Paclitaxel, Albumin-Bound (Abraxane) [Medicare]

Number: 0834m

Commercial CPB  |  Medicare CPB

Medicare Part B Step Therapy Criteria

Abraxane, for the indication listed below:

• Non-small cell lung cancer (NSCLC)

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of paclitaxel or docetaxel
  2. Intolerable adverse event to paclitaxel or docetaxel
  3. Paclitaxel or docetaxel is contraindicated for the member.

Policy

Note: Requires Precertification:

Precertification of Abraxane is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Abraxane for Medicare Advantage plans, call (866) 503-0857 or fax (844) 268-7263.

1. Criteria for Initial Approval

   Aetna considers albumin-bound paclitaxel (Abraxane) medically necessary for the treatment of the following indications:

   1. Kaposi sarcoma;
   2. Breast cancer - for treatment in any of the following settings:
      
      
      1. Recurrent or metastatic disease; or
      2. As a substitute for paclitaxel or docetaxel due to hypersensitivity reactions or contraindication to standard hypersensitivity premedications;
   3. Cutaneous melanoma - for treatment of metastatic or unresectable cutaneous melanoma, as a single-agent or in combination with carboplatin as second-line or subsequent therapy;
   4. Endometrial carcinoma;
   5. Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer - for treatment of persistent or recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer;
   6. Hepatobiliary cancers -  for treatment of unresectable or metastatic intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer in combination with gemcitabine;
   7. Non-small cell lung cancer (NSCLC) - for treatment in any of the following settings:
      
      
      1. Recurrent, advanced or metastatic disease; or
      2. As a substitute for paclitaxel or docetaxel due to hypersensitivity reactions or contraindication to standard hypersensitivity premedications;
   8. Pancreatic adenocarcinoma;
   9. Small bowel adenocarcinoma - for treatment of advanced or metastatic small bowel adenocarcinoma, including advanced ampullary cancer, as a single agent or in combination with gemcitabine;
   10. Uveal melanoma - for treatment of uveal melanoma, as a single-agent therapy for distant metastatic disease.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of albumin-bound paclitaxel (Abraxane) therapy medically necessary for treatment in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Abraxane (Paclitaxel, Albumin-Bound) is available for injectable suspension as lyophilized powder containing 100 mg of paclitaxel formulated as albumin-bound particles in single-use vial for reconstitution; for intravenous use.

Metastatic Breast Cancer

After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for Abraxane is 260 mg/m² administered intravenously (IV) over 30 minutes every 3 weeks.

Non-Small Cell Lung Cancer (NSCLC)

The recommended dose of Abraxane is 100 mg/m² administered as an IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Administer carboplatin on Day 1 of each 21-day cycle immediately after Abraxane.

Adenocarcinoma of the Pancreas

The recommended dose of Abraxane is 125 mg/m² administered as an IV infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after Abraxane on Days 1, 8 and 15 of each 28-day cycle.

Please note that dose adjustments vary by indication. Please see Full Prescribing Information for complete recommendations regarding dose adjustments.

Source: Celgene, 2020

Experimental and Investigational

Aetna considers albumin-bound paclitaxel (Abraxane) experimental and investigational for the following indications (not an all-inclusive list):

• Adrenocortical cancer
• Ampullary cancer (cancer of ampulla of Vater)
• Anal cancer
• Angiosarcoma
• Bladder cancer
• Bone sarcoma (chondrosarcoma, Ewing's sarcoma, and osteosarcoma)
• Cancer of unknown primary
• Cervical cancer
• Gastric cancer
• Glioma
• Head and neck cancer (including esophageal cancer regardless of the histology, nasopharyngeal carcinoma, squamous-cell carcinoma of the hypopharynx, oropharynx, and oral cavity)
• Hepatocellular cancer (HCC)
• Lymphoma
• Leiomyosarcoma
• Mesothelioma
• Multiple myeloma
• Neuroendocrine carcinoma
• Parotid cancer
• Peritoneal carcinomatosis
• Primary carcinoma of the urethra
• Prostate cancer
• Pulmonary carcinosarcoma with interstitial lung disease
• Small cell lung cancer
• Soft-tissue sarcoma
• Thymic carcinoma
• Thyroid cancer
• Upper genitourinary tract tumors
• Urothelial carcinoma of the prostate
• Vulvar carcinoma
• Wilms’ tumor.

Aetna considers hepatic arterial infusion of albumin-bound paclitaxel (Abraxane) for the treatment of metastatic melanoma to the liver experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers albumin-bound paclitaxel (Abraxane) and sintilimab combination therapy for gastric cancer, and soft tissue sarcoma experimental and investigational.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Metastatic Breast Cancer

  Abraxane is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

• Non-Small Cell Lung Cancer

  Abraxane is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

• Adenocarcinoma of the Pancreas

  Abraxane is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

Compendial Uses

• Breast cancer
• Non-small cell lung cancer
• Pancreatic adenocarcinoma
• Cutaneous melanoma
• Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer
• Kaposi sarcoma
• Endometrial carcinoma
• Hepatobiliary cancers: intrahepatic choliangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer
• Uveal melanoma
• Small bowel adenocarcinoma

Abraxane [nano-particle albumin bound (nab) paclitaxel], an antimicrotubule agent, promotes microtubule assembly from tubulin dimers and stabilizes microtubules to prevent depolymerization. This stability causes inhibition of the normal dynamic reorganization of the microtubules which is necessary for important interphase and mitotic functions in the cells.

Abraxane carries a black box warning for risk of severe myelosuppression. Abraxane (nab-paclitaxel) therapy should not be administered to patients who have baseline neutrophil counts of less than 1,500 cells/mm³. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving Abraxane. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. Do not substitute for or with other paclitaxel formulations. 

Abraxane carries the following warnings and precautions: sensory neuropthy, sepsis with or without neutropeinia when used in combination with gemcitabine, pneumonitis when used with gemcitabine, and severe hypersensitivity reactions. Exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, consider dose reduction and closely monitor patients with hepatic impairment. Abraxane contains albumin derived from human blood, which has a theoretical risk of viral transmission (Celgene, 2020).

Abraxane can cause fetal harm when administered to a pregnant woman. Based on findings in genetic toxicity and animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with Abraxane and for at least six months after the last dose of Abraxane. In addition, the safety and effectiveness of Abraxane in pediatric patients have not been evaluated (Celgene, 2020).

Adrenocortical Carcinoma

Demeure et al (2012) hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC).  SPARC is proposed to act as a mechanism for the increased efficacy of nab-paclitaxel.  In this study, the transcriptomes of 19 ACC tumors and 4 normal adrenal glands were profiled on Affymetrix U133 Plus2 expression microarrays to identify genes representing potential therapeutic targets.  Immunohistochemical analysis for target proteins was performed on 10 ACC, 6 benign adenomas, and 1 normal adrenal gland.  Agents known to inhibit selected targets were tested in comparison with mitotane in the 2 ACC cell lines (H295R and SW-13) as well as in mouse xenografts.  SPARC expression is increased in ACC samples by 1.56 +/- 0.44 fold (μ +/- standard deviation).  Paclitaxel and nab-paclitaxel showed in-vitro inhibition of H295R and SW-13 cells at IC50 concentrations of 0.33 μM and 0.0078 μM for paclitaxel and 0.35 μM and 0.0087 μM for nab-paclitaxel compared with mitotane concentrations of 15.9 μM and 46.4 μM, respectively.  In-vivo nab-paclitaxel treatment showed a greater decrease in tumor weight in both xenograft models than mitotane.  The authors concluded that biological insights garnered through expression profiling of ACC tumors merited further investigation into the use of nab-paclitaxel for the treatment of ACC.

Ampullary Carcinoma

Kapp and colleagues (2016) stated that ampullary carcinoma is a rare tumor and evidence on the treatment of recurrent metastatic disease is scarce.  These investigators reported the case of a 60-year old patient with an R0-resected node-positive adenocarcinoma of the papilla of Vater of an initially diagnosed intestinal subtype who developed pulmonary metastases 2 months after adjuvant gemcitabine chemotherapy and, subsequently, liver metastases.  Palliative combination chemotherapy with standard regimens for intestinal-type adenocarcinoma (FOLFOX and FOLFIRI) failed.  However, subsequent combination chemotherapy with nab-PTX and gemcitabine, a regimen with proven efficacy in metastatic adenocarcinoma of the pancreas, resulted in a durable, very good partial remission.  Treatment was manageable and well tolerated.  Primary tumor and metastatic tissue were re-assessed by immunohistochemistry and had to be re-classified to a mixed phenotype containing predominant elements of the pancreato-biliary subtype.  The authors concluded that the findings of this case suggested that combination chemotherapy with nab-PTX and gemcitabine could represent a promising option for the treatment of this rare disease and warrants further investigation within controlled clinical trials.  Moreover, they stated that thorough characterization of ampullary carcinomas by histo-morphology and additional immunohistochemistry should become mandatory in order to start a chemotherapeutic regimen tailored for the definitive subtype.

Anal Cancer

NCCN’s clinical practice guideline on “Anal cancer” (Version 1.2021) does not mention the use of albumin-bound paclitaxel as a therapeutic option.

Angiosarcoma

Biliary Tract Cancer

Cheon and associates (2021) stated that a recent phase-II clinical trial reported prolonged survival in patients with advanced biliary tract cancer (BTC) following treatment with nab-paclitaxel plus gemcitabine-cisplatin (Gem/Cis/nab-P). In a retrospective, multi-center study, these researchers examined the clinical outcomes of Gem/Cis/nab-P in Asian patients with advanced BTC in a real-world setting. They reviewed the data of patients who received Gem/Cis/nab-P for the management of advanced BTC between September 2019 and April 2021 at 4 centers in Korea. Patients were classified into the Gem/Cis/nab-P and nab-P addition groups depending on the starting point of nab-P administration. A total of 178 patients treated with Gem/Cis/nab-P were included in the study. Of these, 43.8 % had intra-hepatic cholangiocarcinoma (CCA), 34.8 % had extra-hepatic CCA, and 21.3 % had gall bladder cancer. A total of 117 (65.7 %) patients received Gem/Cis/nab-P as the 1st-line treatment, while 61 (34.3 %) were treated with gemcitabine-cisplatin-based chemotherapy followed by nab-P addition. The ORR and disease control rate (DCR) in all patients were 42.1 % and 84.8 %, respectively. The ORR in the Gem/Cis/nab-P group was 47.9 %, while that in the nab-P addition group was 31.1 %. The median PFS and OS were 8.5 months (95 % CI: 6.9 to 10.1) and 14.6 months (95 % CI: 10.2 to 19.0), respectively. In patients who received Gem/Cis/nab-P as initial treatment, the median PFS was 9.4 months (95 % CI: 7.9 to 10.9) and the median OS was not-reached (95 % CI: not available). Anemia (n = 42, 23.6 %), neutropenia (n = 40, 22.5 %), and thrombocytopenia (n = 16, 9.0 %) were the most common grade 3 to 4 toxicities. A total of 20 patients (11.2 %) had conversions from unresectable to resectable disease and underwent surgery with curative intent. The authors concluded that Gem/Cis/nab-P showed favorable real-life safety and effectiveness outcomes in Korean patients with advanced BTC, which was consistent with the phase-II trial outcomes. Moreover, these researchers stated that It is necessary to confirm the long-term survival outcomes of patients who receive Gem/Cis/nab-P chemotherapy through a phase-III clinical trial.

The authors stated that this study had several drawbacks. First, this trial was retrospective in design; thus, subject to unintentional bias. Second, the follow-up duration was short to allow evaluation of the long-term survival of patients who received Gem/Cis/nab-P chemotherapy. Third, the patients’ treatment courses were heterogeneous in terms of the starting dose, prior systemic therapy (Gem/Cis-based regimen), and timing of nab-P administration.

Jung and colleagues (2022) noted that advanced BTC is associated with poor survival. A recent phase-II clinical trial of triplet combination chemotherapy (gemcitabine, cisplatin, and nab-paclitaxel) has shown promising results. These researchers compared the effectiveness of triplet and standard doublet chemotherapy in a real-world setting. Patients with advanced BTC treated with triplet and doublet chemotherapy regimens were recruited. The propensity-score nearest neighbor matching method with a ratio of 1:1 was used to create a matched cohort for comparison; PFS, OS, and safety profiles were examined in both groups. A total of 68 patients (n = 34 per group) were included in the matched cohort, and their baseline characteristics were well balanced. Survival outcomes in the triplet chemotherapy group were not better than those in the doublet chemotherapy group, with a median PFS of 7.5 months (95 % CI: 4.1 to 10.9) versus 7.2 months (95 % CI: 5.6 to 8.9) (HR, 0.93; 95 % CI: 0.53 to 1.62; p = 0.793) and a median OS of 13.7 months (95 % CI: 8.8 to 18.7) versus 12.2 months (95 % CI: 8.4 to 16.0) (HR 0.73; 95 % CI: 0.38 to 1.41; p = 0.354), respectively. Furthermore, the treatment-related severe AEs 9e.g., neutropenia) were more common in the triplet chemotherapy group. The authors concluded that gemcitabine, cisplatin, and nab-paclitaxel did not improve the PFS or OS compared to that achieved by standard chemotherapy in patients with advanced BTC. These researchers stated that the benefits of triplet chemotherapy in advanced BTC require examination in large RCTs.

Bladder Cancer

In a phase I study, McKiernan et al (2011) evaluated the DLT and maximum deliverable dose of intra-vesical nab-paclitaxel in patients with non-muscle invasive bladder cancer.  Inclusion criteria for trial were recurrent high-grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intra-vesical regimen failed.  Six weekly instillations of nab-paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved.  The primary end point was DLT and the secondary end point was RR.  A total of 18 patients were enrolled in the study.  One patient demonstrated measurable systemic absorption after 1 infusion.  Grade 1 local toxicities were experienced by 10 (56 %) patients with dysuria being the most common, and no grade 2, 3 or 4 drug-related local toxicities were encountered.  Of the 18 patients, 5 (28 %) had no evidence of disease at post-treatment evaluation.  The authors concluded that intra-vesical nab-paclitaxel exhibited minimal toxicity and systemic absorption in the first human intra-vesical phase I trial.  They stated that a larger phase II study has begun to formally evaluate the activity of this regimen.

Bone Sarcoma

Wagner et al (2014) stated that the combination of docetaxel and gemcitabine is frequently used to treat recurrent bone sarcoma. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is less toxic and more active than docetaxel or paclitaxel for breast cancer patients. The combination of nab-paclitaxel and gemcitabine has pre-clinical synergy and is approved to treat pancreatic cancer. These researchers observed growth inhibition and improved survival with nab-paclitaxel in a Ewing sarcoma xenograft, and activity was additive with gemcitabine in an osteosarcoma model. Primary Ewing sarcoma tumors expressed the transport protein SPARC, previously associated with nab-paclitaxel activity. The authors concluded that these findings provided rationale for further evaluation of nab-paclitaxel with gemcitabine for bone sarcoma.

Breast Cancer

Taxanes are conventional treatment for metastatic breast cancer (MBC); however, the solvents (e.g., ethanol and polyoxyethylated castor oil) employed as vehicles in these formulations result in severe toxicities.  The Food and Drug Administration (FDA) approved a solvent-free formulation of paclitaxel for the treatment of MBC that uses 130-nanometer albumin-bound (nab) technology (Abraxane; nab-paclitaxel) to circumvent the requirement for solvents.  Nab-paclitaxel utilizes the natural properties of albumin to reversibly bind paclitaxel, transport it across the endothelial cell, and concentrate it to the areas of the tumor.  The proposed mechanism of drug delivery entails glycoprotein 60-mediated endothelial cell transcytosis of paclitaxel-bound albumin as well as accumulation in the areas of the tumor by albumin binding to SPARC (secreted protein, acidic and rich in cysteine; an albumin-binding matrix-associated protein).  Published reports have shown that nab-paclitaxel is markedly more effective than paclitaxel formulated as cremophor EL (CrEL, Taxol), with almost double the response rate (RR), increased time to disease progression and increased overall survival (OS) in second-line patients.  The absence of CrEL from the formulation is associated with decreased neutropenia and rapid improvement of peripheral neuropathy with nab-paclitaxel, compared with CrEL-paclitaxel.  For these reasons, nab-paclitaxel can be infused using higher doses of paclitaxel than that achievable with CrEL-paclitaxel, with shorter infusion duration and without the requirement for corticosteroid and anti-histamine pre-medication to reduce the risk of solvent-mediated hypersensitivity reactions (Gradishar, 2006).  In January 2005, the FDA approved albumin-bound paclitaxel (Abraxane) for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.  Prior therapy should have included an anthracycline unless clinically contraindicated.

Yamamoto et al (2011) stated that nab-paclitaxel displays greater anti-tumor activity and less toxicity than solvent-base paclitaxel.  In a phase I trial of nab-paclitaxel (single agent activity), the maximum tolerated dose (MTD) was 300 mg/m2 with the dose limiting toxicities (DLT) being sensory neuropathy, stomatitis, and superficial keratopathy.  In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over a 30-min infusion without pre-medication every 3 weeks) mediated a superior objective response rate (ORR) and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hr injection with standard pre-medication).  The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group.  However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction.  Weekly administration of nab-paclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given tri-weekly.  The authors noted that nab-paclitaxel has already been approved in 42 countries for the treatment of MBC previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting.

Cancer of Unknown Primary

NCCN’s clinical practice guideline on “Occult Primary (Cancer of Unknown Primary (CUP)” (Version 2.2021) does not mention the use of albumin-bound paclitaxel as a therapeutic option.

Esophageal Cancer

Shi and colleagues (2013) examined the safety and effectiveness of Nab-PTX combined with cisplatin (DDP) in patients with metastatic esophageal SCC (ESCC).  Patients with histologically confirmed ESCC were treated with Nab-PTX 250 mg/m(2) and DDP 75 mg/m(2) intravenously on day 1, every 21 days.  Evaluation was performed after every 2 cycles of therapy and the therapy was continued until disease progression or unacceptable toxicity.  From April 2010 to December 2012, a total of 33 patients were enrolled – 10 patients had recurrent and metastatic tumors after surgery and 23 patients were diagnosed with unresectable metastatic disease.  Patients received a median of 4 cycles of therapy (ranging from 2 to 6 cycles).  Twenty patients achieved PR and 9 patients achieved SD; no CR was observed.  The objective response rate was 60.6 % and the disease control rate was 87.9 %.  The median PFS was 6.2 months (95 % CI: 4.0 to 8.4 months) and the median OS was 15.5 months (95 % CI: 7.6 to 23.4 months).  Only 4 patients experienced grade 3 adverse events, including vomiting, neutropenia, and sensory neuropathy.  The most common adverse events were nausea/vomiting (81.8 %), neutropenia (63.6 %), leucopenia (48.5 %), anemia (24.2 %) and sensory neuropathy (24.2 %).  The authors concluded that the combination of Nab-PTX and DDP is a highly effective and well-tolerated first-line treatment in metastatic ESCC.  The findings of this study were confounded by the combinational use of albumin-bound paclitaxel and cisplatin.  The clinical value of albumin-bound paclitaxel in the treatment of metastatic esophageal squamous cell carcinoma needs to be ascertained in well-designed studies.

Gastric Cancer

Zhang et al (2013) noted that gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease.  In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied.  Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51 μM) and epirubicin (0.12 μM to 0.25 μM).  Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3.  After a 2-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in-vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 %, respectively (p = 0.002).  Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues.  There was an increase in median animal survival after Nab-PTX treatment (93 days) compared to controls (31 days, p = 0.0007), oxaliplatin (40 days, p = 0.0007) or to docetaxel therapy (81 days, p = 0.0416).  The strong anti-tumor activity of Nab-PTX in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application.  Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of Nab-PTX use in gastric cancer based on this putative biomarker.

Nakasya and colleagues (2022) noted that paclitaxel plus ramucirumab (PTX + RAM) is the standard 2nd-line chemotherapy for unresectable advanced or recurrent gastric cancer (AGC). Nanoparticle albumin-bound paclitaxel (nab-PTX) is an improved, more convenient form of PTX and is non-inferior to PTX. Although some retrospective and single-arm phase-II clinical trials regarding nab-PTX + RAM have been reported, comparative studies are lacking. In a retrospective, non-randomized study, these researchers compared the efficacy and toxicity of nab-PTX + RAM and PTX + RAM using propensity score matching. Clinical data of 265 patients treated for AGC with nab-PTX + RAM or PTX + RAM were retrospectively collected. Nab-PTX was administered at dosages of 100 mg/m2, replacing PTX in the standard PTX + RAM regimen; PFS, OS, and toxicity were compared using 1:1 propensity score matching. A total of 190 (72 %) patients were matched. The median PFS was 5.3 (95 % CI: 4.4 to 6.3) and 4.7 (95 % CI: 3.2 to 5.3) months in the nab-PTX + RAM and PTX + RAM groups, respectively [HR = 0.76, 95 % CI: 0.56 to 1.03, p = 0.07]. The median OS was 11.5 (95 % CI: 9.2 to 15.0) and 9.9 (95 % CI: 8.0 to 12.7) months, respectively (HR = 0.78, 95 % CI: 0.56 to 1.07, p = 0.12). Grade-3 and grade-4 neutropenia was observed more frequently in the nab-PTX + RAM group (72 % versus 56 %, p = 0.03). No treatment-related deaths occurred. The authors concluded that nab-PTX + RAM exhibited more favorable trends in terms of PFS and OS but was more myelosuppressive than PTX + RAM. Moreover, these researchers stated that as neutropenia is commonly manageable toxicity, nab-PTX + RAM presents a treatment alternative for AGC. Moreover, these researchers stated that further studies including RCTs are needed.

The authors stated that this study had 2 main drawbacks. First, this was a retrospective, non-randomized study, and the sample size was small. Although these researchers employed propensity score matching to balance the patient background characteristics in the treatment groups, they could not adjust for unmeasured confounding factors, which might have affected the results. Furthermore, the sample size shrank further when matched pairs were made, which weakened the statistical power. Second, the difference in proportion receiving post-study treatment might have partly affected OS. Considering this bias, OS data should be interpreted with caution.

Glioma

Zhang and colleagues (2020) stated that paclitaxel showed little benefit in the treatment of glioma due to poor penetration across the blood-brain barrier (BBB).  Low-intensity pulsed ultrasound (LIPUS) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain.  These investigators examined the distribution, toxicity, and efficacy of LIPUS delivery of 2 different formulations of paclitaxel, ABP and paclitaxel dissolved in cremophor (CrEL-PTX), in pre-clinical glioma models.  The efficacy and biodistribution of ABP and CrEL-PTX were compared with and without LIPUS delivery.  Anti-glioma activity was evaluated in nude mice bearing intra-cranial patient-derived glioma xenografts (PDX).  Paclitaxel biodistribution was determined in sonicated and non-sonicated nude mice.  Sonication was performed using a 1-MHz LIPUS device (SonoCloud), and fluorescein was used to confirm and map BBB disruption.  Toxicity of LIPUS-delivered paclitaxel was assessed through clinical and histologic examination of treated mice.  Despite similar anti-glioma activity in-vitro, ABP extended survival over CrEL-PTX and untreated control mice with orthotropic PDX.  US-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABP.  Repeated courses of LIPUS-delivered CrEL-PTX and CrEL alone were lethal in 42 % and 37.5 % of mice, respectively, whereas similar delivery of ABP at an equivalent dose was well-tolerated.  The authors concluded that US delivery of paclitaxel across the BBB was a feasible and effective treatment for glioma; ABP was the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.

Head and Neck Cancer

Damascelli et al (2007) studied the safety and effectiveness of intra-arterial induction chemotherapy with nab-paclitaxel in advanced head and neck cancer.  A total of 60 previously untreated patients with locally advanced squamous-cell carcinoma (SCC) of the oral cavity, oropharynx, or hypopharynx in stage T3/T4 and any nodal stage received 2 to 4 cycles of nab-paclitaxel by infusion into the external carotid artery or one of its branches, without pre-medication, at an initial dose of 230 mg/m2 and subsequently a reduced dose of 150 mg/m2.  Response was evaluated by physical examination and multi-detector computed tomography in all patients, and also by positron emission tomography with [18F]fluorodeoxyglucose in 38 patients.  Definitive treatment was surgery, chemotherapy, radiation therapy, or chemo-radiation therapy.  Intra-arterial chemotherapy had a low incidence of complications and produced CR or PR in 45 of 60 treated patients (75 %).  Seven patients (11.67 %) had SD and 8 (13.33%) had progressive disease (PD).  High-grade bone marrow depression was rare.  An unexpected toxicity was reversible facial nerve palsy on the side of infusion, which occurred in 6 patients at initial dosage.  Reduction of the dose eliminated this specific toxicity without any loss of efficacy.  The authors concluded that the promising response rates and tolerability of intra-arterial chemotherapy with nab-paclitaxel justify further investigation of this formulation, alone or in combination with other agents, in advanced SCC of the head and neck.

Desai et al (2009) noted that SPARC up-regulation is a poor prognostic factor in head and neck cancer.  It was hypothesized that because of a SPARC-albumin interaction, tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of nab-paclitaxel.  These researchers tested this hypothesis by correlating the response to nab-paclitaxel and SPARC tumor expression in a retrospective analysis of a 60-patient clinical study of nab-paclitaxel as monotherapy against head and neck cancer.  A total of 16 tumor specimens were available for analysis.  There were 11 responders (CR/PR) and 5 non-responders (SD/PD) among the 16 nab-paclitaxel-treated patients (12/16 SPARC-positive, 75 %).  Response to nab-paclitaxel was higher for SPARC-positive patients (10/12, 83 %) than SPARC-negative patients (1/4, 25 %).  The SPARC-negative patients exhibited significantly lower response than the ORR among all 60 patients (1/4, 25 % versus 45/60, 75 %).  The authors concluded that although preliminary, data are supportive of the hypothesis that SPARC over-expression may correlate with response to nab-paclitaxel.  They stated that if confirmed in larger studies, treatment with nab-paclitaxel may convert a poor prognosis SPARC-positive patient population into a group with better clinical outcomes.

Adkins et al (2013) stated that CR at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisplatin and 5-fluorouracil [5-FU]) is a favorable predictive factor for OS and disease control in patients with locally advanced squamous cell carcinoma of the head and neck.  In most series, the rate of CR at the primary site after induction PF was 20 % to 30 %.  These researchers evaluated the effectiveness and feasibility of induction nanoparticle albumin-bound paclitaxel (Nab-PTX) and cetuximab given with PF (ACPF) followed by definitive chemo-radiation therapy (CRT) in a phase II trial.  Patients with squamous cell carcinoma of the head and neck were treated with ACPF (Nab-PTX 100 mg/m(2)/week; cetuximab 250 mg/m(2)/week; cisplatin 75 mg/m(2) on day 1; 5-FU 750 mg/m(2)/day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m(2) on days 1, 22, and 43 of RT).  Complete response at the primary tumor site after 2 cycles of ACPF was the primary end-point.  A total of 30 patients were enrolled, of which 22 (73 %) had large (T3/T4) primary tumors.  The CR rate at the primary tumor site after 2 cycles of ACPF was 53 % and the overall response rate was 100 %.  Twenty-nine (96 %) patients completed 3 cycles of ACPF, 26 (90 %) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81 %) received greater than 2 of the 3 planned doses of cisplatin with RT.  The estimated 2-year OS and PFS rates were 84 % and 65 %, respectively.  The authors concluded that induction ACPF resulted in a high CR rate (53 %) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT.  Moreover, they stated that further investigation of ACPF is warranted.

Hepatic Arterial Infusion

Fu and associates (2011) stated that liver involvement in patients with metastatic cancer has limited options and poor outcomes.  In a phase I clinical trial, these researchers examined the safety, activity, and pharmacokinetic characteristics of hepatic arterial infusion (HAI) of nab-paclitaxel.  Cohorts of 3 patients having predominant hepatic metastases received HAI nab-paclitaxel at 3 dose levels (180, 220, and 260 mg/m2, respectively) infused for more than 1 hr every 3 weeks (3 + 3 design).  Some patients participated in comparative pharmacokinetic studies (i.v. versus HAI), receiving their first course i.v., to determine peak concentrations and effect of first-pass hepatic extraction compared with subsequent courses administered by HAI.  The highest dose level was expanded to determine the safety and activity of HAI nab-paclitaxel.  A total of 38 patients were treated.  There were no DLT  at doses up to 260 mg/m2.  Common adverse events included alopecia, fatigue, myelosuppression, nausea, and vomiting.  Three patients had SD for 4 or more months and 2 patients (1 of 12 with breast cancer and 1 of 1 with cervical cancer) achieved a PR lasting for 5 and 15 months, respectively.  Peak concentrations were lower (approximately 50 %) with greater hepatic extraction of drug (approximately 42 %) following HAI than i.v. infusion based on AUC comparison of drug exposure.  The authors stated that HAI nab-paclitaxel showed partial hepatic extraction.  At doses 260 mg/m2 or less given for 1 hr every 3 weeks, the treatment was well-tolerated and showed activity in advanced cancer patients with predominant liver metastases.

Hepatic Arterial Infusion of Nab-Paclitaxel Metastatic Melanoma to the Liver

Vera-Aguilera and associates (2018) stated that hepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anti-cancer therapy to liver metastases that derive their blood supply from the hepatic artery.  Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination; nab-paclitaxel has demonstrated efficacy in MM and first-pass hepatic metabolism.  Therefore, these researchers hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end-organ of interest, with minimal systemic exposure.  These investigators performed a single-institution, open-label, phase I/II clinical trial of HAI of nab-paclitaxel in MM patients with liver metastasis.  Patients received treatment every 21 days at 4 different dose levels.  The primary objective of the phase I portion of the study was safety and determination of the MTD.  The primary objective of the phase II portion of the study was ORR per RECIST 1.0.  A total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma.  The MTD was 220 mg/m and 19 patients were treated at this dose.  There was 1 patient (5 %) with a PR at this dose, and 8 patients (42 %) with SD at this dose.  The authors concluded that HAI nab-paclitaxel demonstrated rare objective responses in melanoma patients with liver metastases. Moreover, they stated that this treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses; but should not be considered effective monotherapy.

Hepatobiliary Cancers

Shroff et al. (2019) report on a phase 2 clinical trial that found treatment of advanced biliary tract cancers with nab-paclitaxel plus gemcitabine-cisplatin prolonged median progression-free survival and overall survival vs those reported for historical controls treated with gemcitabine-cisplatin alone. This open-label, single-arm, phase 2 clinical trial conducted at the University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Arizona, enrolled 62 patients with advanced biliary tract cancers between April 14, 2015, and April 24, 2017. Patients initially received gemcitabine, 1000 mg/m2, cisplatin, 25 mg/m2, and nab-paclitaxel, 125 mg/m2, on days 1 and 8 of 21-day cycles. Owing to hematologic adverse events among the first 32 patients enrolled, these starting doses were reduced to 800, 25, and 100 mg/m2, respectively, for the remaining 28 patients. The primary trial end point was investigator-assessed progression-free survival in the intention-to-treat population. Of 60 patients who started treatment, 38 (63%) had intrahepatic cholangiocarcinoma, 9 (15%) had extrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, 47 (78%) had metastatic disease, and 13 (22%) had locally advanced disease. Median follow-up was 12.2 months, and median progression-free survival was 11.8 months. The partial response rate was 45%, and the disease control rate was 84%. Median overall survival was 19.2 months. Patients in the safety population (n = 57) received a median of 6 (interquartile range, 3-11) cycles of treatment; 26 patients (46%) remained on their starting dose throughout the trial. Grade 3 or higher adverse events occurred in 58% of patients, and 9 patients (16%) withdrew owing to adverse events. Neutropenia was the most common grade 3 or higher adverse event, occurring in 19 patients (33%) overall. Post hoc analyses showed that treatment efficacy was not significantly associated with starting dose, tumor type, or disease status and that tolerability was improved with reduced- vs high-dose treatment. The authors state that these findings will be tested in a phase 3 randomized clinical trial.

Lymphoma

Goyal and colleagues (2017) noted that compared with solvent-based taxanes, nab-paclitaxel has demonstrated tolerability and improved effectiveness in several solid tumor malignancies.  Studies evaluating nab-paclitaxel in patients with lymphoma are lacking.  In this phase-I/phase-II clinical trial, these researchers determined the safety and effectiveness of nab-paclitaxel in patients with relapsed/refractory (R/R) lymphoma.  Eligible patients (R/R to greater than or equal to 2 prior systemic therapies) received weekly nab-paclitaxel on days 1, 8 and 15 every 28 days.  Dosing was initiated at 100 mg/m2 with dose escalations in 25 mg/m2 increments up to 150 mg/m2 in a classic 3 + 3 design.  A total of 20 heavily pre-treated patients (median 5 prior regimens), including 65 % with refractory disease, enrolled.  The maximum dose tested was well-tolerated and grade 3/4 hematologic adverse events (AEs; neutropenia 25 %, thrombocytopenia 20 % and anemia 15 %) were modest.  The ORR was 10 % with 2 PRs, leading to a decision to close the study prematurely.

Mesothelioma

Kanai and associates (2016) stated that malignant pleural mesothelioma (MPM) is a rare tumor with a poor prognosis.  Although cisplatin plus pemetrexed is the standard chemotherapy for patients with unresectable MPM, few agents are available for MPM patients who do not tolerate pemetrexed.  These investigators reported the 1st case of an MPM patient for whom the combination of nanoparticle albumin-bound paclitaxel and carboplatin (nabPC) repetitively achieved tumor regression.  A 76-year old man was diagnosed with epithelioid MPM; 1 cycle of carboplatin plus pemetrexed and 2 cycles of gemcitabine were administered but failed to inhibit tumor progression.  By contrast, 4 cycles of nabPC resulted in a good response.  Upon disease progression, 4 cycles of nabPC were performed again and resulted in a modest response.  The authors concluded that based on the present case, nabPC is a potential alternative chemotherapeutic agent for MPM, especially for MPM patients who do not tolerate pemetrexed.

Multiple Myeloma

In a phase II clinical trial, Hersh et al (2010) evaluated the safety and effectiveness of nab-paclitaxel in previously treated (PT) and chemotherapy-naive (CN) patients with metastatic melanoma (MM).  Patients with histologically or cytologically confirmed, measurable MM were enrolled.  Nab-paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m2 (in PT patients) or 150 mg/m2 (in CN patients).  A total of 37 patients were treated in each cohort.  The RR was 2.7 % in the PT cohort and 21.6 % in the CN cohort; the response plus SD rate was 37.8 % and 48.6 % in the PT and CN cohorts, respectively.  The median PFS was 3.5 months and 4.5 months, and the median OS was 12.1 months and 9.6 months, respectively.  The probability of being alive and free of disease progression at 6 months was 27 % for the PT cohort and 34 % for the CN cohort; the probability of surviving 1 year was 49 % and 41 %, respectively, for the PT and CN cohorts.  Approximately 78 % of the PT patients and 49 % of the CN patients were treated without dose reduction.  Eight (22 %) CN patients discontinued therapy because of toxicities.  Drug-related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue.  The authors concluded that nab-paclitaxel was found to be well-tolerated and demonstrated activity in both PT and CN patients with MM.  The RR, PFS, and OS compared favorably with current standard dacarbazine therapy and combination therapies for melanoma.  They stated that nab-paclitaxel therapy of MM should be investigated further in controlled clinical trials.

Kottschade et al (2011) noted that there is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of MM.  ABI-007 is an albumin-bound formulation of paclitaxel that has demonstrated single-agent activity against MM.  In a parallel phase II trial, these researchers examined the effects of nab-paclitaxel in patients with unresectable stage IV melanoma who were either CN or PT.  The treatment regimen consisted of ABI-007 (100 mg/m2) and carboplatin AUC administered on days 1, 8, and 15 every 28 days.  The primary aim of this study was ORR (RECIST).  A total of 76 patients (41 CN and 35 PT) were enrolled between November 2006 and July 2007.  Three patients withdrew consent prior to starting treatment.  The median number of treatment cycles was 4.  There were 10 (25.6 %) responses (1 CR and 9 PR) in the CN cohort (90 % CI: 16.7 % to 42.3 %) and 3 (8.8 %) responses (3 PR) in the PT cohort (90 % CI: 2.5 % to 21.3 %).  Median PFS was 4.5 months in the CN cohort and 4.1 months in the PT cohort.  Median OS was 11.1 months in the CN group and 10.9 months in the PT group.  Severe toxicities in both groups (Common Terminology Criteria for Adverse Effects version 3.0 greater than or equal to grade 3) included neutropenia, thrombocytopenia, neurosensory problems, fatigue, nausea, and vomiting.  The authors concluded that the weekly combination of ABI-007 and carboplatin appears to be moderately well-tolerated, with promising clinical activity as therapy in patients who are chemotherapy naive and with modest anti-tumor activity in those previously treated.

Kottschade et al (2013) conducted a phase 2 trial in chemotherapy-naive patients with unresectable stage IV MM who were randomized to temozolomide (200 mg/m(2) on days 1 through 5) and bevacizumab (10 mg/kg intravenously on days 1 and 15) every 28 days (Regimen TB) or Nab-PTX (100 mg/m(2), or 80 mg/m(2) post-addendum 5 secondary to toxicity, on days 1, 8, and 15), bevacizumab (10 mg/kg on days 1 and 15), and carboplatin (area under the curve [AUC] 6 on day 1, or AUC 5 post-addendum 5) every 28 days (Regimen ABC).  Accrual goal was 41 patients per regimen.  The primary aim of this study was to estimate PFS rate at 6 months (PFS6) in each regimen.  A regimen would be considered promising if its PFS6 rate was greater than 60 %.  A total of 93 eligible patients (42 TB and 51 ABC) were enrolled.  The majority of patients had M1c disease (20 TB and 26 ABC).  The median PFS and OS times with ABC were 6.7 months and 13.9 months, respectively.  Median PFS time and median OS with TB were 3.8 months and 12.3 months, respectively.  The most common severe toxicities (greater than or equal to grade 3) in both regimens were cytopenias, fatigue, and thrombosis.  Among the first 41 patients enrolled onto each regimen, PFS6 rate was 32.8 % (95 % CI: 21.1 % to 51.2 %) for TB and 56.1 % (90 % CI: 44.7 % to 70.4 %) for ABC.  The authors concluded that the addition of bevacizumab to Nab-PTX and carboplatin showed promising activity despite tolerability issues.

Albumin-bound paclitaxel is also being studied in other types of cancers such as adrenocortical cancer, angiosarcoma, bladder cancer, endometrial cancer, head and neck cancer (including squamous-cell carcinoma of the hypopharynx, oropharynx, and oral cavity), hepatocellular cancer, and prostate cancer.  However, the effectiveness of albumin-bound paclitaxel in these cancers has not been established.

Multiple Myeloma, Neuroendocrine Carcinoma, Peritoneal Carcinomatosis and Soft-Tissue Sarcoma

Van De Sande and colleagues (2018) stated that nanoparticles hold considerable promise for aerosol-based intra-peritoneal delivery in patients with carcinomatosis.  Recently, results from pre-clinical and early clinical trials suggested that albumin-bound paclitaxel (ABP, Abraxane) may result in superior efficacy in the treatment of peritoneal metastases (PM) compared to the standard solvent-based paclitaxel formulation (Taxol).  These researchers proposed a phase-I clinical trial of pressurized intra-peritoneal aerosol chemotherapy (PIPAC) using ABP in patients with breast, ovarian, or upper gastro-intestinal (GI) cancer.  Eligible patients with advanced, biopsy-proven PM from breast, ovarian, gastric, hepatobiliary, or pancreatic origin will undergo 3 PIPAC treatments using ABP with a 4-week interval.  The dose of ABP will be escalated from 35 to 140 mg/m² using a Bayesian approach until the MTD is determined.  The primary end-point is DLT; secondary analyses include surgical morbidity, non-access rate, pharmacokinetic and pharmacodynamic analyses, quality of life (QOL), and exploratory circulating biomarker analyses.  The authors concluded that ABP holds considerable promise for intra-peritoneal aerosol delivery.  The aim of this study is to determine the dose level for future randomized phase-II clinical trials using ABP in PIPAC therapy.

Higuchi and associates (2019) noted that undifferentiated / unclassified soft-tissue sarcomas (USTS) is recalcitrant neoplasms that is usually treated with doxorubicin (DOX)-containing regimens as 1st-line therapy.  Nanoparticle albumin-bound paclitaxel (nab-PTX) is a nanotechnology-based drug and is widely used in pancreatic cancer in combination with gemcitabine (GEM).  These researchers examined the efficacy of nab-PTX in combination with GEM, compared to conventional drugs such as docetaxel (DOC), GEM combined with DOC, or 1st-line drug DOX on a USTS not-otherwise specified (USTS / NOS) from a striated muscle implanted in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model.  USTS PDOX models were randomized into 6 groups: untreated control; DOX; DOC; nab-PTX; GEM combined with DOC; and GEM combined with nab-PTX.  Tumor size and body weight were measured.  Tumor growth was inhibited to the greatest extent by GEM combined with nab-PTX.  Tumors treated with GEM combined with nab-PTX had the most necrosis.  Body weight of the treated mice was not significantly different from the untreated controls.  The authors concluded that the findings of this study demonstrated the power of the PDOX model to identify a novel effective treatment strategy of the combination of GEM and nab-PTX for recalcitrant soft-tissue sarcomas; and these results suggested that combination of GEM and nab-PTX could be a promising therapeutic strategy for USTS.

Nab-Paclitaxel for Metastatic Breast Cancer

Lu and colleagues (2021) stated that although various clinical trials and real-life studies have examined the value of nab-paclitaxel mono-chemotherapy for MBC, the safety and effectiveness of nab-paclitaxel remain unclear; and need to be systematically evaluated. These investigators carried out electronic searches for prospective clinical trials evaluating nab-paclitaxel monotherapy for MBC. Requisite data were extracted, integrated and analyzed from the included studies according to the different study designs using systematic review and meta-analysis. Meta-regression and subgroup analysis were further performed to examine the potential risk factors affecting each individual outcome of interest following nab-paclitaxel monotherapy. A total of 22 studies with 3,287 MBC patients were included. A total of 1,685 MBC patients received nab-paclitaxel as 1st-line therapy, 640 patients as further-line therapy, and 962 patients as mixed-line therapy. A total of 1,966 MBC patients (60.40 %) received nab-paclitaxel weekly, 1,190 patients (36.56 %) received nab-paclitaxel tri-weekly and 99 patients (3.04 %) received nab-paclitaxel bi-weekly. The overall incidence rates of all-grade neutropenia, leukopenia, peripheral sensory neuropathy, and fatigue were 52 % (95 % CI: 38 % to 66 %, I2 = 98.97 %), 58 % (95 % CI: 43 % to 73 %, I2 = 97.72 %), 58 % (95 % CI: 48 % to 68 %, I2 = 97.17 %), and 49 % (95 % CI: 41 % to 56 %, I2 = 94.39 %), respectively. The ORR was 40 % (95 % CI: 35 % to 45 %, I2 = 98.97 %), and the clinical benefit rate (CBR) was 66 % (95 % CI: 59 % to 73 %, I2 = 98.97 %) following nab-paclitaxel monotherapy. The median PFS was 7.64 months (95 % CI: 6.89 to 8.40 months, I2 = 92.3 %), and the median OS was 24.51 months (95 % CI: 21.25 to 27.78 months, I2 = 92.7 %). Treatment line, HER2-negative status and dosage were found to be sources of heterogeneity among the included studies. According to the meta-regression and subgroup analysis, grade 3/4 neutropenia occurred less frequently in HER2-negative patients than in the entire population (p = 0.046). Patients who received 1st-line nab-paclitaxel monotherapy showed a higher ORR (p = 0.006) and longer PFS (p = 0.045). Efficacy outcomes were not affected by the administration schedule; however, within the same schedule, patients appeared to have a superior ORR (p = 0.044) and longer PFS (p = 0.03) with an increasing dosage of nab-paclitaxel administered. The authors concluded that the benefits brought by nab-paclitaxel mono-chemotherapy in the treatment of MBC were considerable while the harm was generally manageable. Moreover, these researchers stated that in consideration of the substantial heterogeneity among included studies, further study and validation are needed to determine the roles which the dosage, schedule and other factors play actually in nab-paclitaxel chemotherapy.

The authors stated that this study had several drawbacks. First, despite the included studies were designed prospectively, some publications were not of high quality. Second, the strength of part of the conclusions these researchers came to were limited due to the significant heterogeneity encountered, the publication bias and the lack of statistical difference. Third, the HER2-negative population, nab-paclitaxel dosage and treatment line were demonstrated to be potential sources of heterogeneity among studies; however, other sources of heterogeneity still existed. Fourth, several characteristics of the MBC patients, such as race, menopausal status, and different metastatic sites, were not extracted or analyzed, which might lead to uncomprehensive results.

Xie and associates (2021) noted that visceral metastases account for 48 % to 67 % of MBC patients and presage a worse OS. Previous study suggested potential effect of nab-paclitaxel on patients with visceral metastases subgroups. In a prospective, single-center, open-label, phase-II clinical trial, these researchers examined the safety and effectiveness of nab-paclitaxel in such a high-risk group of patients. This trial included MBC patients with visceral metastases (n = 80); they received nab-paclitaxel (Abraxane, 125 mg/m2, D1, D8, D15 every 28 days). The median PFS was 5.1 months (95 % CI: 4.2 to 6.0 months), with an ORR of 33.8 % (95 % CI: 21.3 to 43.8 %) and CBR of 66.2 % (95 % CI: 56.3 to 75.0 %). In univariate analysis, patients with pre-menopausal status had a trend of better treatment outcome. Multi-variate analysis demonstrated non brain metastasis (adjusted HR 0.31, 95 % CI: 0.12 to 0.83, p = 0.019) and 1st-line treatment (adjusted HR 0.37, 95 % CI: 0.17 to 0.81, p = 0.013) as independent predictors of longer PFS. The overall safety was acceptable with most common treatment-related, grade greater than or equal to 3 toxicities of neutropenia (16.3 %) and sensory neuropathy (3.7 %). The authors concluded that this phase-II clinical trial documented satisfactory safety and effectiveness of nab-paclitaxel in MBC patients with visceral metastases, providing evidence for relative clinical practice. Patients in 1st-line therapy had better treatment outcome. For patients with pre-menopausal status or brain metastasis, further alternatives (e.g.,, combined chemotherapy or targeting therapy) might be needed. This study also demonstrated the safety and effectiveness of 125 mg/m2 nab-paclitaxel among Asian patients.

Taira and co-workers (2022) reported their findings on QOL in a randomized phase-II clinical trial to determine the optimal dose of 3-week cycle nab-paclitaxel (q3w nab-PTX) in patients with MBC. Patients with HER2-negative MBC were randomly assigned to 3 different doses of q3w nab-PTX (SD 260 mg/m2 versus MD: 220 mg/m2 versus LD 180 mg/m2). QOL was assessed at baseline and during the 2nd, 4rth and 6th courses of treatment using the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), Cancer Fatigue Scale (CFS) and EuroQol 5-Dimension (EQ-5D). Comparisons were carried out with mixed-model repeated measures (MMRM). A total of 141 patients were enrolled in the parent study, and 136 (96 %) (44, 45 and 47 in the SD, MD, and LD groups, respectively) were included in the analysis. MMRM analysis showed that the difference from the baseline FACT-Taxane trial outcome index at MD and LD were significantly higher than that at SD (MD versus SD, p < 0.001, LD versus SD, p < 0.001). Differences from baseline for FACT-Taxane total, physical and emotional well-being, and taxane subscale scores at MD and LD were also higher than at SD. The difference from baseline for the CFS score at LD was lower than at SD (p = 0.013) and those for EQ-5D utility scores at MD and LD were higher than at SD (MD versus SD, p = 0.011, LD versus SD, p < 0.001). The authors concluded that QOL of patients treated with 220 or 180 mg/m2 of q3w nab-PTX was significantly better than that of patients treated with 260 mg/m2. Moreover, these researchers stated that further investigation is needed to confirm these findings in a larger trial.

The authors stated that a drawback of this trial was that it was based on a secondary endpoint of a small, randomized phase-II study, with no adjustment for multiple tests. Furthermore, a relatively short-term evaluation up to the 6th cycle was used, and long-term effects were not examined. In addition, a weekly schedule of nab-PTX is more commonly used to treat patients with BC, and the significance of these findings for the reduced dose of q3w nab-PTX may be limited. Nab-PTX at 100 mg/m2 can be administered weekly to reduce the incidence and degree of myalgia. Nonetheless, it was not until recently that the weekly nab-PTX regimen was adopted in Japan for the treatment of patients with MBC due to previous failures to demonstrate its superiority to q3w docetaxel in terms of PFS. There should be room for less frequent regimens, especially in patients with limited access to clinics or in those who might benefit from minimizing the risk of coronavirus infection during the COVID-19 pandemic.

Furthermore, there is an ongoing phase-II clinical trial entitled “A Randomized Phase II Study Evaluating Different Schedules of Nab-Paclitaxel in Metastatic Breast Cancer (SNAP Trial)” (last updated March 2, 2021). The estimated completion date of this trial is April 2023. https://clinicaltrials.gov/ct2/show/NCT01746225.

Nab-Paclitaxel and Trastuzumab Combination for the Treatment of Breast Cancer

Tanaka and associates (2015) stated that neoadjuvant chemotherapy plus trastuzumab results in a 30 % to 50 % pathologic complete response (pCR) rate in human epidermal growth factor receptor 2 (HER2)-positive BC and has been associated with improved therapeutic outcomes.  Thus, the pCR rate can be useful in evaluating novel agents in this patient population.  Nanoparticle albumin-bound-PTX can reduce the toxicity of PTX while maintaining its efficacy.  In a phase II clinical trial, these researchers evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+) BC.  They treated patients with stage I to IIIA BC using neoadjuvant epirubicin/cyclophosphamide (EC) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks (q3w) for 4 cycles, followed by nab-PTX (260 mg/m(2)) plus trastuzumab q3w for 4 cycles.  The primary end-point was the pCR rate.  The secondary end-points included the clinical response rate, disease-free survival (DFS), pathologic response rate (defined as pCR or minimal residual invasive disease only in the breast), breast-conserving surgery rate, and safety.  A total of 46 patients were enrolled; 1 patient met the exclusion criteria because of the co-existence of another malignant disease; thus, only 45 patients were evaluated in the entire study.  One patient experienced rapid disease progression during EC therapy, leaving 44 patients evaluable for nab-PTX treatment.  Of the 45 patients, 49 % achieved a pCR.  The pCR rate was 36 % and 71 % in those with estrogen receptor-positive and -negative cancer, respectively.  Of all the study treatments, the most frequent reason for delay or dose reduction was hematologic toxicity; only 1 patient required a dose reduction for nab-PTX because of peripheral neuropathy.  The authors concluded that neoadjuvant therapy using this combination appeared to be safe and effective.  These encouraging findings need to validated in phase III clinical trials.

Ricciardi and colleagues (2016) stated that neoadjuvant therapy is a well-established approach for the treatment of locally advanced or inflammatory BC and has been increasingly used in recent years not only as a management strategy but also as a research tool.  Recently, nab-PTX/trastuzumab combinations have been associated with promising activity in different clinical settings.  In the present case, these investigators reported a pCR after neoadjuvant treatment with the nab-PTX/trastuzumab combination in a locally advanced HER2-positive BC patient, with a good toxicity profile.  The authors concluded that this combination may represent a valid therapeutic option in the neoadjuvant therapy for HER2-positive locally advanced BC.

Tezuka and co-workers (2017) stated that although the concurrent use of anthracycline-containing chemotherapy and taxane with trastuzumab are considered the treatment of choice for the primary systemic therapy of HER2-overexpressing early BC, non-anthracycline regimens, such as concurrent administration of docetaxel and carboplatin with trastuzumab, exhibited similar efficacies in a previous study.  In addition, tri-weekly treatment with nab-paclitaxel resulted in significantly higher response rates and a favorable safety profile compared with standard paclitaxel for metastatic BC patients in another phase III study.  Based on these results, a phase I clinical trial of combination therapy with nab-paclitaxel, carboplatin and trastuzumab was planned, in order to estimate its safety and effectiveness for HER2-overexpressing locally advanced BC.  The present trial was designed to determine the DLT, MTD and recommended dose of this combination treatment in women with HER2-overexpressing locally advanced BC.  The starting dose of nab-paclitaxel was 220 mg/m2 (level 1), and the dose was escalated to 260 mg/m2 (level 2).  Nab-paclitaxel was administered with carboplatin (area under the curve, 6 mg/ml/min) and trastuzumab tri-weekly.  A total of 6 patients were enrolled.  Although no DLT was observed during the 1st cycle, 4 patients developed grade-4 thrombocytopenia, 2 had grade-4 neutropenia and 3 exhibited a grade-4 decrease in hemoglobin levels.  The authors concluded that in the present phase I study, although no patients experienced DLTs, this regimen was associated with severe hematological toxicities and it was not well-tolerated.  However, considering the high efficacy and lower risk of cardiotoxicity and secondary carcinogenesis with taxane, platinum and trastuzumab combination therapy, further evaluation of another regimen including weekly administration or a more accurate dose setting should be conducted.

Nab-Paclitaxel and Sintilimab Combination Therapy for Gastric Cancer

Mei and colleagues (2022) noted that the prognosis of stage III GC is not satisfying and the specific chemotherapy regimens for GC of stage IIIC based on the 8th edition of the UICC/AJCC TNM staging system are still inconclusive. Peritoneal recurrence is the common and severe relapse pattern. Nanoparticle albumin-bound paclitaxel (nab-PTX) is safer and more effective than PTX in the peritoneal metastasis. Clinical trial has demonstrated the safety and effectiveness of sintilimab in GC. A combination of nab-PTX, S-1 and sintilimab could be a promising triplet regimen as adjuvant therapy for GC. These investigators described the design of a prospective, single-arm, open-label, phase-I/II clinical trial (the Dragon-VII Trial); its objective is to examine the safety and effectiveness of the combination of nab-PTX, S-1 and sintilimab. Phase-I will examine the safety feasibility and recommended dose of this combination; the primary endpoints are safety and determination of the recommended dose for subsequent phase-II study. Phase-II will examine the potential anti-tumor activities at the recommended dose and safety in extended population; the primary endpoint is 3-year relapse-free survival. These researchers hope to find patients who benefit from this triplet regimen and the results of this study will contribute to establish treatment standards for clinical practice in patients with stage IIIC GC.

Nab-Paclitaxel and Sintilimab Combination Therapy for Soft Tissue Sarcoma

Tian and colleagues (2022) noted that there is increasing evidence that combination therapy with nab-paclitaxel and programmed cell death protein 1 (PD-1) inhibitor is safe and effective in treating many types of malignant tumors.  However, clinical data demonstrating the effect of this treatment combination for patients with metastatic soft tissue sarcoma (STS) are currently limited.  In a retrospective study, these researchers examined the clinical data of patients with metastatic STS who received nab-paclitaxel plus PD-1 inhibitor (sintilimab) therapy between January 2019 and February 2021.  The safety and effectiveness of the combined treatment were evaluated in terms of the median PFS, estimated using the Kaplan-Meier method.  The univariate Cox proportional hazards model was employed to analyze the relationship between clinicopathological parameters and PFS.  All statistical analyses were 2-sided; p < 0.05 was considered statistically significant.  A total of 28 patients treated with nab-paclitaxel plus sintilimab were enrolled in this study.  The ORR was 25 %, the DCR was 50 %, and the median PFS was 2.25 months (95 % CI: 1.8 to 3.0 months).  The most common grade 1 or 2 AEs were alopecia (89.3 %; 25/28), leukopenia (25.0 %; 7/28), fatigue (21.4 %; 6/28), anemia (21.4 %; 6/28), and nausea (21.4 %; 6/28).  The most common grade 3 AEs were neutropenia (10.7 %; 3/28) and peripheral neuropathy (10.7 %; 3/28).  No grade 4 AEs were observed.  Among the present study cohort, patients with angiosarcoma (n = 5) had significantly longer PFS (p = 0.012) than patients with other pathological subtypes, including undifferentiated pleomorphic sarcoma (n = 7), epithelioid sarcoma (n = 5), fibrosarcoma (n = 4), synovial sarcoma (n = 3), leiomyosarcoma (n = 2), pleomorphic liposarcoma (n = 1), and rhabdomyosarcoma (n = 1); those who experienced t3 or more AEs had significantly longer median PFS than those who experienced less than 3 AEs (p = 0.018).  The authors concluded that nab-paclitaxel plus PD-1 inhibitor is a promising treatment regimen for advanced STS.  Moreover, these researchers stated that RCTs are needed to further demonstrate its efficacy and optimal application scenario. 

The authors stated that this study had several drawbacks.  This included but was not limited to the relatively low number of patients and short follow-up duration, as well as the lack of monitoring patients’ immune status during the treatment period.  In addition, this study also identified some problems that require investigation.  First, it is still unknown which drug plays a major role in this combination.  Moreover, the potential synergistic mechanisms between these 2 drugs should be elucidated.  The optimal dosage regimen for nab-paclitaxel is also unclear.  Finally, given that the effect of this combination therapy varied among subtypes of STSs, further clinical studies with larger sample sizes should be carried out to determine which patients would benefit most from this treatment protocol.

Nasopharyngeal Carcinoma

Ke and associates (2017) determined the safety and effectiveness of induction nab-paclitaxel combined with cisplatin followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC).  Patients with stage III-IVb NPC received nab-paclitaxel (260 mg/m2) combined with cisplatin (80 mg/m2) intravenously on days 1 and 22, followed by cisplatin (80 mg/m2) on days 43 and 64, concomitant with intensity-modulated radiation therapy.  From July 2010 to November 2013, a total of 36 eligible patients with non-metastatic stage III to IVb NPC were enrolled.  The objective response rates were 97.2 % (8 CRs and 27 PRs) and 100 % (30 CRs and 6 PRs) after 2 cycles of induction chemotherapy (ICT) and CCRT, respectively.  With a median follow-up time of 45 months, the estimated 3-year PFS and cancer-specific survival were 86.1 % (95 % CI: 69.8 to 99.8 %) and 91.7 % (95 % CI: 68.9 to 100.0 %), respectively.  The most frequent grade 3 to 4 toxicities were neutropenia (8.6 %) and nausea (8.6 %) after ICT and thrombocytopenia (34.3 %) and leukopenia (28.6 %) after CCRT.  The authors concluded that nab-paclitaxel combined with cisplatin as an ICT regimen showed encouraging anti-tumor effects and manageable toxicities in LA-NPC.  They stated that further randomized controlled trials (RCTs) in phase III of nab-paclitaxel in patients with LA-NPC are needed.

Non-Small Cell Lung Cancer

In a phase III clinical trial, Socinski et al (2012) compared the safety and effectiveness of nab-paclitaxel plus carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus carboplatin in advanced non-small cell lung cancer (NSCLC).  A total of 1,052 untreated patients with stage IIIB to IV NSCLC were randomly assigned 1:1 to receive 100 mg/m2 nab-paclitaxel weekly and carboplatin at AUC 6 once every 3 weeks (nab-PC) or 200 mg/m2 sb-paclitaxel plus carboplatin AUC 6 once every 3 weeks (sb-PC).  The primary end point was objective ORR.  On the basis of independent assessment, nab-PC demonstrated a significantly higher ORR than sb-PC (33 % versus 25 %; RR ratio, 1.313; 95 % CI: 1.082 to 1.593; p = 0.005) and in patients with squamous histology (41 % versus 24 %; RR ratio, 1.680; 95 % CI: 1.271 to 2.221; p < 0.001).  Nab-PC was as effective as sb-PC in patients with non-squamous histology (ORR, 26 % versus 25 %; p = 0.808).  There was an approximately 10 % improvement in PFS (median, 6.3 versus 5.8 months; hazard ratio [HR], 0.902; 95 % CI: 0.767 to 1.060; p = 0.214) and OS (median, 12.1 versus 11.2 months; HR, 0.922; 95 % CI: 0.797 to 1.066; p = 0.271) in the nab-PC arm versus the sb-PC arm, respectively.  Patients greater than or equal to 70-year old and those enrolled in North America showed a significantly increased OS with nab-PC versus sb-PC.  Significantly less grade greater than or equal to 3 neuropathy, neutropenia, arthralgia, and myalgia occurred in the nab-PC arm, and less thrombocytopenia and anemia occurred in the sb-PC arm.  The authors concluded that administration of nab-PC as first-line therapy in patients with advanced NSCLC was effective and resulted in a significantly improved ORR versus sb-PC, achieving the primary end point; nab-PC produced less neuropathy than sb-PC.

Ovarian, Peritoneal and Fallopian Tube Cancer

In a phase II clinical trial, Teneriello et al (2009) reported the effectiveness and toxicity of nab-paclitaxel in patients with recurrent ovarian, peritoneal, or fallopian tube cancer.  A total of 47 patients enrolled in this study (44 assessable patients).  Main inclusion criteria were histologically or cytologically confirmed epithelial cancer of the ovary, fallopian tube, or peritoneum (any stage, grade 2 to 3 if stage I) and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) or elevated cancer antigen 125 (CA-125) (greater than 70 U/ml) in patients without measurable disease.  Patients received nab-paclitaxel 260 mg/m2 administered intravenously (i.v.) for 30 mins on day 1 of a 21-day cycle for 6 cycles or until disease progression.  Median age was 65.5 years; 76 % of patients had stage IIIC or IV disease, 81 % had Eastern Cooperative Oncology Group performance status of 0, and 94 % had prior surgery.  For assessable patients, the ORR was 64 % (15 complete responses [CR] and 13 partial responses [PR] among 44 assessable patients).  In patients evaluated with RECIST only, the ORR was 45 % (1 CR and 4 PR of 11 patients).  In patients with only elevated CA-125, ORR was 82 % (7 CR and 2 PR of 11 patients).  In patients meeting both RECIST and CA-125 criteria, the ORR was 64 % (7 CR and 7 PR of 22 patients).  Median time to response was 1.3 months (range of 0.5 to 4.8 months).  Estimated median progression-free survival (PFS) was 8.5 months.  The most frequent grade 3 to 4 treatment-related toxicities were neutropenia (24 %) and neuropathy (9 %).  The authors concluded that nab-paclitaxel is active in this group of patients with recurrent ovarian, peritoneal, or fallopian tube cancer.  The ORR was 64 %; toxicities were manageable.  They stated that further studies of nab-paclitaxel in combination with platinum are warranted.

In a phase II clinical study, Coleman et al (2011) evaluated the effects of nab-paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer.  Eligible patients had platinum- and taxane-resistant ovarian cancer, defined by persistent or progressive disease following primary chemotherapy (n = 5) or recurrence within 6 months of treatment completion (n = 42).  All patients had measurable disease, no prior therapy for recurrent disease and Gynecologic Oncology Group performance status of less than or equal to 2.  Treatment was nab-paclitaxel, 100 mg/m2 days 1, 8, and 15 on a 28-day schedule.  The primary endpoint was RECIST version 1.0 RR, evaluated in a 2-stage design (with power of 0.90 for a RR of 25 % and with alpha of 0.05 for RR of 10 %).  A total of 51 patients were enrolled of which 47 were evaluable; median time from front-line therapy completion to registration was 21 days.  Patient demographics included median age of 59 (34 to 78) years, serous histology: 72 %, and high-grade: 81 %.  Efficacy: 1 CR and 10 PR were confirmed (23 %); 17 patients (36 %) had stable disease (SD).  The median PFS was 4.5 months (95 % confidence interval [CI]: 2.2 to 6.7); OS was 17.4 months (95 % CI: 13.2 to 20.8).  Seventeen patients (36 %) had PFS greater than 6 months.  Toxicity: there were no grade 4 events; grade 3 events were neutropenia (n = 6), anemia (n = 3), gastro-intestinal (n = 2), metabolic (n = 2), pain (n = 2), and leukopenia (n = 1).  The authors concluded that nab-paclitaxel has note-worthy single-agent activity and is tolerable in this cohort of refractory ovarian cancer patients previously treated with paclitaxel.

Prostate Cancer

In a phase II clinical trial, Shepard et al (2009) examined the safety and effectiveness of neoadjuvant nab-paclitaxel in patients with high-risk, locally advanced prostate cancer.  Eligible patients had locally advanced prostatic adenocarcinoma, clinical stage cT2b or greater, Gleason score 8 or greater, or serum prostate specific antigen (PSA) 15 ng/ml or greater without metastatic disease.  Patients received 2 cycles of 150 mg/m2 nab-paclitaxel weekly for 3 weeks during each 4-week cycle, followed by radical prostatectomy with bilateral lymphadenectomy.  Efficacy assessments included pathological and PSA response.  A total of 19 patients completed neoadjuvant therapy and 18 underwent radical prostatectomy.  Median pre-treatment PSA was 8.5 ng/ml and median Gleason score was 8.  Despite the lack of complete pathological responses 5 of 18 patients (28 %) had organ-confined disease and 9 of 18 (50 %) had specimen-confined disease.  Post-chemotherapy PSA was decreased in 18 of 19 (95 %) patients and median decrease was 2.9 ng/ml (35 %, p < 0.001).  An initial PSA after radical prostatectomy of 0.02 ng/ml or less was achieved in 17 of 18 (94 %) patients.  There were no significant peri-operative complications.  Cytoplasmic vacuolization (focal in 10 and extensive in 7) was evident in all but 1 patient (94 %); 10 patients (56 %) had grade-3 and 1 had grade-4 neutropenia with no febrile neutropenia.  The authors concluded that neoadjuvant nab-paclitaxel was well-tolerated.  Similar to their experience with neoadjuvant docetaxel, there were no pathological CR although a possible histological anti-tumor effect was observed.

Grunwald and Rickmann (2014) noted that recent years have seen dramatic changes in the biological understanding and treatment of solid tumors.  Based on the tumor biology, targeting agents have been developed which directly affect the underlying genetic or immunological changes found in specific tumor entities.  Significant increases in survival have delivered the functional proof of the concept of targeted and immunological tumor therapy.  The management and adherence of the patient as well as optimized cooperation with clinicians are decisive for the results of therapy and disease control.  Several solid tumors are currently under investigation in clinical studies evaluating the (sequential) therapy with targeting and immunologically active agents, e.g., tyrosine kinase and mTOR inhibitors, targeting antibodies, such as bevacizumab, specific antagonists, such as enzalutamide and immunological checkpoint inhibitors via PD(L)1 and/or CTLA 4 antibodies.  Currently approved agents have dramatically changed the landscape of treatment options especially for prostate cancer.  Such agents include hormone therapy with enzalutamide and abiraterone, radiotherapy with cabazitaxel and xofigo (radium 223), metastatic breast cancer (eribulin and everolimus), renal cell carcinoma (sunitinib, sorafenib, axitinib, everolimus and temsirolimus), non-small cell lung cancer (crizotinib and afatinib), colorectal cancer and gastrointestinal stromal tumor (regorafenib) and melanoma (ipilimumab and vemurafenib).  The treatment of rarer tumors, such as pancreatic and hepatocellular cancer and soft tissue sarcoma has entered the stage of targeted therapy with the approval of nanoparticle albumin-bound (nab)-paclitaxel, sorafenib, and eribulin/pazopanib.  Current clinical trials are focusing on the best time-point and sequence of therapy and also improvement in the management of these promising agents.

Bhattacharyya et al (2015) stated that packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumor-specific uptake and therapeutic potential.  To this end, these researchers conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into approximately 60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by 7-fold compared with free drug and 2-fold compared with the Food and Drug Administration (FDA)-approved taxane nano-formulation (Abraxane).  The tumor uptake of the CP-PTX nanoparticle was 5-fold greater than free drug and 2-fold greater than Abraxane.  In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumor regression after a single dose in both tumor models, whereas at the same dose, no mice treated with Abraxane survived for greater than 80 days (breast) and 60 days (prostate), respectively.  The authors concluded that these results showed that a molecularly engineered nanoparticle with precisely engineered design features outperformed Abraxane, the current gold standard for PTX delivery.

Ojima et al (2016) stated that paclitaxel and docetaxel were 2 epoch-making anti-cancer drugs and have been successfully used in chemotherapy for a variety of cancer types.  In the year 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer.  Albumin-bound paclitaxel (nab^™-paclitaxel; Abraxane) nano-droplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast cancer).  Abraxane in combination with gemcitabine for the treatment of pancreatic cancer was approved by FDA in 2013.  Accordingly, there have been a huge number of patent applications dealing with taxane anti-cancer agents in the last 5 years.  Thus, it is a good time to review the progress in this area and find the next wave for new developments.  This review covered the patent literature from the year 2010 to early 2015 on various aspects of taxane-based chemotherapies and drug developments.  The authors concluded that 3 FDA-approved taxane anti-cancer drugs will continue to expand their therapeutic applications, especially through drug combinations and new formulations.  Inspired by the success of Abraxane, new nano-formulations are emerging.  Highly potent new-generation taxanes will play a key role in the development of efficacious tumor-targeted drug delivery systems.

van Wamel et al (2016) stated that acoustic cluster therapy (ACT) is a novel approach for ultrasound mediated, targeted drug delivery.  In the current study, these researchers investigated ACT in combination with paclitaxel and Abraxane^® for treatment of a subcutaneous human prostate adenocarcinoma (PC3) in mice.  In combination with paclitaxel (12 mg/kg given i.p.), ACT induced a strong increase in therapeutic efficacy; 120 days after study start, 42 % of the animals were in stable, complete remission versus 0 % for the paclitaxel only group and the median survival was increased by 86 %.  In combination with Abraxane (12 mg paclitaxel/kg given i.v.), ACT induced a strong increase in the therapeutic efficacy; 60 days after study start 100 % of the animals were in stable, remission versus 0 % for the Abraxane only group, 120 days after study start 67 % of the animals were in stable, complete remission versus 0 % for the Abraxane only group.  For the ACT + Abraxane group 100 % of the animals were alive after 120 days versus 0 % for the Abraxane only group.  The authors concluded that proof of concept for ACT has been demonstrated; ACT markedly increased the therapeutic efficacy of both paclitaxel and Abraxane for treatment of human prostate adenocarcinoma in mice.

An UpToDate review on “Overview of the treatment of disseminated castration-sensitive prostate cancer” (Dawson, 2017) does not mention paclitaxel protein bound particles (Abraxane) as a therapeutic option.

Pulmonary Carcinosarcoma with Interstitial Lung Disease

Niwa and colleagues (2018) noted that carcinosarcoma is a rare histological type of NSCLC, and its prognosis has been reported to be worse compared with other NSCLCs; nab-PTX + carboplatin (CBDCA) achieved a favorable response rate in patients with NSCLC.  These researchers administered nab-PTX + CBDCA to a 68-year old man with post-operative recurrent carcinosarcoma with interstitial lung disease (ILD).  A PR was evident after 4 cycles of chemotherapy.  The authors concluded that to their best knowledge, the present study was the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD.

The authors stated that there were several drawbacks in this single-case study.  First, these investigators could not exclude the possibility that the new lesions in the right lung after brain surgery originated from another primary lung cancer.  Although these researchers did not perform histopathology, they assumed that the new legions were contralateral lung metastasis, because they were unable to detect tumors in the right lung in CT scans acquired before left-upper lobectomy.  Thus, these researchers believed that it was reasonable to conclude that nab-PTX + CBDCA is a useful therapeutic option for patients with pulmonary sarcomatoid carcinomas with ILD.  Second, these investigators could not exclude the increase in risk of acute exacerbation of ILD.   They stated that further studies of the safety and efficacy of this regimen for treating pulmonary sarcomatoid carcinomas, including carcinosarcomas with ILD, are needed.

Small Cell Lung Cancer

UpToDate reviews on “Treatment of refractory and relapsed small cell lung cancer” (Kelly, 2013) and “Treatment protocols for small-cell carcinoma of the lung” (Brenner et al, 2013) do not mention the use of albumin-bound paclitaxel as a therapeutic option for small cell lung cancer.  Furthermore, according to the 2013 NCCN Drugs & Biologics Compendium, small cell lung cancer is not a recommended indication of Abraxane (albumin-bound paclitaxel).

Yosida and associates (2016) noted that since nab-PTX exerts clinically meaningful anti-tumor effects on various malignancies, including BC, gastric cancer and NSCLC, these investigators hypothesized that treatment with nab-PTX may also be beneficial for patients with SCLC.  They evaluated the safety and effectiveness of weekly, single-agent nab-PTX in patients with refractory or relapsed SCLC.  Between May, 2013 and February, 2015, a total of 9 patients with refractory or relapsed SCLC were treated with single-agent nab-PTX at the Kyoto University Hospital.  The medical records of the patients were retrospectively reviewed.  All patients had been previously treated with greater than or equal to 2 lines of chemotherapy prior to receiving nab-PTX.  The median number of cycles of nab-PTX was 2 (range of 1 to 4) and 3 PR were observed (response rate: 33 %).  The toxicity was generally mild and manageable: Grade 3/4 adverse events were only observed in 1 patient (grade 3 leukopenia).  The authors concluded that  weekly administration of nab-PTX may be a viable treatment option in patients with refractory or relapsed SCLC.  They stated that considering that therapeutic options are quite limited in this patient population, further evaluation of this regimen may prove valuable in the clinical setting.

Thymic Cancer

Igawa and colleagues (2015) noted that thymic large cell neuroendocrine carcinomas (LCNECs) are rare, and the optimal regimen for 2nd and subsequent lines of chemotherapy for the treatment of LCNECs remains unknown.  In the present case study, a 59-year old male with post-operative recurrent thymic LCNEC was treated with nab-PTX and carboplatin every 4 weeks as 3rd-line chemotherapy, and a PR was achieved following 4 cycles of this regimen.  The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including peripheral neuropathy, were severe.  Therefore, the patient was able to tolerate this salvage chemotherapy.  The authors stated that to their best knowledge, the present study is the first case demonstrating clinically meaningful anti-tumor activity by combination chemotherapy with carboplatin and nab-PTX, resulting in a positive response in a patient with thymic LCNEC Shima and co-workers (2016) stated that thymic carcinoma is a rare neoplasm with a poor outcome due to its aggressive characteristics.  For patients who are not operable, radiation therapy and/or palliative chemotherapy are indicated.  However, no optimal chemotherapy regimen has been established.  These investigators reported the case of a 22-year old man with advanced lymphoepithelioma-like thymic carcinoma refractory to conventional chemotherapy with carboplatin plus solvent-based paclitaxel (sb-PAC) treatment.  The patient was subsequently treated with carboplatin plus nab-PTX.  The treatment resulted in a PR following 3 cycles of chemotherapy.  Since only grade 3 neutropenia, but no other severe adverse effects, was observed, no dose reduction was required.  To the best of the authors’ knowledge, the current study is the 1st to present the response to chemotherapy with carboplatin plus nab-PTX in a patient with lymphoepithelioma-like thymic carcinoma.  The authors concluded that considering that no standard treatment has been established in thymic carcinoma, nab-PTX may merit further investigation in this rare, but aggressive disease.

Urothelial Cancer

In a phase II clinical trial, Ko and associates (2013) evaluated the effectiveness and tolerability of Nab-PTX in patients with platinum-refractory urothelial cancer.  In this open-label, single-group, 2-stage study at 5 centers in Canada, these researchers enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with 1 previous platinum-containing regimen.  Patients received Nab-PTX at 260 mg/m(2) intravenously every 3 weeks.  Treatment continued until disease progression or occurrence of unacceptable toxic effects.  The primary end-point was objective tumor response, defined by a CR or PR according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria.  Tumor response and safety were assessed in all patients who received at least 1 cycle of Nab-PTX.  These investigators enrolled 48 patients between October 16, 2008, and June 23, 2010.  Patients received a median of 6 cycles (range of 1 to 15).  A total of 47 patients were evaluable; 1 (2.1 %) had a CR and 12 (25.5 %) had PRs, resulting in an overall response of 27.7 % (95 % CI: 17.3 to 44.4).  The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79 %), pain (37 of 48; 77 %), alopecia (34 of 48; 71 %), and neuropathy (30 of 48; 77 %).  The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23 %), fatigue (5 of 48; 23 %), hypertension (3 of 48; 6 %), neuropathy (3 of 48, 6 %), and joint stiffness or pain (2 of 48; 4 %).  The authors concluded that Nab-PTX was well-tolerated in this population of patients with pre-treated advanced urothelial cancer with an encouraging tumor response.  Moreover, they stated that these results warrant further study of Nab-PTX in second-line treatment of urothelial cancer.

Vulvar Cancer

In a prospective, single-arm, single-center, pilot study, Han et al (2012) evaluated the effectiveness of weekly paclitaxel/carboplatin chemotherapy in patients with locally advanced, metastatic, or recurrent vulvar squamous cell carcinoma.  This study was initiated to examine response rate of 9 weekly courses of paclitaxel (60 mg/m) and carboplatin (area under the curve, 2.7).  These researchers used this regimen in the neoadjuvant or metastatic setting when surgery would cause serious morbidity or was not an option owing to distant metastases.  Primary outcome was response rate, measured according to Response Criteria in Solid Tumors criteria.  Treatment toxicity, surgical morbidity, and type of surgery were also evaluated.  These investigators treated 6 patients in the period between May 2009 and May 2011, of which 4 patients had a diagnosis of locally advanced disease and 2 patients had a diagnosis of recurrent disease.  A median number of 7.5 cycles of paclitaxel/carboplatin weekly was administered (range of 3 to 9).  No objective response was observed.  Paclitaxel/carboplatin weekly was discontinued after a mean of 4.3 weekly cycles in 3 patients owing to local disease progression.  After a median follow-up of 4.2 months (range of 1 to 29 months), 3 patients died as a result of progressive disease; and 1 patient died as a consequence of intercurrent disease.  The 2 remaining patients underwent radical vulvectomy + bilateral inguino-femoral lymphadenectomy after neoadjuvant chemotherapy.  The main chemotherapy-related toxicity was anemia and could be managed conservatively with erythropoietin and intravenous iron therapy.  The authors concluded that weekly administration of paclitaxel-carboplatin has limited clinical benefit in the treatment of vulvar squamous cell carcinoma.

Raspagliesi et al (2014) evaluated the efficacy and toxicity of paclitaxel and cisplatin in locally advanced vulvar cancer.  From 2002 to 2009, 10 patients with stage III-IV locally advanced squamous cell carcinoma of the vulva were prospectively treated with 3 courses of paclitaxel-ifosfamide-cisplatin or paclitaxel-cisplatin; 9 of them subsequently underwent radical local excision or radical partial vulvectomy and bilateral inguino-femoral lymphadenectomy.  The clinical response rate of all enrolled patients was 80 %, whereas the pathological responses included 1 case with complete remission, 2 with persistent carcinoma in-situ, and 6 invasive cancer cases with tumor shrinkage of more than 50 %.  Four patients had positive nodes; 40 % of patients experienced grade 3 to 4 bone marrow toxicity, which was successfully managed with granulocyte-colony stimulating factor, even in cases of elderly patients.  Median progression-free survival after surgery was 14 months (range of 5 to 44 months).  Six of the 7 recurrent cases were local, and 3 of them were treated with salvage surgery while the other 3 received radiation with or without chemotherapy.  After a median follow-up period of 40 months (range of 5 to 112 months), 55.5 % of patients remained alive with no evidence of disease, including 2 long-term survivors after recurrence at 5 and 9 years.  The authors concluded that based on the high response rate and manageable toxicity, multi-modality treatments including concurrent chemoradiation or different regimens of neoadjuvant chemotherapy, with paclitaxel and cisplatin with or without ifosfamide followed by surgery could be considered as a therapeutic option for locally advanced vulvar cancer.  (This was a small study and albumin-bound paclitaxel was not the drug used)

An UpToDate review on “Vulvar cancer: Staging, treatment, and prognosis” (Elkas et al, 2014) states that “Primary chemoradiotherapy or brachytherapy are therapeutic options that may allow sparing of rectal function or obviate the need for surgery entirely in women with primary carcinoma of the Bartholin gland.  Chemoradiation may be particularly effective in cancers with squamous histology.  For advanced disease, single case reports describe activity for liposomal doxorubicin and paclitaxel”.  This review does not mention albumin-bound paclitaxel.

Other Cancers

Fader and Rose (2009) examined the effects of Abraxane for the treatment of gynecologic cancer patients with severe hypersensitivity reactions to paclitaxel.  A total of 5 patients with gynecologic cancers (cervical cancer, n = 1; endometrial cancer, n = 2; and ovarian cancer, n = 2) received Abraxane after having a hypersensitivity reaction to paclitaxel.  All 5 patients tolerated Abraxane well, experiencing no reactions or major side effects to the drug.  The authors concluded that Abraxane is well-tolerated in women with gynecologic cancer who have experienced a paclitaxel-associated hypersensitivity reaction.  They stated that further studies are ongoing to determine the clinical activity of Abraxane in the treatment of these malignancies.

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 "+":
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
96367	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); additional sequential infusion of a new drug/substance, up to 1 hour (List separately in addition to code for primary procedure)
96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); concurrent infusion (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J9264	Injection, paclitaxel protein-bound particles, 1 mg
Other HCPCS codes related to the CPB:
J9045	Injection, carboplatin, 50 mg
J9171	Injection, docetaxel, 1 mg
J9201	Injection, gemcitabine hydrochloride, 200 mg
J9267	Injection, paclitaxel, 1 mg
J9355	Injection, trastuzumab, 10 mg
ICD-10 codes covered if selection criteria are met:
C17.0 - C17.9	Malignant neoplasm of small intestine [small bowel adenocarcinoma]
C22.1	Intrahepatic bile duct carcinoma
C22.0-C23.0	Malignant neoplasm of liver and intrahepatic bile ducts and gallbladder
C24.0	Malignant neoplasm of extrahepatic bile duct
C24.1	Malignant neoplasm of ampulla of Vater
C25.0 - C25.9	Malignant neoplasm of pancreas
C33 - C34.92	Malignant neoplasm of trachea, bronchus and lung [non-small-cell lung cancer] [not covered for small cell lung cancer]
C43.0 - C43.9, D03.0 - D03.9	Malignant melanoma of skin [not covered for hepatic arterial infusion of nab-paclitaxel for metastatic melanoma to the liver]
C46.0 - C46.9	Kaposi's sarcoma [Aids related]
C48.1 - C48.8	Malignant neoplasm of peritoneum
C50.011 - C50.929	Malignant neoplasm of breast
C54.1	Malignant neoplasm of endometrium
C56.1 - C57.4	Malignant neoplasm of ovary and other uterine adnexa
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of ureter
C69.40 - C69.42	Malignant neoplasm of ciliary body [uveal melanoma]
D06.0 - D06.9	Carcinoma in situ of cervix uteri
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C07	Malignant neoplasm of parotid gland
C11.0 - C11.9	Malignant neoplasm of nasopharynx
C15.3 - C15.9	Malignant neoplasm of esophagus [squamous-cell]
C16.0 - C16.9	Malignant neoplasm of stomach
C21.0 - C21.1	Malignant neoplasm of anus and anal canal
C22.0, C22.2 - C22.9	Malignant neoplasm of liver and intrahepatic bile ducts
C24.8 - C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [Pulmonary carcinosarcoma]
C37	Malignant neoplasm of thymus
C40.00 - C41.9	Malignant neoplasms of bone and articular cartilage [bone sarcoma, chondrosarcoma, Ewing's sarcoma, and osteosarcoma]
C45.0	Mesothelioma of pleura
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue [leimyosarcoma]
C51.9	Malignant neoplasm of vulva, unspecified
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.2 - C54.9	Malignant neoplasm of corpus uteri [except isthmus uteri]
C61	Malignant neoplasm of prostate [urothelial carcinoma]
C64.1 - C64.9	Malignant neoplasm of kidney, except pelvis [Wilms' tumor]
C67.0 - C67.9	Malignant neoplasm of bladder
C68.0	Malignant neoplasm of urethra
C71.0 - C71.9	Malignant neoplasm of brain
C73	Malignant neoplasm of thyroid gland
C74.00 - C74.92	Malignant neoplasm of adrenal gland
C76.0	Malignant neoplasm of head, face and neck
C78.6	Secondary malignant neoplasm of retroperitoneum and peritoneum
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct [not covered for metastatic melanoma to the liver]
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C80.0 - C80.1	Disseminated and other malignant neoplasm, unspecified
C81.00 - C88.4	Lymphomas
C90.00 - C90.02	Multiple myeloma
D07.1	Carcinoma in situ of vulva

The above policy is based on the following references: