Oxaliplatin (Eloxatin)

Number: 0683

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

  1. Criteria for Initial Approval

    Aetna considers oxaliplatin injection (Eloxatin) medically necessary for the treatment of the following indications:

    1. Ampullary adenocarcinoma;
    2. Anal carcinoma - for metastatic anal cancer;
    3. B-Cell lymphomas (including follicular lymphoma [grade 1-2], histologic transformation of indolent lymphomas to diffuse large B-Cell lymphoma, mantle cell lymphoma, diffuse large B-Cell lymphoma, high-grade B-Cell lymphomas, HIV-related B-Cell lymphomas, and post-transplant lymphoproliferative disorders);
    4. Bladder cancer (including non-urothelial and urothelial cancer with variant histology);
    5. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL);
    6. Classic Hodgkin lymphoma; 
    7. Colorectal cancer (including anal adenocarcinoma, appendiceal adenocarcinoma, and colon and rectal cancers);
    8. Esophageal and esophagogastric junction cancers;
    9. Gastric cancer;
    10. Biliary tract cancers (including, intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer);
    11. Neuroendocrine and adrenal tumors (including neuroendocrine tumors of the gastrointestinal tract, lung, and thymus, neuroendocrine tumors of the pancreas, well differentiated grade 3 neuroendocrine tumors and poorly differentiated/large or small cell carcinoma/mixed neuroendocrine-non-neuroendocrine neoplasms);
    12. Occult primary tumors (cancer of unknown primary);
    13. Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer - epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, carcinosarcoma (malignant mixed Müllerian tumors), clear cell carcinoma of the ovary, mucinous carcinoma of the ovary, grade 1 endometrioid carcinoma, low-grade serous carcinoma/ovarian borderline epithelial tumors (low malignant potential), and malignant germ cell tumor residual disease;
    14. Pancreatic adenocarcinoma;
    15. Primary cutaneous lymphomas (including mycosis fungoides/Sezary syndrome and primary cutaneous CD30+ T-Cell lymphoproliferative disorders);
    16. Small bowel adenocarcinoma;
    17. T-Cell lymphomas (including peripheral T-Cell lymphomas, adult T-Cell leukemia/lymphoma, hepatosplenic T-Cell lymphoma, extranodal NK/T-Cell lymphoma, and breast implant-associated anaplastic large cell lymphoma (ALCL);
    18. Testicular cancer.

    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 oxaliplatin (Eloxatin) therapy medically necessary for an indication in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

  3. Related Policies

    1. CPB 0371 - Brachytherapy
    2. CPB 0375 - Photodynamic Therapy
    3. CPB 0516 - Colorectal Cancer Screening
    4. CPB 0535 - Virtual Gastrointestinal Endoscopy

Dosage and Administration

Oxaliplatin (Eloxatin) is available as 50 mg (5 mg/mL) or 100 mg (5 mg/mL) in a single-dose vial for injection. 

Colon Cancer and Colorectal Cancer

The recommended dosage is as follows:

Administer Eloxatin 85 mg/m2 as an intravenous infusion over 120 minutes concurrently with leucovorin over 120 minutes in separate bags, followed by fluorouracil on Day 1 of each 14-day cycle. Administer fluorouracil and leucovorin on Day 2 as recommended.

  • Adjuvant treatment of stage III colon cancer: Continue treatment for up to 12 cycles or unacceptable toxicity. 
  • Advanced colorectal cancer: Continue treatment until disease progression or unacceptable toxicity. 

Source: Hospira, 2021; sanofi-aventis, 2023

Experimental and Investigational

Aetna considers oxaliplatin (Eloxatin) injection experimental and investigational for the treatment of members with the following types of cancer (not an all-inclusive list) since its effectiveness for these indications has not been established:

  • Acute myeloid leukemia
  • Breast cancer
  • Cervical cancer
  • Endometrial cancer
  • Head and neck cancer
  • Hepatocellular cancer
  • Melanoma
  • Mesothelioma
  • Neuroendocrine tumors of the gastro-intestinal (GI) tract (except pancreas, and poorly differentiated neuroendocrine carcinomas), lung, and thymus)
  • Non-small cell lung cancer
  • Prostate cancer
  • Urethral cancer.

Aetna considers pressurized intra-peritoneal aerosol chemotherapy (PIPAC) with oxaliplatin (Eloxatin) for peritoneal metastasis experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers chemo-protective interventions (pharmacological and/or non-pharmacological interventions) experimental and investigational for prevention of oxaliplatin-induced peripheral neuropathy.

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Other CPT codes related to the CPB:
96401 - 96450 Chemotherapy administration
96446 Chemotherapy administration into the peritoneal cavity via indwelling port or catheter [pressurized intra-peritoneal aerosol chemotherapy (PIPAC)]

HCPCS codes covered if selection criteria are met:
J9263 Injection, oxaliplatin, 0.5 mg

Other HCPCS codes related to the CPB:
Q0083 - Q0085 Chemotherapy administration

ICD-10 codes covered if selection criteria are met:
C15.3 - C15.9 Malignant neoplasm of esophagus
C16.0 - C16.9 Malignant neoplasm of stomach [gastric carcinoma]
C17.0 - C17.9 Malignant neoplasm of small intestine, including duodenum
C18.0 - C20 Malignant neoplasm of colon and rectum
C21.0 - C21.8 Malignant neoplasm of anus and anal canal [metastatic anal cancer]
C22.1 Intrahepatic bile duct carcinoma
C23 Malignant neoplasm of gallbladder
C24.0 Malignant neoplasm of extrahepatic bile ducts
C24.1 Malignant neoplasm of Ampulla of Vater
C25.0 - C25.9 Malignant neoplasm of pancreas
C44.500 Unspecified malignant neoplasm of anal skin [metastatic anal cancer]
C44.510 Basal cell carcinoma of anal skin [metastatic anal cancer]
C44.520 Squamous cell carcinoma of anal skin [metastatic anal cancer]
C44.590 Other specified malignant neoplasm of anal skin [metastatic anal cancer]
C48.0 - C48.8 Malignant neoplasm of retroperitoneum and peritoneum
C56.1 - C56.9 Malignant neoplasm of ovary [Clear cell carcinoma of the ovary malignant germ cell tumors and mucinous carcinoma]
C57.00 - C57.02 Malignant neoplasm of fallopian tube
C62.00 - C62.92 Malignant neoplasm of testis [Malignant germ cell tumor]
C67.0 - C67.9 Malignant neoplasm of bladder
C7A.00 – C7A.8, C7B.00 – C7B.8 Malignant neuroendocrine tumors
C80.1 Malignant (primary) neoplasm, unspecified [unknown primary site]
C81.70 - C81.79 Other Hodgkins lymphoma [classic Hodgkin lymphoma]
C82.00 - C82.99, C84.00 - C84.49, C84.a0 - C86.4, C91.40 - C91.42, C96.0 - C96.4, C96.a - C96.9 Other malignant neoplasms of lymphoid and histiocytic tissue
C83.00 - C83.99, C84.60 - C84.79, C86.5 - C86.6 Lymphosarcoma and reticulosarcoma and other specified malignant tumors of lymphatic tissue [angioimmunoblastic T-cell lymphoma]
C91.10 - C91.12 Chronic lymphocytic leukemia of B-cell type
C91.50 - C91.52 Adult T-cell leukemia/lymphoma (HTLV-1-associated)
D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
E34.0 Carcinoid syndrome [poorly controlled]
R59.0 Localized enlarged lymph nodes
Z85.038, Z85.048 Personal history of malignant neoplasm of large intestine, rectum and rectosigmoid junction

Background

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

Oxaliplatin, in combination with infusional fluorouracil and leucovorin, is indicated for:

  • Adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor.
  • Treatment of advanced colorectal cancer.

Compendial Uses

  • Colon cancer
  • Rectal cancer
  • Esophageal or esophagogastric junction cancers
  • Gastric cancer
  • Biliary tract cancers

    • Extrahepatic cholangiocarcinoma
    • Intrahepatic cholangiocarcinoma
    • Gallbladder cancer

  • Bladder cancer (including non-urothelial and urothelial cancer with variant histology)
  • Neuroendocrine and adrenal tumors

    • Neuroendocrine tumors of the gastrointestinal tract, lung, and thymus
    • Neuroendocrine tumors of the pancreas
    • Well differentiated grade 3 neuroendocrine tumors
    • Poorly differentiated/large or small cell disease/mixed neuroendocrine-non-neuroendocrine neoplasms

  • Occult primary tumors (cancer of unknown primary)
  • Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer

    • Epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer
    • Carcinosarcoma (malignant mixed Müllerian tumors)
    • Clear cell carcinoma of the ovary
    • Mucinous carcinoma of the ovary
    • Grade 1 endometrioid carcinoma
    • Low-grade serous carcinoma/ovarian borderline epithelial tumors (low malignant potential)
    • Malignant germ cell tumors

  • Pancreatic adenocarcinoma
  • Testicular cancer
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
  • Anal carcinoma
  • B-Cell lymphomas

    • Follicular lymphoma (grade 1-2)
    • Histologic transformation of indolent lymphomas to diffuse large B-cell lymphoma
    • Mantle cell lymphoma
    • Diffuse large B-cell lymphoma
    • High-grade B-cell lymphomas
    • Human immunodeficiency virus (HIV)-related B-cell lymphomas
    • Post-transplant lymphoproliferative disorders

  • Primary cutaneous lymphomas

    • Mycosis fungoides/Sezary syndrome
    • Primary cutaneous CD30+ T-Cell lymphoproliferative disorders

  • T-Cell lymphomas

    • Peripheral T-Cell lymphomas
    • Adult T-Cell leukemia/lymphoma
    • Extranodal natural killer (NK)/T-Cell lymphoma
    • Hepatosplenic T-Cell lymphoma
    • Breast Implant-Associated Anaplastic Large Cell Lymphoma (ALCL)

  • Classic Hodgkin lymphoma
  • Small bowel adenocarcinoma
  • Ampullary adenocarcinoma

Chemo-Protective Interventions for Prevention of Oxaliplatin-Induced Peripheral Neuropathy

Peng et al (2022) noted that oxaliplatin-induced peripheral neuropathy (OIPN) has significant clinical impact on the QOL for cancer patients and is a DLT; and studies on examining preventive measures have been inconclusive.  In a systematic review and meta-analysis, these investigators examined available pharmacological and non-pharmacological interventions for prevention of chronic OIPN.  They searched PubMed-Medline, Embase and Scopus from January 1, 2005 to August 8, 2020 as well as major conferences' abstracts for randomized controlled trials (RCTs) that examined the effectiveness of any preventive measure for OIPN.  The primary outcome measure was the incidence of chronic OIPN with a preventive intervention as compared to placebo or no intervention.  The pooled RR and its 95 % CI were calculated using a random effects model.  A network meta-analysis was carried out to derive indirect evidence of any preventive effect of an intervention against placebo when original trials compared one intervention against another.  A total of 44 studies were analyzed describing 29 chemo-protective interventions, including combinations, and 1 non-pharmacological intervention.  Ratings were evaluated via a combination of outcomes with quality assessment using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.  Of the 30 interventions examined, there were 6 interventions supporting potential effectiveness, 11 interventions with insufficient evidence and 13 interventions not recommended.  The authors concluded that despite the many pharmacological interventions reported in recent studies, there is insufficient evidence of any clinical success in OIPN prevention.  These investigators stated that given the encouraging results observed in pre-clinical studies on OIPN prevention and emergence of non-pharmacological interventions in CIPN prevention, future studies could examine their potential.  Moreover, studies with adequate recruitment, randomization and blinding, and standardized reporting of outcomes are needed.

The authors stated that this study had several drawbacks common to most meta-analyses.  First, it employed summary data rather than individual patient data, which limited the ability of the study to control for confounders between trials.  Second, analysis could only be carried out on studies that were published and searchable via English-based databases, which introduced an inherent publication bias.  This was mitigated by including conference abstracts in the literature search.  Third, the lack of a standardized assessment method for OIPN limited comparison across trials.

Colorectal Cancer

Colorectal cancer is the second-leading causes of cancer death in the United States.  It is the nation's third most common cancer accounting for approximately 15 % of all new cancer cases.  Metastatic disease is present at diagnosis in 30 % of the patients, and about 50 % of early-stage patients will eventually present with metastatic disease.  For many years, standard treatment of colorectal cancer was 5-fluorouracil (5-FU)-based therapy.  Recent availability of newer agents, including capecitabine, irinotecan and oxaliplatin, has significantly expanded the options available for the management of patients with advanced colorectal cancer, with consequent improvements in survival.  On February 12, 2004, the U.S. Food and Drug Administration (FDA) approved cetuximab (Erbitux), a monoclonal antibody, as a combination treatment with irinotecan for the treatment of patients with advanced colorectal cancer that has spread to other parts of the body; or alone if patients can not tolerate irinotecan.  Although cetuximab has been demonstrated to shrink tumors in some patients and delay tumor growth, especially when used as a combination treatment, it has not been shown to extend patients' lives.

Oxaliplatin is a 3rd-generation platinum analog.  It is believed to work via the formation of reactive platinum complexes, which inhibit DNA synthesis by forming inter-strand and intra-strand cross-linking of DNA molecules, thus disrupting DNA replication and transcription.  Oxaliplatin has been reported to exhibit cytotoxic efficacy as well as a well-tolerated safety profile.  The main side effect of oxaliplatin is a sensory neuropathy exacerbated by cold exposure.  Pre-clinical studies have demonstrated that oxaliplatin is synergistic with FU and SN-38, the active metabolite of irinotecan.  Furthermore, oxaliplatin has been shown to be effective when used in combination with 5-FU and leucovorin (LV) for the treatment of advanced colorectal cancer.

In January 2004, the FDA approved Eloxatin (oxaliplatin for injection) in combination with 5-FU/LV for the first-line treatment of advanced colorectal cancer.  The drug was previously approved in August 2002 for second-line treatment of patients with metastatic carcinoma of the colon or rectum (patients whose disease has recurred or progressed during or within 6 months of completion of first-line therapy with the combination of bolus 5-FU/LV and irinotecan).  The expanded approval was based on clinical data that showed that patients with advanced colorectal cancer treated with oxaliplatin given in combination with 5-FU/LV as first-line chemotherapy had a statistically significant improvement of nearly 5 months in median survival time compared to patients treated with a standard treatment of irinotecan in combination with 5-FU/LV.

Goldberg et al (2004) suggested that oxaliplatin and 5-FU/LV should be considered standard first-line treatment for patients with advanced colorectal cancer.  In this study, a total of 795 patients with metastatic colorectal cancer who had not been previously treated for advanced disease were randomized to receive
  1. oxaliplatin and infused 5-FU/LV;
  2. irinotecan and bolus 5-FU/LV; or
  3. oxaliplatin and irinotecan with no 5-FU/LV.
The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity.  A median time to progression of 8.7 months, response rate of 45 %, and median survival time of 19.5 months were observed in the oxaliplatin/5-FU/LV group.  These results were significantly superior to those observed for the irinotecan/5-FU/LV (6.9 months, 31 %, and 15.0 months) and oxaliplatin/irinotecan (6.5 months, 35 %, and 17.4 months) groups.

In addition to treatment of colorectal carcinoma, oxaliplatin has been approved by the FDA for use as adjuvant treatment of stage III colon cancer patients who have undergone complete resection of the primary tumor.  This approval was based on phase III clinical studies that demonstrated an improvement in disease-free survival, but no demonstrated benefit in overall survival after a median follow-up of 4 years. 

The U.S. Pharmacopeial Convention has concluded that oxaliplatin is indicated for use in combination with 5-FU/LV for the treatment of advanced carcinoma of the colon or rectum.  According to the USP-DI, oxaliplatin is also indicated, in combination with 5-FU/LV or capecitabine, for the first-line treatment of non-resectable, advanced, or metastatic colon or rectal carcinoma.  Prior adjuvant or palliative 5-FU-based chemotherapy and radiation therapy are permitted.  The U.S. Pharmacopoeia has stated that oxaliplatin is indicated for use in combination with infusional 5-FU/LV for the adjuvant treatment of stage III cancer patients who have undergone complete resection of the primary tumor.  The indication is based on an improvement in disease-free survival, with no demonstrated benefit in overall survival after a median follow-up of 4 years.

The FDA-approved labeling of Eloxatin has the following recommendations regarding dosing and administration for colorectal cancer:

  • Administer Eloxatin in combination with 5-fluorouracil/leucovorin every 2 weeks:

    • Day 1: Eloxatin 85 mg/m2 intravenous infusion in 250–500 mL 5% Dextrose Injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion
    • Day 2: leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2–4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion

  • Reduce the dose of Eloxatin to 75 mg/m2 (adjuvant setting) or 65 mg/m2 (advanced colorectal cancer):

    • if there are persistent grade 2 neurosensory events that do not resolve
    • after recovery from grade 3/4 gastrointestinal toxicities (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. Delay next dose until neutrophils ≥1.5 × 109/L and platelets ≥75 × 109/L

  • Discontinue Eloxatin if there are persistent Grade 3 neurosensory events
  • Never prepare a final dilution with a sodium chloride solution or other chloride-containing solutions.

The most common adverse reactions with oxaliplatin (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported.

Eloxatin is contraindicated in persons with a known allergy to oxaliplatin or other platinum-based compounds.

Black Box Warning:

Anaphylactic reactions to Eloxatin have been reported, and may occur within minutes of Eloxatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms.

Warnings and Precautions: 

  • Allergic Reactions: Monitor for development of rash, urticaria, erythema, pruritis, bronchospasm, and hypotension.
  • Neuropathy: Reduce the dose or discontinue Eloxatin if necessary.
  • Pulmonary Toxicity: May need to discontinue Eloxatin until interstitial lung disease or pulmonary fibrosis are excluded.
  • Hepatotoxicity: Monitor liver function tests.
  • Pregnancy. Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus.

Larsen and colleagues (2019) stated that in case of response to chemotherapy, unresectable liver metastases from colorectal cancer (CRC) can be converted to resectable and thereby obtain a chance of cure. In a prospective, phase-II clinical trial, these researchers examined the response rate with intra-hepatic oxaliplatin in combination with systemic 5-fluorouracil (5-FU) +/- cetuximab.  Secondary aims were to evaluate the conversion rate from unresectable to resectable liver metastases, median PFS, median OS, and toxicity.  A total of 45  chemotherapy-naïve patients with liver metastases from CRC were treated.  Calcium folinate and 5-FU were delivered systemically while oxaliplatin was delivered alternating between systemic and intra-hepatic administration.  When oxaliplatin was delivered via the intra-hepatic route, infusion time was reduced to 10 mins followed by embolic material.  In patients with KRAS wild-type tumors, cetuximab was added.  The treatment was well-tolerated and only pain in the liver and a mild increase in liver enzymes were observed following intra-hepatic oxaliplatin.  Subjects obtained a response rate of 82 %.  Furthermore, 58 % converted from having unresectable to resectable liver metastases.  The median OS and PFS were 38.7 months (95 % CI: 33.0 to 44.3) and 12.9 months (95 % CI: 10.2 to 15.6), respectively.  The authors concluded that intra-hepatic infusion of oxaliplatin with systemic 5-FU to patients with chemotherapy-naïve CRC is feasible and with low toxicity.  A high response rate and long median OS were obtained.  These preliminary findings need to be validated by well-designed studies.

Esophageal Cancer

Treatments for esophageal cancer and gastroesophageal junction cancer have centered on combined-modality therapy: combinations of 5-FU, cisplatin, and radiation.  More recently, oxaliplatin has been studied for the treatment of esophageal cancer.  Khushalani et al (2002) examined the dosage and schedule of oxaliplatin (OXP) used in combination with protracted-infusion (PI) 5-FU and external-beam radiation therapy (XRT) for patients with primary esophageal carcinoma (EC).  Eligibility included therapeutically naive EC patients with clinical disease stages II, III, or IV.  Initial doses and schedules for cycle 1 consisted of OXP 85 mg/m2 on days 1, 15, and 29; PI 5-FU 180 mg/m2 for 24 hours for 35 days; and XRT 1.8 Gy in 28 fractions starting on day 8.  At completion of cycle 1, eligible patients could undergo an operation or begin cycle 2 without XRT.  Post-operative patients were eligible for cycle 2.  Stage IV patients were allowed 3 cycles in the absence of disease progression.  OXP and 5-FU increases were based on dose-limiting toxicity (DLT) encountered in cohorts of three consecutive patients.  Thirty-eight eligible patients received therapy: 22 non-invasively staged as IV and 16 non-invasively staged as II and III.  Thirty-six patients completed cycle 1, 29 patients started cycle 2, and 24 patients completed cycle 2.  The combined-modality therapy was well-tolerated, but DLT prevented OXP and 5-FU escalation.  No grade 4 hematologic toxicity was noted.  Eleven grade 3 and two grade 4 clinical toxicities were noted in eight patients.  After cycle 1, 29 patients (81 %) had no cancer in the esophageal mucosa. Thirteen patients underwent an operation with intent to resect the esophagus; 5 patients (38 %) exhibited pathologic complete responses.  The authors concluded that OXP 85 mg/m(2) on days 1, 15, and 29 administered with PI 5-FU and XRT is safe, tolerable, and seems effective against primary EC.  The role of OXP in multi-modality regimens against EC deserves further evaluation.

Oxaliplatin appears to be as effective as cisplatin for esophageal cancer, with better tolerability.  Sumpter et al (2005) reported on a planned interim analysis to establish the optimal dose of capecitabine (X) to be used within a multicenter, randomized study evaluating the potential roles of oxaliplatin (O) and X in chemonaiive patients with advanced esophagogastric cancer. Patients were randomized to one of four regimens: epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX.  A total of 204 patients were randomized at the time of the protocol planned interim analysis.  Combined complete and partial response rates were ECF 31% (95% confidence interval [CI]: 18.7 to 46.3), EOF 39 % (95 % CI: 25.9 to 53.1), ECX 35 % (95 % CI: 21.4 to 50.3), and EOX 48 % (95 % CI: 33.3 to 62.8).  The investigators concluded that the replacement of C by O does not appear to impair efficacy

Guidelines from the National Comprehensive Cancer Network (2006) guidelines on esophageal cancer state that an oxaliplatin-based regimen may be indicated for recurrent or metastatic disease in patients with Karnofsky performance score greater than 60 or Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 2.

Gastric Cancer

The U.S. Pharmacopeial Convention (2004) has concluded that gastric cancer is an accepted off-label indication for oxaliplatin.  Several clinical trials have demonstrated response rates in the order of 40 to 60 % with combination chemotherapy regimens that incorporate oxaliplatin. 

Zhang et al (2004) reported on the results of a controlled clinical trial involving 48 patients with advanced gastric cancer were divided into a group treated with an oxaliplatin-containing regimen (oxaliplatin, leukovorin, 5-fluorouracil, and etoposide (VP-16) and control group receiving a standard chemotherapy regimen containing DDP in place of oxaliplatin (DDP, leukovorin, 5-fluorouracil, andVP-16).  The response rate was 64 % (16/25) in the oxaliplatin-treatment group (25 cases) and 34.8 % (8/23) in the control group receiving standard chemotherapy (23 cases), a difference that was statistically significant (p < 0.05).  The median survival and 1-year survival rates were 11.5 months and 45.6 % for the treatment group versus 10.5 months and 36.5 % for the control group.  There was, however, no statistical difference in 2 groups for overall survival (p > 0.05, log-rank test).  The main differences in side effects were significantly more sensory neuritis in the treatment group and significantly more nausea and vomiting in the control group.  The incidence of other side effects were similar between groups.  The investigators concluded that the oxaliplatin-containing regimen was effective and well-tolerated for gastric carcinoma.

Yang et al (2004) reported on the results of a controlled clinical study comparing combination chemotherapy with oxaliplatin and hydroxycamptothecine with a standard chemotherapy regimen of VP-16, leucovorin calcium and 5-fluorouracil in 43 patients with advanced gastric cancer.  The response rate was 58.3 % (14/24) in the treatment group and 42.1 % (8/19) in the control group, a difference that was statistically significant.  The investigators reported that these chemotherapy regimens were well tolerated.

Rivera and associates (2019) stated that the phase-III ToGA Trial established cisplatin, fluoropyrimidine and trastuzumab as the standard treatment in HER2-positive advanced gastric cancer (AGC).  However, as shown in HER2-negative AGC, oxaliplatin-based regimens could improve tolerance remaining effective.  In a prospective, multi-center, non-randomized, non-controlled, open-label and national (Spanish) phase-II clinical trial, these investigators examined the potential activity and safety of capecitabine, oxaliplatin (XELOX) and trastuzumab in patients with HER-2 positive AGC.  Patients with HER2-positive AGC or gastro-esophageal junction (EGJ) cancer received XELOX and trastuzumab as 1st-line treatment.  Primary end-point was objective response rate (ORR) of the tumor.  A total of 45 patients from 10 hospitals in Spain were included from September 2011 to December 2013.  Median age was 65 years, 82.2 % were men, 69 % had gastric cancer and 31 % had EGJ tumors.  At a median follow-up of 13.7 months (7.1 to 20.9), the estimated median PFS and OS were 7.1 (95 % CI: 5.5 to 8.7) and 13.8 months (95 % CI: 10.1 to 17.4), respectively, with 8.9 %, 37.8 % and 31.1 % of patients achieving complete response (CR), partial response (PR) and stable disease (SD).  Regarding safety, 44.4 % of the patients had grade-3 or greater adverse events (AEs) with diarrhea (26.6 %), fatigue (15.5 %), nausea (20 %) and vomiting (13.3 %) being the most frequent.  Only 2 patients (4.4 %) developed asymptomatic grade-2 left ventricle ejection fraction (LVEF) reduction.  The authors concluded that XELOX-trastuzumab is a promising and effective therapy as 1st-line treatment for patients with HER2-positive AGC, with comparable results to the ones obtained with other "platinum-based" regimens.  This scheme is feasible and tolerable with a low incidence of cardiac toxicity.  These preliminary findings need to be validated by well-designed studies.

Takahari and colleagues (2019) noted that trastuzumab with cisplatin and fluoropyrimidines improves OS in patients with HER2-positive AGC.  S-1 plus oxaliplatin (SOX) is one of the standard regimens for HER2-negative AGC in Japan.  However, few studies have evaluated trastuzumab combined with SOX in patients with HER2-positive AGC.  In a multi-center, phase-II study conducted at 10 institutions in Japan, patients with HER2-positive AGC received S-1 twice-daily on days 1 to 14 and oxaliplatin and trastuzumab on day 1 of a 21-day cycle.  The primary end-point was the confirmed ORR, and the secondary end-points were OS, PFS, and safety.  The sample size was 75 to have 90 % power with an alpha error of 0.1 (1-sided), expecting an ORR of 65 % and threshold of 50 %.  From June 2015 to January 2018, a total of 75 patients were enrolled.  The ORR was 70.7 % [95 % CI:  59.0 to 80.6].  The median OS and PFS were estimated as 18.1 months (95 % CI: 15.6 to 26.5) and 8.8 months (95 % CI: 7.4 to 12.2), respectively.  The major grade-3 or grade-4 AEs were sensory neuropathy (16.0 %) and neutropenia (10.7 %).  The authors concluded that trastuzumab with SOX exhibited promising activity with well-tolerated toxicities for patients with HER2-positive AGC.  These preliminary findings need to be validated by well-designed studies.

Hepatobiliary Cancers

Vienot and Neuzillet (2020) stated that biliary tract cancers (BTC) are a heterogeneous group of epithelial neoplasms, with a poor prognosis.  Advanced BTC remains a challenging, non-curable disease.  These investigators provided an overview of the therapeutic options in advanced BTC and new strategies under development.  Gemcitabine plus platinum chemotherapy is the standard 1st-line therapy in this setting.  Recently, 5-FU, folinic acid plus oxaliplatin (FOLFOX) regimen became the only 2nd-line therapy to be prospectively validated beyond failure of gemcitabine plus cisplatin combination in a phase-III clinical trial, even though chemotherapy yielded modest survival improvement over best supportive care.  Anti-epidermal growth factor receptor and anti-angiogenic antibodies have not demonstrated any survival benefit in unselected patient populations.  In recent years, knowledge about the molecular heterogeneity of BTC has considerably increased with the advent of large-scale genomic and transcriptomic analyses, opening up new perspectives for so-called personalized targeted therapies.  Patients with BTC may be particularly good candidates for biomarker-driven strategies in clinical practice.  Among current developments, the targeting of fibroblast growth factor receptor and isocitrate dehydrogenase gene alterations are the most promising avenues, and combination immunotherapies are under investigation.

Non-Hodgkin's Lymphoma

Oxaliplatin has been used alone or in combination in the treatment of patients with recurrent or refractory non-Hodgkin's lymphoma (NHL).

Addeo et al (2004) noted that high and intermediate grade NHL require treatments with aggressive chemotherapy schedules.  However, low grade NHLs display a low chemo-responsiveness and patients aged greater than 65 years often do not tolerate anthracycline and corticosteroid-containing chemotherapy regimens.  Therapeutic options in this subset of patients are watchful waiting, oral alkylating agents, purine nucleoside analogues, combination chemotherapy, interferon and monoclonal antibodies.  The approval of rituximab, an unconjugated chimeric antibody against the CD20 antigen for the treatment of B-cell NHL marked a milestone in the development of antibody treatment.  Moreover, promising results have also been found with oxaliplatin in patients with NHL and reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy.  On the basis of these considerations these researchers performed a feasibility study in NHL in patients aged over 65 years using as schedule: 130 mg/m2 oxaliplatin every 21 days and 375 mg/m2 rituximab weekly.  A total of 8 patients were enrolled -- 2 males and 6 females (mean age of 69.2 +/- 3.1 years; median of 67 years) affected by intermediate or high grade stage III/IV NHL.  Six patients have cardiac abnormalities (myocardial function between 45 % and 50 %) and 1 increase of transaminasemia due to active chronic hepatitis.  All the patients included in the study were treated for at least 3 cycles and 31 cycles were completed.  These researchers recorded grade I/II (CTC) neurotoxicity in 30 %, grade I anemia in 25 % and grade I neutropenia in 20 % of the patients.  No infusional reactions, liver or renal toxicity neither nausea and/or vomiting were recorded.  One complete response (CR), 3 partial response (PR) and 3 minimal response were obtained at 11 months of median time follow-up.  These results demonstrated the feasibility of this schedule, which offers a suitable alternative regimen to treat elderly patients with NHL and shows a good efficacy and an acceptable toxicity profile.

In a phase II clinical trial, Oki et al (2005) examined the activity of oxaliplatin in patients with recurrent or refractory NHL.  Patients with recurrent and refractory NHL who received a maximum of 3 previous chemotherapy regimens were considered eligible if they had an ECOG performance status of 0 to 2 and adequate organ function.  Oxaliplatin was administered in an outpatient setting at a dose of 130 mg/m(2) by 2-hour intravenous infusion every 21 days for less than or equal to 6 cycles in the absence of disease progression.  A total of 31 patients (23 with aggressive NHL and 8 with indolent NHL) were enrolled, of whom 30 were assessable for toxicity, response, and survival.  The median patient age was 62 years, and 20 % of the patients previously received platinum-containing therapy.  Eighty-three percent of the patients were refractory to their last treatment regimens.  Grade 3 and 4 toxic effects (according to the National Cancer Institute's Common Toxicity Criteria [version 2.0]) included sensory neuropathy (10 %), neutropenia (17 %), and thrombocytopenia (20 %).  Objective responses occurred in 8 (27 %; 95 % CI: 13 to 47 %) of the patients.  Responses were observed in platinum-naive patients as well as in those previously treated with platinum.  The overall median failure-free survival duration was 3.0 months (range of 0.1 to 18.1 months).  The authors concluded that oxaliplatin had favorable single-agent activity in previously treated patients with refractory lymphoma.  The favorable safety profile and the ease of its administration in outpatient settings warrant investigating it in combination with other active drugs for the treatment of recurrent and refractory NHL.

In a phase II clinical trial, Alinari et al (2005) assessed the effectiveness and toxicity profile of oxaliplatin in a group of heavily pre-treated patients with NHL.  A total of 19 pre-treated patients were enrolled.  The drug was administered intravenously on day 1 of a 21-day schedule, at a dose of 130 mg/m2 for a total of 6 cycles.  One (5 %) patient achieved CR and 5 patients (27 %) had PR, thus giving an overall response rate of 32 %.  The patient in CR suffered from an aggressive B NHL.  One of the 5 patients in PR had an aggressive B NHL, whereas the remaining 4 had an indolent B NHL.  The treatment was well-tolerated with minimal hematologic and extra-hematologic toxicity.  These data suggest and confirm the effectiveness and low toxicity of oxaliplatin in the treatment of patients with heavily pretreated NHL.  Further trials using oxaliplatin alone or in combination with other conventional drugs are needed.

Woehrer et al (2005) stated that patients with relapsed diffuse large B-cell lymphoma (DLBCL) who are either not suitable for stem cell transplantation or suffer from relapsed disease after standard 2nd-line chemotherapy face a dismal prognosis.  Most of them have a reduced performance status and do not tolerate intensive chemotherapy.  These researchers reported their findings on 20 patients with relapsed DLBCL who were given rituximab 375 mg/m(2) intravenously on day 1, Ara-C 2 x 1,000 mg intravenously on day 2, dexamethasone 40 mg intravenously on days 1-4, and oxaliplatin 130 mg/m(2) intravenously over 2 hours on day 3 (R-ADOx).  Five patients (25 %) achieved CR, 9 (45 %) had a PR, 2 (10 %) had stable disease with improvement in performance status, while 4 patients (20 %) progressed.  The median survival was 11 months (range of 1 to 13).  Despite extensive pre-treatment, side effects were relatively mild and consisted of thrombocytopenia WHO grade III in 9 (45 %) and grade IV in 2 (11 %) patients, leukocytopenia WHO grade III in 10 (50 %) cases (with infectious episodes in 2 patients), and transient peripheral neuropathy in 9 (45 %) patients.  The authors concluded that R-ADOx is well-tolerated in heavily pretreated patients with an impaired performance status.  In addition, it displays impressive therapeutic activity given the highly unfavorable patient characteristics and should be further investigated for treatment of DLBCL.

In a pilot study, Corazzelli and colleagues (2006) evaluated the clinical activity, toxicity and mobilizing capacity of a new salvage regimen, which combines gemcitabine and oxaliplatin with ifosfamide and rituximab (R-GIFOX) in patients with relapsed and refractory CD20(+) NHL.  Patients were scheduled to receive 3 courses of therapy followed by mobilization and autologous stem cell transplantation (ASCT) or 3 more courses if ineligible for ASCT.  R-GIFOX consisted of rituximab (375 mg/m(2) on day 1, gemcitabine (1000 mg/m(2) on day 2, oxaliplatin (130 mg/m(2) on day 3 and ifosfamide (5 g/m(2) on day 3 as a 24-hour single infusion in patients aged less than or equal to 65 years, or fractionated over 3 days (days 3 to 5) in patients aged over 65 years.  Treatment was given every 2 weeks with G-CSF support (5 microg/kg/day or 10 microg/kg/day at the end of the third course for stem cell mobilization).  Responses were evaluated by the integrated FDG-PET/IWC criteria after the 3rd course and at the end of the entire program.  A total of 14 patients (median age of 63 years, range of 37 to 78 years) with relapsed (n = 9) or primary progressive (n = 5) aggressive (diffuse large cell, mantle cell, follicular G3), advanced (stage IV 71 %), poor risk (IPI 3 to 5, 50 %) NHL were accrued in this study.  Patients had received a median of 2 previous treatment lines (range of 1 to 4).  The median number of R-GIFOX courses delivered was 4 (range of 1 to 6).  Thirteen patients completed at least 3 courses of therapy and were evaluable for response.  The overall response rate assessed after 3 courses of R-GIFOX was 77 %, with 7 CR and 3 PR.  Effective CD34(+) cell mobilization was obtained in 4 of 6 eligible patients and 2 had ASCT.  Hematologic and extra-hematologic toxicity was tolerable.  Failure-free survival was 79.6 % at median follow-up of 6 months (range of 2 to 12).  Molecular remissions were documented in 2 patients with mantle cell NHL.  The authors concluded that the R-GIFOX regimen is feasible, tolerable, effective and able to mobilize peripheral stem cells in patients with relapsed and refractory aggressive NHL.

In a phase II clinical trial, El Gnaoui et al (2007) assessed the effectiveness and toxicity of rituximab, gemcitabine and oxaliplatin (R-GemOx) for patients with relapsed or refractory B-cell lymphoma who are not candidates for high-dose therapy.  Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo.  Forty-six patients with relapsed or refractory B-cell lymphoma received up to 8 cycles of R-GemOx (rituximab 375 mg/m2 on day 1, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2 on day 2).  The majority (72 %) had diffuse large B-cell lymphoma.  After 4 cycles of R-GemOx, the overall response rate was 83 % [50 % complete response (CR)/unconfirmed CR (CRu)].  High CR/CRu rates were observed in all histological subtypes.  In patients who had previously received rituximab, the CR/CRu rate after eight cycles was 65 %. The 2-year event-free and overall survival rates (median follow-up of 28 months) were 43 % and 66 %, respectively.  Among responders, the probability of being disease free for 2 years was 62 %. Treatment was generally well-tolerated.  The investigators reported that R-GemOx shows promising activity with acceptable toxicity in patients with relapsed/refractory B-cell lymphoma who are not eligible for HDT.

Rodríguez et al (2007) reported the results of R-GemOx, in 14 patients with relapsing (n = 9) or refractory (n = 5) mantle cell lymphoma. The median number of cycles was 5.5 for a total of 72 cycles. The median age was 69.5 years with high-risk features.  Patients received a mean number of prior treatment lines of 1.79.  Sixty-four percent achieved a total response rate of 85%.  With a median follow-up of 11 months, overall survival and progression-free survival were 58% and 45% at 12 months. The major toxicity was thrombopenia grade III-IV (35%).  Factors related with overall survival were ECOG performance status and adjusted International Prognostic Index (a-IPI) at GEMOX-R.  The authors concluded that R-GemOx displays an outstanding efficacy with an excellent toxicity profile in a pretreated elderly population.

In a phase II trial, López et al (2008) assessed the results of a R-GemOx regimen in patients with refractory or relapsing diffuse large-cell lymphoma (DLCL).  A total of 32 patients received R-GemOx regimen in 2-week intervals if feasible or every 3 weeks for a planned six to eight courses. The median age of the population was 69 years.  Forty-one percent of the patients were primary refractory and 59% after relapsing.  At R-GemOx , 75% of patients had a stage III-IV and an a-IPI greater than 1 was observed in 69%. The response rate was 43% with 34% complete response.  Neutropenia and thrombopenia grade III-IV were observed in 43% of the patients and neurotoxicity grade III-IV in 7% of cases.  Median follow-up for alive patients was 13 months and the median survival was 9.1 months.  At 12 months, the overall survival and progression-free survival were 41% and 29%, respectively.  The investigators concluded that R-GemOx is a new salvage regimen for DLCL with high activity and relatively safe toxicity profile, which can be offered to elderly patients not candidates of ASCT consolidation.  The high efficacy of the regimen in this unfavorable population and also in immunocompromised situations warrant further investigation of this regimen in all salvage situations of this type of lymphomas.

Mesothelioma

Hubert et al (2015) stated that peritoneal mesothelioma is a rare disease with poor prognosis. The present study reported a single-center experience with cyto-reductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy with oxaliplatin (HIPEC-OX) over an 8-year period. Prospectively collected data of all consecutive patients with epithelial or multi-cystic peritoneal mesothelioma from August 2004 to October 2012 was analyzed. Patients with sarcomatoid or bi-phasic peritoneal mesothelioma were not included due to general poor prognosis. Treatment consisted in CRS and HIPEC-OX (460 mg/m(2)) at 43 °C during 30 mins. For statistical analysis, Kaplan-Meier survival curves were plotted and compared using log-rank tests. Cox proportional-hazards regression model was used to analyze the influence of different variables on survival. A total of 19 patients with peritoneal mesothelioma underwent laparotomy with CRS and HIPEC-OX with curative intent (15 epithelial, and 4 multi-cystic). Mean follow-up was 36.7 months. The estimated 1-year and 3-year overall survival (OS) rates were 100 % and 91 %, respectively. The estimated 1-year and 3-year disease-free survival (DFS) rates were 77 % and 50 %, respectively. Complications were graded according to the Clavien-Dindo classification and major complications occurred in 57 % of cases. There was no post-operative mortality; histological grade was not a prognostic factor of DFS (p = 0.37). The authors concluded that when comparing survival results as well as morbidity-mortality rates, the present study showed that CRS and HIPEC-OX is a valid treatment for peritoneal mesothelioma. These preliminary findings need to be validated by well-designed studies.

Neuroendocrine Tumors

Dussol et al (2015) noted that the alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by GEMOX in previous studies prompted this study to
  1. confirm the use of GEMOX in a larger population of NET patients,
  2. compare its effectiveness with that of ALKYs, and
  3. explore whether the O6 -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen.
A total of 104 patients with metastatic NETs (37 pancreatic NETs, 33 gastro-intestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKY;. MGMT promoter gene methylation was assessed via pyro-sequencing in 42 patients. Patients received a median of 6 courses of GEMOX; 24 (23 %) had an objective response (OR). The median progression-free survival (PFS) and OS were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22 % and 22 %) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53 % of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (p = 0.03 for OR and p = 0.04 for PFS) but not GEMOX. The authors concluded that GEMOX is effective against NETs; its activity was comparable to that of ALKYs, and it was not influenced by the MGMT status. They stated that these findings suggested that GEMOX might be preferred for patients with unmethylated MGMT tumors.

NCCN’s clinical practice guideline on "Neuroendocrine and adrenal tumors" (Version 1.2023) lists oxaliplatin as category 2A recommendation for neuroendocrine tumors of the pancreas, for management of unresectable locoregional disease and/or distant metastatic disease in patients with symptoms, clinically significant tumor burden, or clinically significant progression. The NCCN guidelines have a category 3 cytotoxic chemotherapy for unresectable and/or metastatic neuroendocrine tumors of the gastro-intestinal tract, lung and thymus (carcinoid tumors). The NCCN guidelines state “The benefits associated with cytotoxic chemotherapy in patients with advanced NETs appear, at best, to be modest. Tumor response rates are generally low, and no PFS benefit has been clearly demonstrated …. The combination of capecitabine and oxaliplatin was assessed in a phase II study, with response rates of 23 % in patients with poorly differentiated neuroendocrine tumors and 30 % in well-differentiated disease …. The panel lists cytotoxic chemotherapy for carcinoid tumors as a category 3 recommendation. While some panelists believe the toxicity of systemic therapy does not warrant its wide-spread use in this population, others believe that it is an important alternative for patients without other options for treatment”.

Ovarian Cancer

Guidelines from NCCN (2023) state that oxaliplatin is an acceptable alternative chemotherapeutic regimen for recurrent epithelial ovarian cancer for Stage II, III, and IV patients with partial responses to their primary paclitaxel and platinum-based chemotherapeutic regimens.  The guidelines note that oxaliplatin has been demonstrated to be active in recurrent epithelial ovarian cancer.

Pancreatic Cancer

Systemic chemotherapy with 5-FU-based combinations had minimal impact on natural history of pancreatic cancer.  Several new agents have been identified over the past decade.  Favorable adverse effect profile and tolerability are clear advantages of single-agent gemcitabine and enable its incorporation into combination regimens.  Currently, the most widely used regimens involve combination partners such as 5-FU, cisplatin, and docetaxel.  Recently, combination therapy using gemcitabine and oxaliplatin has been studied in the treatment of patients with advanced or metastatic pancreatic adenocarcinoma (ACA).

In a phase II clinical study, Alberts et al (2003) examined the effectiveness of gemcitabine and oxaliplatin in patients (n = 47) with advanced or metastatic pancreatic ACA.  Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle.  The primary endpoint of the trial was 6-month survival.  Secondary endpoints included response rate, overall survival, median time to progression and toxicity.  Of the 46 patients assessed for the primary endpoint, 50 % lived for greater than or equal to 6 months.  The median time to progression was 4.53 months.  Five confirmed responses were seen with a median duration of response of 2.7 months.  Overall, the treatment was well-tolerated.  However, 1 patient died as a result of treatment-related hemolytic uremic syndrome.  The authors concluded that gemcitabine and oxaliplatin, at doses of 1000 mg/m2 and 100 mg/m2, respectively, showed moderate activity in patients with pancreatic ACA. 

In a phase II clinical study, Conroy et al (2005) examined the effectiveness of oxaliplatin with irinotecan, leukovorin and 5-fluorouracil in chemotherapy-naive patients with histologically proven pancreatic ACA.  Patients were treated every 2 weeks.  Forty-seven patients were entered, and 46 received treatment.  Thirty-five patients (76 %) had metastatic disease.  Subjects received a median of 8 cycles (range of 1 to 24 cycles).  Grade 3 to 4 neutropenia occurred in 52 % of patients, including 2 patients with febrile neutropenia.  Other relevant toxicities included grade 3 to 4 nausea (20 %), vomiting (17 %), and diarrhea (17 %) and grade 3 neuropathy (15 %).  The confirmed response rate was 26 % (95 % CI: 13 % to 39 %), including 4 % complete responses.  Median time to progression was 8.2 months (95 % CI: 5.3 to 11.6 months), and median overall survival was 10.2 months (95 % CI: 8.1 to 14.4 months).  Between baseline and end of treatment, patients had improvement in all quality of life functional scales, except cognitive functioning.

Decreaux reported on the results of a randomized phase II, open-label multicenter study evaluating oxaliplatin alone, infusional 5-fluorouracil alone and an oxaliplatin/infusional 5-FU combination in untreated, advanced pancreatic carcinoma.  Sixty-three patients were treated: 17 patients received oxaliplatin, 31 patients received oxaliplatin combined with 5-FU, and 15 patients received 5-FU, with a median of 3, 6 and 2 cycles per patient, respectively.  All responses (3 partial responses) occurred in subjects receiving the oxaliplatin/5-FU combination therapy (10 % response rate).  Five of 32 patients evaluable for clinical benefit were responders (oxaliplatin, 14%; oxaliplatin/5-FU combination, 21 %).  Median time to progression and overall survival were higher in the combination arm (4.2 and 9.0 months, respectively) than either single-agent arm (oxaliplatin, 2.0 and 3.4 months; 5-FU, 1.5 and 2.4 months, respectively).  The investigators concluded that, with a 10 % response rate, median overall survival of 9 months and an encouraging safety profile, the oxalliplatin/5-FU combination is effective, appears superior to infusional 5-FU and warrants further studies in pancreatic adenocarcinoma patients.

Based upon results of a phase III clinical study comparing gemcitabine in combination with oxaliplatin (GEMOX) versus gemcitabine alone, guidelines on pancreatic adenocarcinoma from the National Comprehensive Cancer Network (2022) indicate the use of oxaliplatin in combination with gemcitabine for patients with locally advanced or metastatic disease and good performance status.  These guidelines also recommend the use of oxaliplatin as subsequent therapy in combination with fluorouracil/leucovorin or capecitabine for patients with progressive disease and good performance status who have not received prior fluoropyrimidine-based chemotherapy.

Platinum-Containing Regimens for Triple-Negative Metastatic Breast Cancer

Egger and colleagues (2020) noted that in a previous Cochrane review, they found that for women with metastatic breast cancer unselected for triple-negative disease, there is little or no survival benefit and excess toxicity from platinum-based regimens. However, in subgroup analyses, these investigators found preliminary low-quality evidence of a survival benefit from platinum-based regimens for women with metastatic triple-negative breast cancer (mTNBC). This review updated the evidence from the mTNBC subgroup analyses in the previous Cochrane review. These researchers examined the effects of platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with mTNBC. They obtained relevant studies published before 2015 and their extracted results from the mTNBC subgroup analysis in the previous Cochrane review. They searched the Cochrane Breast Cancer Group's Specialized Register, CENTRAL, Medline, Embase, the World Health Organization (WHO)'s International Clinical Trials Registry Platform and ClinicalTrials.gov between 2015 and September 27, 2019. These researchers identified further potentially relevant studies from previous trial reports, systematic reviews, and meta-analyses. Randomized trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with mTNBC were selected for analysis. Individual trials could compare 1 or more platinum-based regimens to 1 or more non-platinum regimens; hence there could be more “treatment-comparisons” (i.e., platinum regimen versus non-platinum regimen comparison) than trials. Trial subjects may have been purposely selected for mTNBC or inadvertently selected as a subgroup. At least 2 independent reviewers evaluated studies for eligibility and quality; and extracted all relevant data from each study. They derived hazard ratios (HRs) for time-to-event outcomes, where possible, and used fixed-effect models for meta-analyses. They analyzed objective tumor response rates (OTRRs) and toxicities as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. They extracted QOL data, if available. These investigators used GRADE to rate the quality of evidence for time-to-event and tumor response outcomes. This review includes 13 treatment-comparisons involving 1,349 women from 10 studies; 12 of the 13 treatment-comparisons were included in 1 or more meta-analyses. Of the 13 treatment-comparisons, 6 and 8 had published or provided time-to-event data on OS or PFS/time to progression (TTP), respectively, that could be included in meta-analyses. A total of 10 treatment-comparisons published or provided OTRR data that could be included in meta-analyses; 8 of the 13 treatment-comparisons were from studies that selected subjects on the basis of mTNBC status, while the other 5 treatment-comparisons were from studies that reported mTNBC results as part of subgroup analyses. Analysis of 6 treatment-comparisons indicated that platinum-containing regimens may have provided a small survival benefit to mTNBC patients (HR 0.85, 95 % CI: 0.73 to 1.00; 958 women; moderate-quality evidence) with no evidence of heterogeneity (p = 0.41; I2 = 1 %). Data from 8 treatment-comparisons showed that platinum regimens may improve PFS/TTP (HR 0.77, 95 % CI: 0.68 to 0.88; 1,077 women; very low-quality evidence). There was marked evidence of heterogeneity (p < 0.0001; I2 = 80 %). There was also low-quality evidence of better tumor response for platinum recipients (RR 1.40, 95 % CI: 1.22 to 1.59; 1,205 women) with some evidence of heterogeneity (p = 0.01; I2 = 58 %). The observed heterogeneity for the PFS/TTP and OTRR outcomes may reflect between-study differences and general difficulties in evaluating tumor response, as well as the varying potencies of the comparators. Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were higher for platinum recipients (RR 4.77, 95 % CI: 1.93 to 11.81; 655 women; low-quality evidence) and rates of grade 3 and 4 anemia were higher for platinum recipients (RR 3.80, 95 % CI: 2.25 to 6.42; 843 women; low-quality evidence). In general, however, relatively few intervention-comparisons could be included in meta-analyses for AEs; none of the studies reported QOL. The authors concluded that for women with mTNBC, there was moderate-quality evidence of a small survival benefit from platinum-based regimens compared to non-platinum regimens. This finding was consistent with findings of a PFS/TTP benefit and improved tumor response from platinum-based regimens. These potential benefits, however, should be weighed against previously identified excess toxicities from platinum-based regimens, especially regimens containing cisplatin. These researchers stated that further randomized trials of platinum-based regimens among women with mTNBC are needed.

Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with Oxaliplatin for Peritoneal Metastasis

Kim and colleagues (2018) stated that pressurized intra-peritoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic intra-peritoneal chemotherapy technique, with advantages such as homogeneous distribution of aerosol and deeper tissue penetration.  Thus far, PIPAC oxaliplatin has been administered at an arbitrary dose of 92 mg/m2.  In a phase-I 3+3 dose escalation study, these researchers determined the dose-related safety profile and tolerability of PIPAC oxaliplatin using an evidence-based approach.  The secondary aim was to evaluate clinicopathologic response and the pharmacokinetic profile.  This trial was carried out for gastric cancer and CRC with predominant peritoneal metastasis starting at a dose of 45 mg/m2.  Safety was evaluated according to Clavien-Dindo Classification and Common Terminology Criteria for Adverse Events (version 4.0).  Clinicopathologic response was assessed using the Peritoneal Regression Grading Score, Peritoneal Cancer Index, and Response Evaluation Criteria In Solid Tumor criteria (version 1.1).  Pharmacokinetic analysis was performed using Inductively Coupled Plasma-Mass Spectrometry assay.  The authors concluded that the findings of this phase-I study could provide the scientific basis to identify the optimal dose for PIPAC with oxaliplatin such that the benefits of this novel and promising intra-peritoneal chemotherapy delivery technique could be maximized.

Dumont and associates (2018) noted that the annual incidence of gastro-intestinal (GI) carcinomas (stomach, small bowel, colon and rectum) is increasing in Western nations, reaching 50,000 new cases each year in France.  Peritoneal carcinomatosis (PC) is diagnosed in 15 % of these patients.  Complete CRS plus HIPEC is the only therapy that can offer patients with PC a chance for long-term survival with a 5-year OS rate of 30 to 60 % versus 0 to 5 % with systemic chemotherapy alone.  However, complete CRS plus HIPEC still presents serious limitations and very few patients (10 %) are candidates for these radical treatments.  PC remains a palliative setting for 90 % of patients with a median survival ranging from 15 to 25 months.  Innovative surgical therapies such as PIPAC therefore need to be developed to improve the prognosis.  Potential benefits were obtained following intra-peritoneal nebulization of oxaliplatin in patients with advanced PC from CRC.  Innovative surgical therapies such as PIPAC have been proposed as palliative loco-regional treatment with some promising results.  The dose of oxaliplatin currently established by nebulization (PIPAC) is really low at 92 mg/m2.  However, the peritoneum acts as a barrier limiting the systemic passage of intra-peritoneal drug.  Oxaliplatin used at higher doses during PIPAC procedures could be a safe option and allow better intra-tumoral penetration of chemotherapy.  The proposed study is a multi-center phase-I/II clinical trial of oxaliplatin dose escalation during PIPAC.  The objective is to determine the maximum tolerated dose (MTD) of pressurized oxaliplatin administered by PIPAC during 2 consecutive procedures at a 4 to 6 week interval for patients with extended PC from the GI tract.  Dose started at 90 mg/m2 and escalation was in 50 mg/m2 steps up to a maximum of 300 mg/m2.  The authors concluded that oxaliplatin is an effective drug in GI cancer and high doses given by the intra-peritoneal route during HIPEC are well-tolerated.  In this phase-I clinical trial, these researchers hypothesized that high-dose oxaliplatin during PIPAC is feasible and safe.  The repeated local administration of high doses of oxaliplatin could improve tumor response and prognosis.

Lurvink and colleagues (2021) stated that PIPAC with oxaliplatin (PIPAC-OX) is increasingly used as a palliative therapeutic option for patients with colorectal peritoneal metastases (CPM). In a systematic review, these researchers examined the safety and efficacy outcomes of PIPAC-OX in patients with CPM. PubMed, Embase, the Cochrane Library, and CINAHL were systematically searched to identify all clinical studies that included at least 1 patient with CPM treated with PIPAC-OX and reported one of the following outcomes: AEs, tumor response, quality of life (QOL), secondary CRS, PFS, OS, and environmental safety of PIPAC-OX. Of 28 included studies, only 14 non-comparative studies separately reported at least 1 outcome of PIPAC-OX for CPM, of which only 2 studies specifically focused on this group. These 14 studies reported AEs (5 studies), tumor response (5 studies), secondary CRS (4 studies), PFS (1 study), OS (5 studies), and environmental safety (2 studies). Except for 5 studies (describing 26 patients), none of the included studies stratified their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and none of the studies reporting survival outcomes stratified results for line of palliative treatment, complicating interpretation. No PIPAC-OX related deaths were reported. No occupational platinum was detected during PIPAC-OX. The authors concluded that the available evidence regarding PIPAC-OX for CPM is limited and difficult to interpret. Despite these limitations, PIPAC-OX appeared safe in patients with CPM and safe for operating personnel. To increase insight in the role of PIPAC-OX in this setting, investigators of ongoing and future studies are encouraged to report separate outcomes of PIPAC-OX for CPM, to stratify their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and to stratify survival results for line of palliative treatment. These investigators stated that these findings may aid in designing future randomized trials that are needed to determine the exact role of PIPAC-OX in patients with CPM.

Small Bowel Cancers and Other Indications

Locher et al (2005) evaluated the effectiveness of 5-FU and either platinum compounds or irinotecan in patients with advanced small bowel adenocarcinoma (SBA), for whom data on the effectiveness of chemotherapy are scarce.  These researchers reviewed data on all patients with advanced SBA who received chemotherapy over a 9-year period at their institution.  A total of 20 patients with advanced SBA received a median of 6 cycles (range of 2-15) of chemotherapy with 5-FU and either cisplatin (n = 15), carboplatin (n = 2), or oxaliplatin (n = 3). The overall response rate was 21%, and median progression-free and overall survival 8 and 14 months, respectively.  Toxicity was moderate.  Second-line chemotherapy with 5-FU and irinotecan resulted in disease stabilization in 4 (50%) of 8 patients (median progression-free survival of 5 months), and in a biological CR in another patient with non-measurable peritoneal carcinomatosis, allowing surgical cytoreduction surgery and hyperthermic intra-peritoneal chemotherapy.  No tumor response or disease stabilization was seen among the patients who received protracted venous infusion of 5-FU (n = 4) or infusional 5-FU and cisplatin (n = 1) as second-line chemotherapy.  The authors concluded that chemotherapy with 5-FU and platinum compounds seems effective and well-tolerated in patients with advanced SBA; and 5-FU-irinotecan combination chemotherapy deserves further investigation in the first-line setting.

Oh et al (2007) stated that docetaxel chemotherapy is the current standard of care for metastatic hormone-refractory prostate cancer (HRPC).  Platinum chemotherapy drugs (e.g., cisplatin and carboplatin) have moderate single-agent activity in HRPC.  Next-generation platinum drugs (e.g., satraplatin and oxaliplatin) may have additional activity in the management of HRPC.  Furthermore, neuroendocrine differentiation may play a role in disease progression, providing a rationale for platinum-based chemotherapy in the management of HRPC.  These investigators reviewed the Medline database for reports related to platinum-based chemotherapy in patients with advanced prostate cancer and evaluated studies that reviewed the role of neuroendocrine differentiation in the progression of HRPC.  Older studies from the 1970s and 1980s suggested a lack of activity of cisplatin and carboplatin; however, those studies were flawed at least in part by their methods of response assessment.  More recent phase II clinical trials of carboplatin suggested a moderate level of clinical and palliative activity when it was used as a single agent.  However, when carboplatin was combined with a taxane and estramustine, high response rates were observed in several recent studies.  In addition, a randomized trial suggested that satraplatin plus prednisone improved progression-free survival compared with prednisone alone.  For patients who progressed after docetaxel, no standard options existed in the literature that was reviewed.  Several preliminary reports suggested that carboplatin and oxaliplatin may have activity as second-line chemotherapy.  Platinum chemotherapeutic drugs historically have been considered inactive in HRPC, although a review of the data suggested otherwise.  In particular, carboplatin induced very high response rates when it was combined with estramustine and a taxane, but it also appeared to have activity in patients who progressed after docetaxel.  Satraplatin plus prednisone is being investigated in a large phase III trial as second-line chemotherapy for HRPC.

In a phase II clinical trial, Bidoli and colleagues (2007) evaluated the response rate safety of new platinum analog regimens, randomizing 147 patients with non-operable IIIB/IV non-small-cell lung cancer (NSCLC) to
  1. carboplatin (area under the curve = 5 mg min/ml) on day 1 plus gemcitabine (GEM) (1000 mg/m(2)) on days 1 and 8 for 6 cycles;
  2. same regimen for 3 cycles followed by docetaxel (Taxotere) (40 mg/m(2)) on days 1 and 8 plus GEM (1250 mg/m(2)) on days 1 and 8 for 3 cycles;
  3. oxaliplatin (130 mg/m(2)) on day 1 plus GEM (1250 mg/m(2)) on days 1 and 8 for 6 cycles.
Intention-to-treat objective response rates were 25 %, 25 % and 30.6 % in arms A, B and C, respectively.  Median survival was 11.9, 9.2 and 11.3 months in arms A, B and C, respectively.  Grade 3/4 neutropenia/anemia occurred in 29 %/12.5 %, 10 %/16.5 % and 8 %/6 % of arms A, B and C, respectively; grade 3/4 thrombocytopenia in 20.5 %, 16.5 % and 6 %; grade 1/2 neurological toxicity in 43 % of arm C.  The authors concluded that oxaliplatin/GEM (arm C) had similar activity to carboplatin/GEM (arm A), but milder hematological toxicity and may be worth testing in a phase III study against carboplatin/GEM in patients not suitable for cisplatin.  The sequential regimen gave no additional benefit.

Raez et al (2010) reviewed the available clinical data from studies investigating the third-generation platinum analog oxaliplatin in patients with advanced NSCLC.  Information was obtained from the PubMed database and from recent presentations at national and international meetings.  Oxaliplatin has been studied as monotherapy and in combination with a wide range of other chemotherapies (alkaloids, gemcitabine, pemetrexed, taxanes, and vinca), mainly in phase II trials.  Preliminary results from studies in which oxaliplatin-based doublets have been combined with targeted agents (e.g., bevacizumab) are now available.  In general, the clinical activity observed with oxaliplatin-based therapy is similar to that seen with other currently used platinum regimens, although outcomes varied between individual trials (response rates, 23 % to 48 %; median progression-free survival, 2.7 to 7.3 months; median overall survival, 7.3 to 13.7 months).  The toxicity profile of oxaliplatin, particularly when compared with cisplatin, makes it an alternative treatment, especially in patients unable to tolerate cisplatin.  However, the authors noted that well-conducted randomized phase III trials are needed to clarify which particular groups of patients with NSCLC may benefit from oxaliplatin-based therapy.

In a phase II clinical trial, Hainsworth and associates (2010) examined the combination of oxaliplatin and capecitabine in patients with recurrent and refractory carcinoma of unknown primary site (CUP).  Patients with CUP who had received at least 1 previous chemotherapy regimen were treated with oxaliplatin (130 mg/m(2) intravenously on day 1) and capecitabine (1000 mg/m(2) orally twice-daily on days 1 to 14).  Treatment cycles were repeated every 21 days.  Patients with objective response or stable disease after 2 cycles continued treatment for 6 cycles or until disease progression.  Nine of 48 patients (19 %) had objective responses to treatment; an additional 22 patients had stable disease at the time of first re-evaluation.  After a median follow-up of 17 months, the median progression-free and overall survivals were 3.7 months and 9.7 months, respectively.  This regimen was reasonably well-tolerated by most patients.  The authors concluded that the combination of oxaliplatin and capecitabine was found to have activity as a salvage treatment for patients with CUP.  This regimen should be considered in patients with clinical and pathological features suggesting a primary site in the gastrointestinal tract.  They stated that further development of the regimen as a first-line therapy, or with bevacizumab added, is indicated.

Moller et al (2010) reported the results obtained with oxaliplatin and capecitabine as second-line therapy in 25 recurrent/refractory CUP patients following first-line treatment with paclitaxel, cisplatin and gemcitabine.  Patients received capecitabine orally (1000 mg/m(2)) twice-daily, days 1 to 14, and oxaliplatin (130 mg/m(2)) intravenously on day 1 in a 3-week schedule.  A total of 25 CUP patients received a median of 3 cycles of capecitabine and oxaliplatin as second-line treatment.  Histopathological assessments suggested the primary site to be of gastro-intestinal tract origin in the majority of the patients (76 %).  These investigators found an objective response rate of 13 %, a median progression-free survival and overall survival rate of 2.3 and 3.9 months, respectively, and 32 % of patients alive at 1 year after initiation of second-line therapy.  The regimen was well-tolerated by most patients.  The authors concluded that these findings showed that there is still a significant need for improved second-line therapy in CUP patients.

Rabinowits et al (2010) examined the effects of fixed-dose every-other-week capecitabine and oxaliplatin for refractory squamous cell carcinoma of the head and neck (SCCHN).  Patients received fixed-dose capecitabine (1500 mg orally twice-daily) on days 1 to 7 and oxaliplatin (85 mg/m) days 1 and 14.  A total of 15 patients with refractory SCCHN were enrolled.  All patients had relapsed after surgery and had failed radiation therapy.  Overall, 13 patients (87 %) had progressed after chemotherapy.  The most common toxicities were grades 1 or 2 fatigue and anemia.  There was a 13 % partial response rate and 33 % stable disease rate for a clinical benefit of 46 % by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.  The authors concluded that fixed-dose capecitabine and oxaliplatin combination on an every-other-week schedule showed activity in refractory SCCHN.  The simplicity and toxicity profile of this regimen compares favorably with other commonly used chemotherapies and should be tested in larger studies.

In a phase II study, Locke and colleagues (2010) examined the effects of oxaliplatin, docetaxel, and GM-CSF in patients with previously treated advanced melanoma.  Eligibility included adequate organ function, performance status less than or equal to 2, at most one prior chemotherapy and one prior immunotherapy, no prior treatment with oxaliplatin or taxanes and no chremophor allergy.  After pre-medication, docetaxel was administered day 1 at 75 mg/m2, then oxaliplatin on day 2 at 85 mg/m2.  GM-CSF (250 mcg/m2) was administered subcutaneously days 3 to 12.  Cycles were 21 days in length, and disease re-evaluation was performed every 2 cycles by RECIST criteria.  A total of 19 patients received at least 1 cycle, 8 with one prior systemic therapy, 5 with 2 prior systemic therapies.  Five patients did not complete 2 cycles and were not formally evaluable for response.  Five patients had stable disease, including 1 who failed 2 prior therapies and went on to receive 10 cycles.  The remaining 9 patients displayed progressive disease after 2 cycles.  Notable toxicities included 7 cases (37 %) of grade III/IV neutropenia and 2 (11 %) hyper-sensitivity reactions.  The authors concluded that this combination of oxaliplatin, docetaxel, and GM-CSF has limited clinical activity in previously treated patients with advanced melanoma.  Exploration in treatment-naïve patients may still be warranted.

Cassier et al (2009) evaluated the effectiveness of gemcitabine-oxaliplatin combination (GEMOX) in the treatment of patients with metastatic neuroendocrine tumors.  A total of 20 consecutive patients with progressive disease were treated with GEMOX, in most cases after failure of other chemotherapy regimens (median = 2).  Patients were followed for evidence of toxicity, response, and survival.  Two patients were chemotherapy-naive at treatment initiation and were excluded from the efficacy analysis.  Toxicity was manageable overall; however, 6 (30 %) patients had to discontinue treatment because of oxaliplatin-induced neurotoxicity (grade 2).  Three (17 %) of 18 patients had a partial response, median progression-free survival was 7.0 months, and median overall survival was 23.4 months.  The authors concluded that gemcitabine-oxaliplatin combination shows interesting activity and is well-tolerated in pretreated patients with neuroendocrine tumors.  These findings need to be validated by well-designed studies.

UpToDate reviews on “Treatment of primary non-muscle invasive urothelial bladder cancer” (Kassouf and Black, 2023), “Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer” (Bellmunt and Gupta, 2023), and “Overview of the initial approach and management of urothelial bladder cancer” (Lerner 2023) do not mention the use of oxaliplatin as a therapeutic option.

An UpToDate review on “Treatment of metastatic urothelial cancer of the bladder and urinary tract” (Bellmunt, 2023) discusses oxaliplatin as a single-agent chemotherapy and noted response rates generally between 10 to 25 percent.

Kuo et al (2010) examined the effectiveness and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer.  Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible.  Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days.  The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required.  Sample size determinations were made using a Simon's 2-stage design with a projected overall response proportion of 13 % with cisplatin alone.  Survival rates were calculated with Kaplan-Meier methods.  Of the 35 patients enrolled, 32 were evaluable.  The median age was 56 (27 to 78); 30 had had prior radiation (23 concomitant with cisplatin).  Patients completed a mean of 4.2 cycles (1 to 11).  There were 2 complete and 5 partial responses for a total response rate of 7/32 (22 %; 95 % CI: 9.3 % to 40.0 %).  Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47 %; 95 % CI: 29.1 % to 65.3 %).  The mean time to best response was 13.5 weeks (95 % CI: 10.6 to 16.4).  The mean progression-free survival was 21 weeks (95 % CI: 14.7 to 27.2) and mean overall survival was 52 weeks (95 % CI: 39.4 to 64.8).  A total of 135 cycles were administered.  There were 28 (20.1 %) grade 3/4 hematologic toxicities and 46 (34.1 %) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy.  There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths.  The authors concluded that the combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin.  Moreover, they stated that further study and comparison with other platinum-based regimens is warranted.  This was a small study and its findings were confounded by the combinational use of paclitaxel and oxaliplatin.

UpToDate reviews on “Management of locally advanced cervical cancer” (Straughton and Yashar, 2023b),“Management of early-stage cervical cancer” (Straughton and Yashar, 2023a), and “Management of recurrent or metastatic cervical cancer” (Wright, 2023) do not mention the use of oxaliplatin as a therapeutic option.  

An UpToDate review on “Overview of the treatment of classical Hodgkin lymphoma in adults” (Canellos and Ak, 2020) does not mention the use of oxaliplatin. Melanoma is addressed in other NCCN guidelines; anal adenocarcinoma and anal melanoma are managed according to the NCCN guidelines for rectal cancer and the NCCN guideline for melanoma, respectively”.

The NCCN guidelines for colon cancer (Version 3.2023) state that “Acknowledging the lack of high-level data, the panel recommends that adenocarcinomas of the appendix be treated with systematic therapy according to these NCCN Guidelines for Colon Cancer.”

Abdel-Rahman (2014) noted that hepato-cellular carcinoma (HCC) is a global health problem, as it is the 6th most common cancer in the world and the 3rd leading cause of cancer-related death.  Many patients with HCC present with disease that is not suitable for any potentially curative therapy; such patients are candidates for palliative trans-arterial or systemic therapies.  Sorafenib is the only systemic therapy to demonstrate modest survival benefit over supportive care in the context of randomized controlled trials.  However, many cytotoxic chemotherapeutics have achieved a range of tumor responses, but so far without convincing survival benefits in smaller phase II studies.

Petrelli and colleagues (2014) stated that advanced HCC, for which loco-regional treatment is not an option, is a candidate for palliative systemic therapy, but an accepted chemotherapy regimen does not exist.  These researchers conducted a systematic literature review and meta-analyses to quantify the benefits of oxaliplatin (OXA)-based chemotherapy in advanced HCC in patients not exposed to sorafenib.  Studies that enrolled advanced HCC patients treated with 1st-line OXA-based chemotherapy were identified using PubMed, Web of Science, SCOPUS, The Cochrane Register of Controlled Trials and EMBASE.  A systematic review was conducted to calculate the pooled response rate and 95 % CI.  The pooled median PFS and OS, weighted on the number of patients of each selected trials, were also calculated.  These investigators tested for significant heterogeneity by Cochran's chi-squared test and I-square index.  A total of 13 studies were included in this review, with 800 patients analyzed.  The pooled response rate was 16.8 %. The median PFS and OS were 4.2 and 9.3 months, respectively, with a 1 year OS of 37 %.  The weighted median PFS/OS and response rate were 4.5/11 months and 20 % in Western patients.  Conversely, in Asiatic studies, the median PFS/OS and response rate were 2.43/6.47 months and 13.2 %, respectively.  The authors concluded that OXA-based chemotherapy is effective in advanced HCC and represents a viable option in these patients.  Moreover, they stated that a head-to-head comparison with sorafenib or a 2nd-line agent should be verified in prospective trials.

In a phase I study, Tsimberidou et al (2014) examined the effect of oxaliplatin with cytarabine and fludarabine therapy for patients with relapsed or refractory acute myeloid leukemia (AML).  Between January 2008 and November 2009, a total of 27 patients were registered in the study.  Patients had histologically confirmed disease, performance status 0 to 2, and adequate organ function.  The treatment regimen consisted of increasing doses of oxaliplatin (25, 30, or 35 mg/ m²/day) on days 1 to 4 (escalation phase), and fludarabine (30 mg/m²) and cytarabine (500 mg/m²) on days 2 to 6, every 28 days for less than or equal to 6 cycles.  The dose-limiting toxicity was defined as any symptomatic grade greater than or equal to 3 non-hematologic toxicity lasting greater than or equal to 3 days and involving a major organ system.  Of 27 patients, 12 were treated in the dose-escalation phase and 15 at the maximum tolerated dose for oxaliplatin (30 mg/m²; expansion phase).  All patients were evaluable for toxicity and response.  Only 1 patient received the 2nd cycle; the remaining patients received no further study treatment, owing to slow recovery from toxicities or physician decision.  Grade 3 to 4 drug-related toxicities included diarrhea (grade 4) and elevated levels of bilirubin (grade 3) and aspartate transaminase (grade 3).  In all, 3 patients had a complete remission and 2 patients complete response without platelet recovery.  The authors concluded that oxaliplatin, cytarabine, and fludarabine therapy had anti-leukemic activity in patients with poor-risk AML, but it was associated with toxicity.  Different schedules and doses may be better tolerated.

The NCCN’s clinical practice guideline on “Acute myeloid leukemia” (Version 6.2023) does not mention oxaliplatin as a therapeutic option.

Testicular Cancer

Testicular germ cell tumors represent the most frequent malignancy in young males aged 20 to 35 years.  Despite the considerably high cure rates provided by first line chemotherapy, 20 to 30 % of cases with advanced disease do not achieve a long-term disease-free survival with first-line chemotherapy. Guidelines from the NCCN (2023) state that oxalliplatin is an acceptable alternative for palliative chemotherapy of testicular cancer when used in combination with gemcitabine after first-line salvage therapy with ifosfamide, cisplatin and vinblastine (VeIP) regimen.

The German Testicular Cancer Study Group (Kollmannsberger et al, 2004) investigated the activity of a gemcitabine plus oxaliplatin regimen in 35 patients with cisplatin-refractory germ cell cancer.  Primary tumor localization was gonadal, retroperitoneal, or mediastinal in 30, 1, and 4 patients, respectively.  Patients had been pretreated with a platinum regimen and 89 % of patients previously had experienced treatment failure after high-dose chemotherapy with peripheral-blood stem-cell transplantation.  Sixty-three percent of patients were considered absolutely cisplatin-refractory or cisplatin-refractory.  Three patients attained a complete remission, 2 patients attained a marker-negative partial remission, and 11 patients attained a marker-positive partial remission, resulting in an overall response rate of 46 % (95 % CI: 30% to 64%).  All 3 patients with complete remission and 1 patient with a marker-negative partial remission remained disease free at 16+, 12+, 4+, and 2+ months of follow-up.  Seven (44 %) of these 16 responses, including 1 complete remission, occurred in cisplatin-refractory patients. Toxicity consisted mainly of myelosuppression, with Common Toxicity Criteria grade 3 occurring in 54 % of patients.  Only 9 % of patients developed neutropenic fever.  The investigators concluded that gemcitabine plus oxaliplatin demonstrates antitumor activity with acceptable toxicity in heavily pretreated patients with relapsed or cisplatin-refractory germ cell tumors, and may offer a chance of long-term survival for selected patients.

Pectasides et al (2004) investigated the efficacy and tolerability of the combination of oxaliplatin and irinotecan in 18 patients with relapsed or cisplatin-refractory germ cell tumors.  The investigators reported that 7 patients (40 %) achieved a favorable response (4 complete and 3 partial responses).  One of the complete responders relapsed after 2.5 months and despite further treatment with high dose chemotherapy, he died 2 months later.  The investigators reported that the remaining 3 patients are continuously disease free for 11+, 14+ and 19+ months.  The partial responders subsequently progressed and died after 2, 3 and 4.5 months, respectively.  The investigators noted that none of the patients with extra-gonadal mediastinal germ cell tumors responded to oxaliplatin and irinotecan chemotherapy.  The investigators reported that the combination of oxaliplatin and irinotecan was well-tolerated. Neutropenia related toxicity (grade 3/4, 17 %), neutropenic infections and sepsis were not common; the investigators posited that this was probably due to prophylactic use of hematopoietic colony stimulating factor.  The investigators stated that thrombocytopenia and anemia were not a serious problem.  Gastrointestinal side effects, specifically grade 3/4 diarrhea and nausea/vomiting were noted in 22 % and 28 % of patients, respectively.  The investigators found that oxaliplatin-associated neurotoxicity was rather low; grade 3 peripheral sensory neuropathy was recorded in 11 % of patients.  The investigators concluded that the combination of oxaliplatin and irinotecan is feasible and associated with significant clinical antitumor activity, mild and manageable toxicity and easy outpatient administration in patients with relapsed or cisplatin-refractory germ cell cancer.  This combination seems to offer a possibility for long-term disease-free status (17 %), despite the poor prognostic features of the study patient group.

In a phase-II clinical trial, Pectasides and colleagues (2004) examined the efficacy and toxicity of the combination of gemcitabine and oxaliplatin (GEMOX) chemotherapy in patients with relapsed or cisplatin-refractory non-seminomatous germ cell tumors (NSGCT).  A total of 29 patients with relapsed or cisplatin-refractory NSGCT were treated with gemcitabine 1,000 mg/m2 on days 1 and 8 followed by oxaliplatin 130 mg/m2 on day 1 every 3 weeks for a maximum of 6 cycles; 24 patients (83 %) were considered refractory and 5 (17 %) absolutely refractory to cisplatin; 28 patients were assessable for response.  Overall, 9 patients (32 %) achieved a favorable response (CR, n = 4; PR, n = 5).  One of the complete responders relapsed after 7 months and went into disease-free status lasting for 11+ months after resection of lung metastases.  The rest of the complete responders are continuously disease-free at 14+, 19+ and 28+ months with the study regimen plus or minus surgery.  One of the complete responders had absolutely cisplatin-refractory disease and another 1 presented with a late relapse.  Toxicity was primarily hematological and generally manageable: 62 % of patients experienced grade 3/4 neutropenia, 10 % neutropenic fever and 41 % grade 3/4 thrombocytopenia.  Non-hematological toxicity consisted mainly of nausea/vomiting; 3 patients (10 %) developed grade 3 neurotoxicity and discontinued treatment.  The authors concluded that the combination of GEMOX was an active, moderately toxic and easily administered regimen in patients with relapsed or cisplatin-refractory NSGCT.  The 14 % long-term disease-free status accomplished in this heavily pre-treated patient population was quite encouraging.

Prince and Forgeson (2013) described the 1st reported case of GEMOX chemotherapy used for recurrent NSGCT of the testis metastatic to the GI tract causing uncontrolled bleeding, which induced a temporary response.

Uchida and associates (2014) examined the feasibility of salvage chemotherapy with GEMOX for patients with refractory testicular germ cell cancer.  A total of 11 patients were treated with GEMOX.  All had experienced disease progression or recurrence and had been treated with the standard induction chemotherapy and at least 1 cycle of cisplatin-based salvage chemotherapy (median of 6 cycles) before the start of GEMOX.  GEMOX consisted of gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 1; 2 patients (18 %) achieved a CR after GEMOX and surgical resection of residual tumor; 1 additional patient responded to GEMOX, but was forced to discontinue treatment due to sensory neuropathy.  This patient achieved CR after further treatment with irinotecan-based chemotherapy and surgery.  All 3 patients have remained continuously free from disease progression at a median follow-up duration of 24 months; 64 % of patients developed grade 3 leukocytopenia and 82 % developed grade 3 or higher thrombocytopenia; however, they were all managed with routine supportive care.  Sensory neuropathy was frequently observed, but no patient experienced neurotoxicity of higher than grade 3.  The authors concluded that GEMOX as salvage chemotherapy was tolerable for intensively pre-treated patients.  These researchers stated that GEMOX may offer a chance of long-term disease-free status even after failure of multiple cycles of chemotherapy.

PD-1 Inhibitors Plus Oxaliplatin or Cisplatin-Based Chemotherapy as First-Line Treatments for Advanced Gastric Cancer

Guo et al (2022) noted that currently, there has been no direct comparison between programmed cell death protein 1 (PD-1) inhibitors plus different chemotherapy regimens in 1st-line treatments for advanced gastric cancer (AGC).  In a network meta-analysis (NMA), these investigators examined the safety and effectiveness of PD-1 inhibitors plus oxaliplatin- or cisplatin-based chemotherapy.  PubMed, Embase, and the Cochrane Central Register were used to identify a series of phase-III RCTs examining 1st-line PD-1 inhibitors plus chemotherapy and phase-III RCTs comparing 1st-line oxaliplatin and cisplatin-based chemotherapy for AGC to perform NMA.  The main outcome was OS and other outcomes included PFS, ORR, and treatment-related AEs (TRAEs).  A total of 8 eligible RCTs involving 5,723 patients were included.  Compared with PD-1 inhibitors plus cisplatin-based chemotherapy, PD-1 inhibitors plus oxaliplatin-based chemotherapy could prolong the OS without statistical significance (HR: 0.82, 95 % CI: 0.63 to 1.06).  However, for patients with combined positive score (CPS) of 1 or higher, PD-1 inhibitors plus oxaliplatin-based chemotherapy significantly prolonged the OS (HR: 0.75, 95 % CI: 0.57 to 0.99).  PFS in PD-1 inhibitors plus oxaliplatin-based chemotherapy was significantly longer than that in PD-1 inhibitors plus cisplatin-based chemotherapy (HR: 0.72, 95 % CI: 0.53 to 0.99).  Regarding safety, the incidence of 3 or higher TRAEs was similar between PD-1 inhibitors plus oxaliplatin-based chemotherapy and PD-1 inhibitors plus cisplatin-based chemotherapy (RR: 0.86, 95 % CI: 0.66 to 1.12).  The surface under the cumulative ranking area curve (SUCRA) indicated that PD-1 inhibitors plus oxaliplatin-based chemotherapy ranked 1st for OS (97.7 %), PFS (99.3 %), and ORR (89.0 %).  For oxaliplatin-based regimens, there was no significant difference between nivolumab plus oxaliplatin-based chemotherapy and sintilimab plus oxaliplatin-based chemotherapy in terms of OS, PFS, ORR, and ≥3 TRAEs.  The authors concluded that compared with PD-1 inhibitors plus cisplatin-based chemotherapy, PD-1 inhibitors plus oxaliplatin-based chemotherapy significantly prolonged PFS.  Considering both safety and effectiveness, PD-1 inhibitors plus oxaliplatin-based chemotherapy might be a better option as 1st-line treatment for AGC.

References

The above policy is based on the following references:

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