ACT-078, l-OHP, LOHP, oxalatoplatin, oxaliplatinum
ELOXATIN
Alkylating agent, cytotoxic
Special pediatric considerations are noted when applicable, otherwise adult provisions apply.
Oxaliplatin belongs to a new class of platinum agent. It contains a platinum atom complexed with oxalate and diaminocyclohexane (DACH). The bulky DACH is thought to contribute greater cytotoxicity than cisplatin and carboplatin.1 The exact mechanism of action of oxaliplatin is not known. Oxaliplatin forms reactive platinum complexes which are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules. Oxaliplatin is not generally cross-resistant to cisplatin or carboplatin, possibly due to the DACH group and resistance to DNA mismatch repair.1,2 Preclinical studies have shown oxaliplatin to be synergistic with fluorouracil and SN-38, the active metabolite of irinotecan.3 Oxaliplatin is a radiation-sensitizing agent.4,5 It is cell-cycle-phase nonspecific.6
| Interpatient variability | inter- and intra-subject variability is low 6 | |
| Distribution | minimal in plasma; accumulation in erythrocytes does not diffuse into plasma or act as a drug reservoir | |
| cross blood brain barrier? | no information found | |
| volume of distribution | ultrafilterable platinum *: 582 +- 261 L 6 | |
| plasma protein binding | 70-95% | |
| Metabolism | rapid nonenzymatic biotransformation to reactive platinum complexes 7 | |
| active metabolite(s) | DACH platinum species 6 | |
| inactive metabolite(s) | several conjugates, 6 including the 1,2-DACH-platinum dichloride (2%) associated with neurotoxicity 3 | |
| Excretion | platinum is mainly by renal excretion and tissue distribution, 8 while platinum metabolites are mainly by renal excretion 1 | |
| urine | 50% within 3 days 9 | |
| feces | minimal 9 | |
| terminal half life | ultrafilterable platinum *: 273 +- 19 h 6 platinum elimination from erythrocytes: 48 days 1 | |
| clearance | ultrafilterable platinum *: 10.1 +- 3.07 L/h 6 | |
| Gender | no information found | |
| Elderly | no information found | |
| Children | no information found | |
| Ethnicity | no information found | |
Adapted from reference 1 unless specified otherwise.
*
Ultrafilterable platinum consists of oxaliplatin and free oxaliplatin metabolites.
| Primary uses: | Other uses: |
| Colorectal cancer 10-12 | Breast cancer 13 |
| Gastric cancer 14 | |
| Germ cell cancer 15 | |
Head and neck cancer16 Lung cancer, non-small cell17 Lymphoma, non-Hodgkin's18 Mesothelioma19,20 Ovarian cancer21,22 Pancreatic cancer23 Prostate cancer24
*Health Canada Therapeutic Products Programme approved indication
No pediatric indications.
is recommended in patients with known hypersensitivity to other platinum agents (eg, cisplatin, carboplatin).
in patients with peripheral sensory neuropathy interfering with function or severe renal dysfunction (CrCl < 30 mL/min).
Oxaliplatin is considered a probable carcinogen, although carcinogenic studies have not been done.
Mutagenicity: Mutagenic in mammalian in vitro mutation chromosome tests.6
No information found.
Oxaliplatin produced embryo-fetal toxicity in rats.
is not recommended due to the potential secretion into breast milk.
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| allergy/immunology | anaphylaxis (0.5-2%) 6,25,26 | I | |||
| blood/bone marrow febrile neutropenia | anemia (64-83%, severe 4-5%) | D | |||
| febrile neutropenia (< 2%) | E | ||||
| immune hemolytic anemia (rare) 27 | I | E | |||
| neutropenia: single agent (15%, severe 3%); with fluorouracil and leucovorin (66%, severe 38%) | E | ||||
| thrombocytopenia: single agent (41%, severe 3%); with fluorouracil and leucovorin (76%, severe 4%) | E | ||||
| constitutional symptoms | fever (36%) | I | E | ||
| dermatology/skin | extravasation hazard: irritant 28-33 | ||||
| alopecia (2%) | |||||
| gastrointestinal | emetogenic potential: high moderate 34 | ||||
| diarrhea: single agent (41%, severe 5%); with fluorouracil and leucovorin (58%, severe 10%) | E | ||||
| mucositis: single agent (4%, severe 2%); with fluorouracil and leucovorin (42%, severe 8%) | E | ||||
| nausea, vomiting (69-71%, severe 12-14%) | I | E | |||
| ORGAN SITE | SIDE EFFECT | ONSET | |||
| Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) | |||||
| hepatic | liver function abnormalities (46%, severe 12%) | E | |||
| infection | infection (23%) | E | |||
| neurology | central neurotoxicity (rare) 35 | D | |||
| neuropathy, sensory (85-95%) | I | E | |||
| pharyngolaryngeal dysesthesia (1-2%) | I | ||||
| renal/genitourinary | renal dysfunction (3%, severe < 1%) | E | |||
Adapted from reference 6 unless otherwise specified.
Peripheral sensory neuropathy is cumulative, dose-related and usually reversible a few months after stopping treatment. Symptoms include sensory ataxia and dysesthesia of the limbs, mouth, throat and larynx, and may be exacerbated by exposure to cold (eg, touching cold surface, drinking cold liquid).1,34 The incidence of grade 2 neuropathy is 10% after 3 treatment cycles and 50% after 10 cycles. Grade 3 neuropathy occurs in 10% after 9 cycles and 50% after 14 cycles, is reversible in 74% of the cases, and begins to recover after 13 weeks. Paresthesia interfering with function (eg, buttoning clothing, holding objects, writing) is seen in 16% of patients after 4 months of treatment and rarely leads to oxaliplatin withdrawal.11 Unlike cisplatin, oxaliplatin neuropathy is related to injury to small rather than large sensory fibres.17 To reduce the incidence and severity of peripheral neuropathy, patients should be considered to
receive infusions of 1 g of calcium gluconate and 1 g of magnesium sulphate prior to and following oxaliplatin treatment for metastatic colorectal cancer, especially if peripheral neuropathy has developed while on oxaliplatin treatment. Calcium/magnesium infusions do not appear to reduce the efficacy of
oxaliplatin-based chemotherapy.36-38 However, they are not recommended in patients with hypercalcemia or
receiving digoxin or thiazide diuretics. Calcium can precipitate arrhythmias when given with digoxin and increase the risk of hypercalcemia with thiazide diuretics.39 Gabapentin PO 100 mg twice daily, with increments of 100 mg PO daily as needed, may be effective in some patients to reduce oxaliplatin neuropathy,40 while carbamazepine does not appear to be effective.41 Other agents used with some success include alpha-lipoic acid IV 600 mg weekly for 3-5 weeks, then followed by oral 600 mg three times daily.42 Oxaliplatin delivered according to 24-hour biologic rhythms (chronomodulated) appears to be associated with less peripheral neuropathy than fixed rate infusion.1,12
Pharyngolaryngeal dysesthesia
with sporadic reduced sensitivity of the larynx and pharynx is seen in 1- 2% of patients shortly after drug infusion. Symptoms usually resolve within hours of onset but the feeling of difficulty in breathing or swallowing may be distressing to the patient. Treatment is usually not needed,
although antihistamines and bronchodilators have been used. To prevent recurrence, infusion time should be extended to 6 hours with subsequent treatments.
1,6
Management of extravasation Extravasation of oxaliplatin may sometimes cause severe local inflammation and potentially tissue necrosis.28-33 The optimal non-pharmacological management of oxaliplatin extravasation is unclear. However, it has been suggested that warm compresses may be preferred over cool compresses30,43,44 which may theoretically precipitate or worsen peripheral sensory neuropathy.
Elderly patients 11
over 65 may be at higher risk of severe (grades 3-4) diarrhea.
Women 11
may be at higher risk of severe (grades 3-4) neutropenia.
Incidences of adverse events 1,45
are generally similar between oxaliplatin used as single agent or with fluorouracil and leucovorin, although severe (grades 3-4) diarrhea, nausea and vomiting, and neurotoxicity are more common with combination therapy.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
| fluorouracil 46 | no influence on fluorouracil pharmacokinetics | ||
| irinotecan 47-49 | induction of irinotecan- related cholinergic syndrome | may potentiate irinotecan inhibition of acetylcholinesterase | give prophylactic atropine before irinotecan |
| topotecan 50 | no effects on topotecan pharmacokinetics | ||
| warfarin 51 | possible increased effect and toxicity of warfarin | unknown; reported increase in effect and toxicity of warfarin may be attributable to fluorouracil; however, patients given fluorouracil and oxaliplatin are more likely to have abnormal INR's than patients given fluorouracil and other agents | check baseline INR; monitor weekly INR during, and for one month after, oxaliplatin and fluorouracil therapy; increase frequency and duration of monitoring if INR unstable; adjust warfarin dose as needed |
Oxaliplatin can be co-administered with leucovorin infusion using a Y-line placed immediately before the site of injection. However, the drugs should not be combined in the same infusion bag. Leucovorin must be diluted using isotonic infusion solutions such as D5W but not NS or alkaline
solutions.
52,53
Incompatibility: The following are incompatible via Y-site injection or in the same infusion solution: alkaline drugs or solutions (eg, fluorouracil, trometamol [alkinising agent], leucovorin products containing trometamol [not currently used in Canadian leucovorin products]),6,41,52-57 chlorides (including sodium chloride at all concentrations). Aluminum-containing IV needles, syringes or sets should not be used to prepare or administer oxaliplatin; aluminum reacts with platinum from oxaliplatin to form a precipitate, resulting in loss of potency.6
| BCCA administration guideline noted in bold , italics | |
| Subcutaneous | no information found |
| Intramuscular | no information found |
| Direct intravenous | no information found |
| Intermittent infusion | in 500 mL D5W over 2 h 11 ; in 250-500 mL D5W over 30 min 9 , 3 h 58 , or 6 h 12 ; administer before fluoropyrimidines (eg, fluorouracil) 6 ; do not piggyback or flush lines with sodium chloride solution 6 |
| Continuous infusion | chronomodulated infusion over 5 days using programmable-in-time pump 12 |
| Intraperitoneal | no information found |
| Intrapleural | no information found |
| Intrathecal | no information found |
| Intra-arterial | investigational, over 4 h 59 |
| Intravesical | no information found |
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or in patients with other toxicities.
Adults:
Cycle Length: BCCA usual dose noted in bold, italics Intravenous: 1 week58: 35 mg/m2 IV for one dose on day 1
weeks1,10,60: 85 mg/m2 (range 80-100 mg/m2) IV for one dose on
day 1 weeks1,3,60: 130 mg/m2 (range 85-135 mg/m2) IV for one dose on day 1 30 mg/m2/day by continuous IV infusion for 5 consecutive days (total dose per cycle 150 mg/m2)61 35 mg/m2/day by chronomodulated IV infusion for 5 consecutive days (total dose per cycle 175 mg/m2)61 weeks: 85 mg/m2 IV for one dose on days 1 and 15 (total dose per cycle 170 mg/m2)62 50 days: 50 mg/m2 IV for one dose on days 1,8, 15, 22, 29, 36 (total dose per cycle 300 mg/m2)63
Concurrent radiation: 4
investigational, 130 mg/m2 IV on days 1 and 29 concurrent with radiation
Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no
guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression"
Dosage in neurotoxicity:6
| Duration of Neurotoxicity | Severity | Dose |
| > 7 days 6,11 | troublesome | reduce dose from: 130 mg/m2 to 100 mg/m2; or from 85 mg/m2 to 65 mg/m2; or from 65 mg/m2 to 50 mg/m2 |
| persists until next cycle 6 | no functional impairment | reduce dose from 85 mg/m2 to 65 mg/m2 |
| > 7 days 11 | functional impairment | reduce dose from 85 mg/m2 to 50 mg/m2 |
| persists until next cycle 6,11 | functional impairment | discontinue * |
*if neurotoxicity improves following discontinuation, resumption of therapy may be considered
6,64
| CrCl (mL/min) | Dose |
| > 30 | 100% 65 |
| < 30 | no information found |
Dosage in renal failure:
CrCl (mL/min) = N x (140 - Age) x wt (kg) Serum Creatinine (umol/L) where N = 1.04 for females and 1.23 for males Dosage in hepatic failure: No adjustment required for mild to moderate liver dysfunction6; no information found regarding severe hepatic insufficiency.
Dosage in dialysis:
no information found
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Misset JL, Bleiberg H, Sutherland W, et al. Oxaliplatin clinical activity: a review. Critical Reviews in Oncology-Hematology 2000; 35(2):75-93.
Cvitkovic E, Bekradda M. Oxaliplatin: a new therapeutic option in colorectal cancer. Seminars in Oncology 1999; 26(6):647-62.
Freyer G, Bossard N, Romestaing P, et al. Oxaliplatin (OXA), 5-fluorouracil (5FU), L-folinic acid (FA) and concomitant irradiation in patients with rectal cancer: A phase 1 study. Proceedings of the American Society of Clinical Oncology 2000; 19:260a-abstract 1012.
Carraro S, Roca E, Cartelli C, et al. Oxaliplatin (OXA), 5-fluorouracil (5-Fu) and leucovorin (LV) plus radiotherapy in unresectable rectal cancer (URC): Preliminary results. Proceedings of the American Society of Clinical Oncology 2000; 19:291a-abstract 1140.
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Extra JM, Marty M, Brienza S, et al. Pharmacokinetics and safety profile of oxaliplatin. Seminars in Oncology 1998; 25(2 Suppl 5):13-22.
Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. Journal of Clinical Oncology 1999; 17(11):3560-8.
de Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first- line treatment in advanced colorectal cancer. Journal of Clinical Oncology 2000; 18(16):2938-47.
Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. Journal of Clinical Oncology 2000; 18(1):136-47.
Cottu PH, Zelek L, Vannetzel J, et al. A phase II study of oxaliplatin (Oxa) and 5-fluorouracil (Fu) in advanced/metastatic breast carcinoma (Abc) patients (Pts) previously treated with taxanes (t): Preliminary results. Proceedings of the American Society of Clinical Oncology 2000; 19:155a-abstract 609G.
Louvet C, Andre T, Tigaud J, et al. Phase II trial of oxaliplatin (OXA) in combination with 5FU and folinic acid (FA) - FOLFOX6 regimen - as first-line treatment for advanced or metastatic gastric cancer (A/MGC) patients. Proceedings of the American Society of Clinical Oncology 2000; 19:265a-abstract 1031.
Soulie P, Garrino C, Bensmaine MA, et al. Antitumoral activity of oxaliplatin/cisplatin-based combination therapy in cisplatin-refractory germ cell cancer patients. Journal of Cancer Research & Clinical Oncology 1999; 125(12):707-11.
Degardin M, Cappelaere P, Krakowski I, et al. Phase II trial of oxaliplatin (L-OHP) in advanced, recurrent and/or metastatic squamous cell carcinoma of the head and neck [letter]. European Journal of Cancer. Part B, Oral Oncology 1996; 32B(4):278-9.
Monnet I, Brienza S, Hugret F, et al. Phase II study of oxaliplatin in poor-prognosis non-small cell lung cancer (NSCLC). ATTIT. Association pour le Traitement des Tumeurs Intra Thoraciques. European Journal of Cancer 1998; 34(7):1124-7.
Germann N, Brienza S, Rotarski M, et al. Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients. Annals of Oncology 1999; 10(3):351-4.
Fizazi K, Caliandro R, Soulie P, et al. Combination raltitrexed (Tomudex(R))-oxaliplatin: a step forward in the struggle against mesothelioma? The Institut Gustave Roussy experience with chemotherapy and chemo-immunotherapy in mesothelioma. European Journal of Cancer 2000; 36(12):1514-21.
Fizazi K, Doubre H, Viala J, et al. The combination of raltitrexed ('Tomudex') and oxaliplatin is an active regimen in malignant mesotherlioma: Results of a phase II study. Proceedings of the American Society of Clinical Oncology 2000; 19:578a-abstract 2276.
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J Clin Oncol (Meeting Abstracts) 2008; 26(15_suppl):4009. Grothey A, Hart LL, Rowland KM, et al. Intermittent oxaliplatin (oxali) administration and time-to- treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial. J Clin Oncol (Meeting Abstracts) 2008; 26(15_suppl):4010. DRUGDEX(r) Evaluations (database on the Internet). Calcium. Thomson MICROMEDEX(r), 2008. Available at: www.micromedex.com. Accessed 1 October 2008. Mariana G, Garrone O, Granetto C, et al. Oxaliplatin induced neuropathy: Could gabapentin be the answer? Proceedings of the American Society of Clinical Oncology 2000; 19:609a-abstract 2397. Wilson RH, Lehky T, Thomas RR, et al. Acute Oxaliplatin-Induced Peripheral Nerve Hyperexcitability. J Clin Oncol 2002; 20(7):1767-1774. Gedlicka C, Scheithauer W, Schull B, et al. Effective Treatment of Oxaliplatin-Induced Cumulative Polyneuropathy With Alpha-Lipoic Acid. J Clin Oncol 2002; 20(15):3359-3361. Stephen Doyle. 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Lane Cove, NSW, Australia; 12 April 2002. Sanofi-Synthelabo. Eloxatin: Summary of product characteristics. New York, NY, USA; 9 August 2002. Suzanne Harris PharmD. Personal communication. Associate Medical Scientist, Oncology Sanofi- Synthelabo Canada; 30 October 2002. Medical Information Faulding (Canada) Inc. Personal communication. 31 October 2002. Vassilaki M, Desses N, V P, et al. Two phase II studies with the combination of oxaliplatin (L-OHP) + 5- fluorouracil (5-FU) + leucovorin (LV) as first line treatment in pts with metastatic colorectal cancer (MCC). Proceedings of the American Society of Clinical Oncology 2000; 19:284a-abstract 1111. Kern W, Beckert B, Lang N, et al. Phase I and pharmacokinetic study of hepatic arterial infusion with oxaliplatin, folinic acid and 5-fluorouracil in patients with hepatic metastases from colorectal cancer. Proceedings of the American Society of Clinical Oncology 2000; 19:289a-abstract 1132. Brienza S, Bensmaine MA, Soulie P, et al. Oxaliplatin added to 5-fluorouracil-based therapy (5-FU +/- FA) in the treatment of 5-FU-pretreated patients with advanced colorectal carcinoma (ACRC): results from the European compassionate-use program. Annals of Oncology 1999; 10(11):1311-6. Caussanel JP, Levi F, Brienza S, et al. Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate. Journal of the National Cancer Institute 1990; 82(12):1046-50. Giornelli G, Roca E, Chacon M, et al. Bimonthly oxaliplatin (L-OHP) and weekly bolus 5-fluorouracil and folinic acid (FA) in patients (Pts) with metastatic colorectal cancer (CRC): A feasible and active regimen. Proceedings of the American Society of Clinical Oncology 2000; 19:295a. Janinis J, Papakostas P, Samelis G, et al. Second-line chemotherapy with weekly oxaliplatin and high- dose 5-fluorouracil with folinic acid in metastatic colorectal carcinoma: a Hellenic Cooperative Oncology Group (HeCOG) phase II feasibility study. Annals of Oncology 2000; 11(2):163-7. Maindrault-Goebel F, Louvet C, Carola E, et al. Oxaliplatin reintroduction in patients pretreated with leucovorin (LV), 5-FU and oxaliplatin for metastatic colorectal cancer. A Gercor study (Meeting abstract). Proceedings of the American Society of Clinical Oncology 2000; 19:255a-abstract 990. Massari C, Brienza S, Rotarski M, et al. Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function. Cancer Chemotherapy & Pharmacology 2000; 45(2):157-64.