No adequate second- or third-line therapy is available in the United States for patients with metastatic colorectal cancer and disease progression following treatment with fluorouracil (5-FU)-based therapy and an irinotecan (CPT-
ABSTRACT: No adequate second- or third-line therapy is available in the United Statesfor patients with metastatic colorectal cancer and disease progression followingtreatment with fluorouracil (5-FU)-based therapy and an irinotecan (CPT-11,Camptosar)-containing regimen, or a combination of the two. Oxaliplatin(Eloxatin), a new platinum analog, has demonstrated high activity in thetreatment of colorectal cancer, especially when combined with 5-FU andleucovorin. The combination of oxaliplatin and 5-FU/leucovorin has been approvedin Europe for the first- and second-line treatment of colorectal cancer. Thiscompassionate-use study was initiated because of the unavailability of the agentin the United States and inadequate US safety data. The following reviewsummarizes data from this ongoing study, the primary focus of which is toprovide oxaliplatin for compassionate use until it receives US Food and DrugAdministration approval and becomes available commercially. [ONCOLOGY14(Suppl 11):30-32, 2000]
Approximately 50% of patients who are diagnosed with colorectalcancer develop metastatic disease. Although there have been improvements in thetreatment of metastatic disease, the currently available options are less thansatisfactory. Combinations of fluorouracil (5-FU) and leucovorin can produceresponses in approximately 25% to 30% of patients with metastatic colorectalcancer and can provide palliation, but have little impact on survival. Theaddition of irinotecan (CPT-11, Camptosar) has resulted in further improvementsin response rates and survival; however, median survival times range between 12and 14 months.
Single-agent oxaliplatin (Eloxatin) has demonstrated consistentbut modest activity in metastatic disease that progressed after treatment with5-FU-based therapy, achieving response rates of approximately 10%.[3,4] Inpreviously untreated patients using a variety of oxaliplatin/5-FU/leucovorinschedules, response rates have been reported to be as high as 40% to 60%, withmedian survivals in excess of 15 months.[5,6]
In a phase II trial, André and coworkers treated 5-FU-refractorycolorectal cancer patients with 5-FU/leucovorin plus oxaliplatin (thisincorporated the 5-FU/leucovorin regimen on which the patients had previouslyprogressed). Significant activity was observed, with patients achieving a 27%objective response rate and a 30% stable disease rate. These datademonstrated that oxaliplatin appeared to add to the efficacy of a variety of5-FU regimens in patients with refractory disease.
The putative mechanism of action of oxaliplatin is similar tothat of cisplatin (Platinol) and other platinum compounds.[8-10] Oxaliplatinforms intrastrand platinum-DNA adducts/crosslinks between two adjacent nucleotide basepairs. The formation of these intrastrand crosslinks inhibits such nuclearprocesses as DNA replication and transcription, resulting in cell death inactively dividing cells. Interstrand crosslinks are also formed but to a lesserextent.
This multicenter, open-label, compassionate-use trial ofoxaliplatin is being conducted at 44 centers in the United States and Canada.The objective is to provide oxaliplatin for compassionate use in patients whohave had at least one prior chemotherapy regimen for locally advanced metastaticcolorectal cancer, but who are ineligible for standard therapies.
The study population consists of patients with advancedadenocarcinoma of the colon or rectum who are not amenable to potentiallycurative treatment. Eligibility requirements are listed in Table1. Patientswere assigned to one of the six regimens described in Table2.
All patients underwent a comprehensive pretreatment evaluation,including history, physical examination, assessment of Eastern CooperativeOncology Group (ECOG) performance status (PS), and laboratory assessment tomeasure organ function. Interim evaluations performed to ensure safety prior toadministration of each cycle included a physical examination, toxicityassessment, and hematology and chemistry studies. Dose modifications were madein the case of hematologic, gastrointestinal, neurologic, or skin toxicities.The planned duration of therapy was eight cycles of oxaliplatin, with furthertreatment requested for patients who required additional therapy after thisperiod. Supportive therapy was given at the discretion of the investigator ortreating physician.
As of June 1999, 1,131 patients had been enrolled. Patientcharacteristics are presented in Table 3. All patients had received priortherapy, with a mean of 1.9 cycles (see Table4). The 5-FU regimen selected bythe investigators and the mean time on therapy are given in Table5. Therecommended dose intensity of oxaliplatin was 43.3 mg/m2/wk, except for thehigh-dose regimen, in which the recommended dose intensity was 36.4 mg/m2/wk.Table 6 lists the dose intensity received by the patients.
Serious adverse events were categorized. On-study deathsoccurred mostly as a result of disease progression, and study drug-relateddeaths accounted for less than 1% of mortality. Hospitalizations were associatedmainly with disease state, and included bowel obstruction, deep vein thrombosis,surgical procedures, dehydration, and nausea and vomiting. The most frequentlyobserved side effects of therapy included laryngeal dysesthesia, anaphylaxis,nausea, vomiting, diarrhea, dehydration, neutropenia, fevers, cramping, rigors,spasms, seizure, and altered mental status and syncope. Laryngeal dysesthesia,usually cold-induced, was readily reversible (following discontinuation ofoxaliplatin therapy).
A peripheral sensory neuropathy was occasionally acute at onset,but was usually cumulative, rarely dose-limiting, and normally reversible withdiscontinuation of the drug. Diarrhea was usually controllable and rarelyrequired hospitalization. Neutropenia and thrombocytopenia also rarely warrantedadditional therapy, but did account for dose delays. The reasons for removingpatients from study are listed in Table 7.
Overall, oxaliplatin was well tolerated and offered significantbenefits to a large group of patients. Time to off-study due to treatmentfailure (mostly progressive disease) was 3.5 months overall (2.8 months for thesingle-agent arm, and 3.6 months for the combination cohorts). Partialremissions and stabilization of metastatic disease were observed.
For patients with metastatic colorectal cancer and diseaseprogression after treatment with 5-FU and irinotecan chemotherapy, oxaliplatinoffers an alternative treatment strategy. The agent is well tolerated andexhibits a manageable toxicity profile. This compassionate-use study is ongoingand data are still being collected.
1. de Gramont A, Bosset JF, Milan C, et al: Randomized trialcomparing monthly low-dose leucovorin and fluorouracil bolus with bimonthlyhigh-dose leucovorin and fluorouracil bolus plus continuous infusion foradvanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815,1997.
2. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan(CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily × 5 LV/FUin patients (PTS) with previously untreated metastatic colorectal cancer (CRC)(abstract 898). Proc Am Soc Clin Biol 18:233a, 1999.
3. Machover D, Diaz-Rubio E, de Gramont A, et al: Twoconsecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma whowere resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95-98,1996.
4. Lévi F, Perpoint B, Garufi C, et al: Oxaliplatin activityagainst metastatic colorectal cancer: A phase II study of 5-day continuousvenous infusion at circadian-rhythm modulated rate. Eur J Cancer 29A:1280-1284,1993.
5. Becouarn Y, Ychou M, Ducreux M, et al: Phase II trial ofoxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients.J Clin Oncol 16:2739-2744, 1998.
6. Diaz-Rubio E, Sastre J, Zaniboni A, et al: Oxaliplatin assingle agent in previously untreated colorectal carcinoma patients: A phase IImulticentric study. Ann Oncol 9:105-108, 1998.
7. André T, Louvet C, Raymond E, et al: Bimonthly high-doseleucovorin and 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastaticcolorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen.Ann Oncol 9:1251-1253, 1998.
8. Schmidt W, Chaney SG: Role of carrier ligand in platinumresistance of human carcinoma cell lines. Cancer Res 53:799-805, 1993.
9. Vaisman A, Varchenko M, Umar A, et al: The role of hMLH1,hMSH3, and hMSH6 defects in cisplatin and oxaliplatin resistance: Correlationwith replicative bypass of platinum-DNA adducts. Cancer Res 58:3579-3585, 1998.
10. Page JD, Husain I, Sancar A, et al: Effect of thediaminocyclohexane carrier ligand on platinum adduct formation, repair, andlethality. Biochemistry 29:1016-1024, 1990.
11. Mitchell EP, LoRusso P, Gococo K, et al: Safety profile ofoxaliplatin (single agent or with 5-FU) from the large North Americancompassionate use experience in advanced colorectal cancer (ACC) (abstract1259). Proc Am Soc Clin Oncol 19:319a, 2000.