Oxaliplatin

Bhavana Devanabanda; Anup Kasi

Oxaliplatin

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Continuing Education Activity

Oxaliplatin is a medication used to manage and treat metastatic colorectal cancer. It is a member of the platinum-based chemotherapeutic class of drugs and is indicated in the adjunctive treatment of stage III colorectal cancer after resection of the primary tumor and for the treatment of metastatic colorectal cancer. It is FDA-approved in combination with infusional 5-fluorouracil and leucovorin. This activity reviews the indications, actions, and contraindications for oxaliplatin as a valuable agent in treating colorectal cancer and will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interaction) pertinent for members of the healthcare team in the treatment of patients with metastatic colorectal cancer and related conditions.

Objectives:

Identify the mechanism of action of oxaliplatin.
Describe the potential adverse effects of oxaliplatin.
Review the appropriate monitoring for patients receiving therapy with oxaliplatin.
Outline interprofessional team strategies for improving care coordination and communication to advance oxaliplatin and improve outcomes.

Indications

Oxaliplatin is an FDA-approved platinum-based antineoplastic medication.[1] It is indicated in the adjunctive treatment of stage III colorectal cancer after resection of the primary tumor and for the treatment of metastatic colorectal cancer.[1][2] It is FDA-approved in combination with infusional 5-fluorouracil and leucovorin in a regimen known as FOLFOX.[1]

In the pediatric population, oxaliplatin is used for treating refractory or relapsed solid tumors in combination with etoposide or ifosfamide or gemcitabine or irinotecan or fluorouracil, and leucovorin.[3][4][5][6][7] Oxaliplatin is also used to treat refractory or relapsed neuroblastoma in combination with doxorubicin.[8][9]

The following are the off-label indications for oxaliplatin:

Advanced biliary adenocarcinoma in combination with capecitabine (a regimen known as CAPOX) or gemcitabine.[10][11]
Fludarabine refractory chronic lymphocytic leukemia in combination with fludarabine, cytarabine, and rituximab.[12]
Esophageal and gastric cancers in combination with epirubicin or capecitabine or docetaxel, leucovorin, and fluorouracil.[13][14][15]
Refractory neuroendocrine tumors in combination with capecitabine.[16]
Refractory or relapsed non-Hodgkin lymphoma in combination with gemcitabine and rituximab.[17]
Advanced ovarian cancer.[18][
Advanced pancreatic cancer in combination with capecitabine or fluorouracil, leucovorin, and irinotecan.[19][20]
Refractory testicular cancer in combination with gemcitabine and paclitaxel.[21]

Mechanism of Action

Oxaliplatin is an alkylating agent and has non-cell cycle-specific cytotoxicity.[1] The platinum complex in the drug binds to DNA and forms cross-links.[22] The cross-links inhibit DNA replication, transcription, and arrest of the cell cycle, resulting in cell death.[22] It works synergistically with fluoropyrimidines such as 5-fluorouracil.[1] Oxaliplatin effectively treats fast-growing tumors like those in the gastrointestinal system, with a high cell turnover rate.[22]

The pharmacokinetics of unbound platinum in plasma following oxaliplatin administration were triphasic, demonstrating a short initial distribution phase followed by a prolonged terminal elimination phase. Oxaliplatin is subject to rapid and extensive nonenzymatic biotransformation and is not metabolized by the CYP450 enzyme system.[23] Oxaliplatin half-life varies significantly depending on the resource consulted and the method used to determine half-life.[24] It is excreted in the urine (approximately 50%) and the feces (2%).

As monotherapy, oxaliplatin only demonstrates modest antineoplastic activity against advanced colorectal cancer, but it is effective in combination therapy.[25]

Administration

Oxaliplatin administration is via intravenous infusion (IV) over two hours.[26] In cases of acute toxicity, the administration is extended to 6 hours.[26] The recommended infusion rate is 1mg/m^2/minute or 85 mg/m^2 dose over 85 minutes every two weeks.[26] Oxaliplatin is moderately emetogenic.[27] To prevent chemotherapy-induced nausea and vomiting (CINV), pretreatment with antiemetics is strongly recommended.[27]

Before administration, ensure proper needle and catheter placement to prevent extravasation and flush the infusion line with D5W.[28] It is common for patients to have vascular pain near the site of IV infusion; pretreatment with fast-acting oxycodone is a recommendation.[29] Monitor the IV site for irritation, redness, pain, and swelling.[29] In the event of extravasation, immediately discontinue treatment, remove the infusion line, aspirate the solution, do not flush, elevate the site and place a warm compress over the infusion site; a cold compress is contraindicated as it can cause acute neurological symptoms.[28]

Adult administration regimens are as follows: (consult facility protocols and manufacturer's package insert for dosing, pre-medications, and toxicity-based dose adjustments)

As an adjuvant in stage III colon cancer: 85 mg/m^2 IV for a single dose on day one of a 14-day cycle, used with 5-FU and leucovorin. Administer 12 cycles.
Advanced colorectal cancer: 85 mg/m^2 IV for a single dose on day one of a 14-day cycle, used with 5-FU and leucovorin.

There is no pediatric indication for oxaliplatin.

Dosing in patients with renal insufficiency (creatinine clearance less than 30): Start 65 mg/m^2 for one dose on day one of a 14-day cycle. Hepatic dosing is undefined.

Adverse Effects

The most common adverse drug effects reported with oxaliplatin monotherapy are:

Systemic: fever, fatigue, nausea, emesis, weakness[30][27]
Nervous system: peripheral sensory neuropathy, pain, headache, insomnia[31]
Gastrointestinal system: diarrhea, abdominal pain, constipation, anorexia, stomatitis[22]
Hepatic: elevated serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin[22]
Hematologic and oncologic: anemia, thrombocytopenia, leukopenia[22]
Musculoskeletal: back pain[32]
Respiratory system: dyspnea, cough[30]

Contraindications

Oxaliplatin is contraindicated in patients who have/are:

Platinum hypersensitivity anaphylaxis[30]
Posterior reversible encephalopathy syndrome[33]
Grade 3 or 4 peripheral sensory neuropathy[34]
Severe renal impairment[35]
Chronic lung disease[36]
Rhabdomyolysis[37]
Sepsis[38]
Pregnant or intending to get pregnant[39]
Breastfeeding[39]

Use in the first trimester should be avoided due to high teratogenicity and embryo or fetal death. Females of reproductive potential should have a pregnancy test prior to initiating therapy and must use appropriate contraception during treatment and for nine months following discontinuation of oxaliplatin. Male patients should continue contraception for six months following treatment cessation.[40] Patients should avoid breastfeeding during treatment and for three months following treatment termination. While there is no data available to assess infant harm in breastfeeding, excretion into breast milk is possible based on the drug's properties. There is no data on oxaliplatin's effect on milk production.

Monitoring

Patients on oxaliplatin therapy must periodically have blood and urine work up to assess complete blood count with differential, basic metabolic panel, liver function tests, renal function tests, and electrocardiogram (ECG) for QT prolongation.[22] It is essential to do a pregnancy test on women of reproductive age before initiating treatment.[22]

Oxaliplatin has a narrow therapeutic index, which most commonly affects the hematopoietic and nervous systems and has gastrointestinal side effects.[22] Periodic neurological exams are a recommendation to assess for acute or chronic oxaliplatin-induced peripheral neuropathy[22]

Drug interactions: Oxaliplatin requires close monitoring when administered with other drugs as it can enhance the adverse/toxic effects or diminish the therapeutic effects. The following drug interactions are important to consider:

Baricitinib
Disease-modifying anti-rheumatic drugs (DMARDs)
Chloramphenicol
Cladribine
Clozapine
Deferiprone
Denosumab
Dipyrone
Echinacea
Erdafitinib
Fingolimod
Fosphenytoin-phenytoin
Haloperidol
Leflunomide
Lenograstim
Lipegfilgrastim
Mesalamine
Natalizumab
Nivolumab
Ocrelizumab
Palifermin
Pidotimod
Pimecrolimus
Promazine
QT-prolonging agents
Roflumilast
Siponimod
Sipuleucel-T
Tacrolimus
Tafenoquine
Taxane derivatives
Tertomotide
Tofacitinib
Topotecan
Upadacitinib
Vaccines

Toxicity

No known antidote exists for oxaliplatin overdose. Oxaliplatin has dose-dependent toxicity on the hematopoietic system. It causes myelosuppression, anemia, and thrombocytopenia.[22] In rare cases with repeated oxaliplatin treatment, hypersensitivity reactions, hemolytic anemia, and secondary immune thrombocytopenia can occur.[22] The therapy is discontinuation and symptomatic management.[22]

Oxaliplatin has dose-limiting toxicity on the nervous system.[22] It can cause acute or chronic peripheral neuropathy.[22] Acute oxaliplatin-induced peripheral neuropathy presents with paresthesia, dysesthesias, or allodynia, usually around the mouth and throat during or after the treatment.[22] Exposure to cold can also trigger these symptoms.[22] The symptoms resolve within a few hours to days following discontinuation.[34] Additional precautions are possible by prolonging the infusion time from two hours to six hours.[34]

Repeated oxaliplatin treatment can result in chronic peripheral neuropathy.[22] It manifests in the distal extremities with paresthesia, hypoesthesia, dysesthesia, and decreased proprioception.[22] It is seen in 10% of patients who receive a cumulative dose of 780 mg/m^2 (9 doses of 85mg/m^2) and 50% of patients who receive a cumulative dose of 1170 mg/m^2 (13 doses).[34] One study has shown a decreased incidence of neurotoxicity in patients receiving supplemental infusions of calcium and magnesium on the day of oxaliplatin administration.[34] There is preliminary and conflicting data on the use of oral n-acetylcysteine, xaliproden, gabapentin, carbamazepine, amifostine, and glutathione in the prevention or amelioration of oxaliplatin-induced neuropathy.[34]

Enhancing Healthcare Team Outcomes

Interprofessional treatment teams consisting of clinicians (MDs, DOs, NPs, and PAs), oncology specialists, nurses, laboratory technologists, pharmacists, and clinicians in different specialties need to be knowledgeable regarding the use and potential adverse events of oxaliplatin. This interprofessional team approach ensures proper administration, management, monitoring, and limitation of the adverse effects. When a patient is on a chemotherapeutic regimen, it is strongly advised to utilize a board-certified oncology specialty pharmacist who can examine the treatment regimen (including pre and post medication), communicate possible drug interactions, and the recommended therapeutic dosage to the clinician.

The assigned nursing staff must monitor the IV site, be cognizant of the adverse effects of the drug, and relay them to the clinician and/or pharmacist. As with pharmacy, having oncology-certified nurses involved in the pre-and post-administration care, in addition to performing administration, can optimize patient outcomes. These nurses will report to the ordering clinician any issues or concerns they see so remedial action (dose adjustments, additional medication, etc.) can be implemented.

Lastly, the clinician must have enough information to determine if the patient is a candidate to receive a drug like oxaliplatin depending on the patient's medical history; here again, consulting with an oncology pharmacist can prove invaluable.

The interpersonal healthcare team is responsible for the following:

Complete blood count, liver function tests, renal function tests, pregnancy test
Proper administration of the drug and monitoring of the IV site
Monitoring toxicity
Monitor the patient for signs and symptoms of CINV, peripheral sensory neuropathy, infection, GI disturbances
Consult with the pharmacist and toxicologist regarding dosing
Consult with the radiologist, pathologist, and surgeon regarding the spread of cancer

The prevention and management of oxaliplatin-induced neurotoxicity start with the patient limiting exposure to cold environments, ensuring proper protection, and staying away from cold food and beverages.[22] One study has shown a decrease in neurotoxicity in patients who received calcium and magnesium infusions before or after oxaliplatin administration.[41] [Level 2] In addition to changing the dosage, the interprofessional treatment team may consider supplementing oxaliplatin with calcium or magnesium in the event of peripheral sensory neuropathy.

WIth an interprofessional team approach to oxaliplatin therapy, patients stand to achieve the best possible outcomes with this drug while minimizing potential adverse effects. [Level 5]

Details

References

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Level 2 (mid-level) evidence