective multi-center study included 30 patients with OC allografted between 1995 and 2005 to determine the outcome of patients with OC treated with allo HCT. Prior to allo HCT, patients were in complete response (n = 1), partial response (n = 7), stable disease (n = 11) or had progressive disease (n = 13). An objective response (OR) was observed in 50 % (95 % CI: 33 to 67) of patients. Three patients of responding patients had an OR following the development of acute graft-versus-host disease (aGVHD). The cumulative incidence of chronic GVHD (cGVHD) was 34 % (95 % CI: 18 to 50). Transplant relative mortality rates were 7 and 20 % on day 100 and 1 year, respectively. With a median follow-up of 74.5 months (range of 16 to 148), median PFS was 6 months and median OS was 10.4 months. Patients who developed cGVHD following allo HCT had a significant OS improvement compared to those who did not (17.6 months versus 6.5 months, p = 0.042). However, PFS was not similarly significantly improved in patients who developed cGVHD (12 months versus 3.7 months, p = 0.81). The authors concluded that Allo HCT in OC may lead to graft-versus-OC effects. Their clinical relevance remains to be shown.
In a phase II clinical trial, Geller et al (2010) evaluated the tumor response and in-vivo expansion of allogeneic natural killer (NK) cells in recurrent ovarian and breast cancer. Patients underwent a lympho-depleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in 7 patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated over-night in 1,000 U/ml interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given 3 times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of greater than or equal to 100 donor-derived NK cells/μL blood 14 days after infusion, based on molecular chimerism and flow cytometry. A total of 20 patients (14 ovarian cancer, 6 breast cancer) were enrolled. The median age was 52 (range of 30 to 65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69 %) patients without TBI and 6/7 (85 %) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (p = 0.03). Serum IL-15 levels increased after the preparative regimen (p < 0.001). Patients receiving TBI had delayed hematologic recovery (p = 0.014). One patient who was not evaluable had successful in-vivo NK cell expansion. The authors concluded that adoptive transfer of haplo-identical NK cells after lympho-depleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. They stated that strategies to augment in-vivo NK cell persistence and expansion are needed.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
CPT codes not covered for indications in the CPB:
Other CPT codes related to the CPB:
38206 - 38215
96401 - 96549
HCPCS codes covered if selection criteria are met:
Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
ICD-9 codes covered if selection criteria are met:
Malignant neoplasm of the ovary [relapsed germ cell tumors]
Malignant neoplasm of ovary and other uterine adnexa whose point of origin cannot be determined [relapsed germ cell tumors]
The above policy is based on the following references:
Droz JP, Pico JL, Ghosn M, et al. Long-term survivors after salvage high dose chemotherapy with bone marrow rescue in refractory germ cell cancer. Eur J Cancer. 1991;27(7):831-835.
Broun ER, Nichols CR, Kneebone P, et al. Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med. 1992;117(2):124-128.
Cannistra SA. Cancer of the ovary. N Engl J Med. 1993;329(21):1550-1559.
Lotz JP, Andre T, Donsimoni R, et al. High dose chemotherapy with ifosfamide, carboplatin, and etoposide combined with autologous bone marrow transplantation for the treatment of poor-prognosis germ cell tumors and metastatic trophoblastic disease in adults. Cancer. 1995;75(3):874-885.
Margolin BK, Doroshow JH, Ahn C, et al. Treatment of germ cell cancer with two cycles of high-dose ifosfamide, carboplatin, and etoposide with autologous stem-cell support. J Clin Oncol. 1996;14(10):2631-2637.
Weaver CH, Greco FA, Hainsworth JD, et al. A phase I-II study of high-dose melphalan, mitoxantrone and carboplatin with peripheral blood stem cell support in patients with advanced ovarian or breast carcinoma. Bone Marrow Transplant. 1997;20(10):847-853.
Stiff PJ, Bayer R, Kerger C, et al. High-dose chemotherapy with autologous transplantation for persistent/relapsed ovarian cancer: A multivariate analysis of survival for 100 consecutively treated patients. J Clin Oncol. 1997;15(4):1309-1317.
Legros M, Dauplat J, Fleury J, et al. High-dose chemotherapy with hematopoietic rescue in patients with stage III to IV ovarian cancer: Long-term results. J Clin Oncol. 1997;15(4):1302-1308.
Fennelly DW, Aghajanian C, Shapiro F, et al. Dose escalation of paclitaxel with high-dose carboplatin using peripheral blood progenitor cell support in patients with advanced ovarian cancer. Semin Oncol. 1997;24(1 Suppl 2):S2-26-S2-30.
Pecorelli S, Odicini F, Maisonneuve P et al. FIGO annual report of the results of treatment in gynaecological cancer: Carcinoma of the ovary. J Epidemiol Biosta. 1998;3:75-102.
Holmberg LA, Demirer T, Rowley S, et al. High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer. Bone Marrow Transplant. 1998;22(7):651-659.
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Mandanas RA, Saez RA, Epstein RB, et al. Long-term results of autologous marrow transplantation for relapsed or refractory male or female germ cell tumors. Bone Marrow Transplant. 1998;21(6):569-576.
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Donato ML, Gershenson DM, Wharton JT, et al. High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: A new regimen for the treatment of advanced ovarian cancer. Gynecol Oncol. 2001;82:420-426.
Ledermann JA, Herd R, Maraninchi D, et al. High-dose chemotherapy for ovarian carcinoma: Long-term results from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT). Ann Oncol. 2001;12(5):693-699.
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De Giorgi U, Rosti G, Papiani G, et al. The status of high-dose chemotherapy with hematopoietic stem cell transplantation in germ cell tumor patients. Haematologica. 2002;87(1):95-104.
Urbano-Ispizua A, Schmitz N, de Witte et al. Allogeneic and autologous transplantation for haematological diseases, solid tumors and immune disorders: Definitions and current practice in Europe. Bone Marrow Transplantation. 2002;29:639-646.
Schilder RJ, Brady MF, Spriggs D, Shea T. Pilot evaluation of high-dose carboplatin and paclitaxel followed by high-dose melphalan supported by peripheral blood stem cells in previously untreated advanced ovarian cancer: A gynecologic oncology group study. Gynecol Oncol. 2003;88(1):3-8.
Australian Cancer Network and National Breast Cancer Centre. Clinical practice guidelines for the management of women with epithelial ovarian cancer. Camperdown, VIC: National Breast Cancer Centre; March 18, 2004.
Stiff PJ, Shpall EJ, Liu PY, et al. Randomized Phase II trial of two high-dose chemotherapy regimens with stem cell transplantation for the treatment of advanced ovarian cancer in first remission or chemosensitive relapse: A Southwest Oncology Group study. Gynecol Oncol. 2004;94(1):98-106.
Bengala C, Guarneri V, Ledermann J, et al. High-dose chemotherapy with autologous haemopoietic support for advanced ovarian cancer in first complete remission: Retrospective analysis from the Solid Tumour Rergistry of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation. 2005;36(1):25-31.
Tiersten A, Selleck M, Smith DH, et al. Phase I/II study of tandem cycles of high-dose chemotherapy followed by autologous hematopoietic stem cell support in women with advanced ovarian cancer. Int J Gynecol Cancer. 2006;16(1):57-64.
Goncalves A, Delva R, Fabbro M, et al. Post-operative sequential high-dose chemotherapy with haematopoietic stem cell support as front-line treatment in advanced ovarian cancer: A phase II multicentre study. Bone Marrow Transplant. 2006;37(7):651-659.
Frickhofen N, Berdel WE, Opri F, et al; German Study Groups Arbeitsgemeinschaft Internistische Onkologie (AIO); Arbeitsgemeinschaft Gynakologische Onkologie (AGO). Phase I/II trial of multicycle high-dose chemotherapy with peripheral blood stem cell support for treatment of advanced ovarian cancer. Bone Marrow Transplant. 2006;38(7):493-499.
Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol. 2007;25(3):247-256.
Pedrazzoli P, Rosti G, Secondino S, et al; European Group for Blood and Marrow Transplantation; Solid Tumors Working Party; Gruppo Italiano per il Trapianto di Midollo Osseo, Cellule Staminali Emopoietiche e Terapia Cellulare. High-dose chemotherapy with autologous hematopoietic stem cell support for solid tumors in adults. Semin Hematol. 2007;44(4):286-295.
Möbus V, Wandt H, Frickhofen N, et al. Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: Intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol. 2007;25(27):4187-4193.
Papadimitriou C, Dafni U, Anagnostopoulos A, et al. High-dose melphalan and autologous stem cell transplantation as consolidation treatment in patients with chemosensitive ovarian cancer: Results of a single-institution randomized trial. Bone Marrow Transplant. 2008;41(6):547-554.
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Bay JO, Cabrespine-Faugeras A, Tabrizi R, et al. Allogeneic hematopoietic stem cell transplantation in ovarian cancer-the EBMT experience. Int J Cancer. 2010;127(6):1446-1452.
Geller MA, Cooley S, Judson PL, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy. 2011;13(1):98-107.
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