Approximately 50% of patients who are diagnosed with colorectal
cancer develop metastatic disease. Although there have been improvements in the
treatment of metastatic disease, the currently available options are less than
satisfactory. Combinations of fluorouracil (5-FU) and leucovorin can produce
responses in approximately 25% to 30% of patients with metastatic colorectal
cancer and can provide palliation, but have little impact on survival. The
addition of irinotecan (CPT-11, Camptosar) has resulted in further improvements
in response rates and survival; however, median survival times range between 12
and 14 months.
Single-agent oxaliplatin (Eloxatin) has demonstrated consistent
but modest activity in metastatic disease that progressed after treatment with
5-FU-based therapy, achieving response rates of approximately 10%.[3,4] In
previously untreated patients using a variety of oxaliplatin/5-FU/leucovorin
schedules, response rates have been reported to be as high as 40% to 60%, with
median survivals in excess of 15 months.[5,6]
In a phase II trial, André and coworkers treated 5-FU-refractory
colorectal cancer patients with 5-FU/leucovorin plus oxaliplatin (this
incorporated the 5-FU/leucovorin regimen on which the patients had previously
progressed). Significant activity was observed, with patients achieving a 27%
objective response rate and a 30% stable disease rate. These data
demonstrated that oxaliplatin appeared to add to the efficacy of a variety of
5-FU regimens in patients with refractory disease.
The putative mechanism of action of oxaliplatin is similar to
that of cisplatin (Platinol) and other platinum compounds.[8-10] Oxaliplatin
forms intrastrand platinum-DNA adducts/crosslinks between two adjacent nucleotide base
pairs. The formation of these intrastrand crosslinks inhibits such nuclear
processes as DNA replication and transcription, resulting in cell death in
actively dividing cells. Interstrand crosslinks are also formed but to a lesser
This multicenter, open-label, compassionate-use trial of
oxaliplatin is being conducted at 44 centers in the United States and Canada.
The objective is to provide oxaliplatin for compassionate use in patients who
have had at least one prior chemotherapy regimen for locally advanced metastatic
colorectal cancer, but who are ineligible for standard therapies.
The study population consists of patients with advanced
adenocarcinoma of the colon or rectum who are not amenable to potentially
curative treatment. Eligibility requirements are listed in Table
were assigned to one of the six regimens described in Table
All patients underwent a comprehensive pretreatment evaluation,
including history, physical examination, assessment of Eastern Cooperative
Oncology Group (ECOG) performance status (PS), and laboratory assessment to
measure organ function. Interim evaluations performed to ensure safety prior to
administration of each cycle included a physical examination, toxicity
assessment, and hematology and chemistry studies. Dose modifications were made
in the case of hematologic, gastrointestinal, neurologic, or skin toxicities.
The planned duration of therapy was eight cycles of oxaliplatin, with further
treatment requested for patients who required additional therapy after this
period. Supportive therapy was given at the discretion of the investigator or
As of June 1999, 1,131 patients had been enrolled. Patient
characteristics are presented in Table 3. All patients had received prior
therapy, with a mean of 1.9 cycles (see Table
4). The 5-FU regimen selected by
the investigators and the mean time on therapy are given in Table
recommended dose intensity of oxaliplatin was 43.3 mg/m2/wk, except for the
high-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 deaths
occurred mostly as a result of disease progression, and study drug-related
deaths accounted for less than 1% of mortality. Hospitalizations were associated
mainly with disease state, and included bowel obstruction, deep vein thrombosis,
surgical procedures, dehydration, and nausea and vomiting. The most frequently
observed 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 of
A peripheral sensory neuropathy was occasionally acute at onset,
but was usually cumulative, rarely dose-limiting, and normally reversible with
discontinuation of the drug. Diarrhea was usually controllable and rarely
required hospitalization. Neutropenia and thrombocytopenia also rarely warranted
additional therapy, but did account for dose delays. The reasons for removing
patients from study are listed in Table 7.
Overall, oxaliplatin was well tolerated and offered significant
benefits to a large group of patients. Time to off-study due to treatment
failure (mostly progressive disease) was 3.5 months overall (2.8 months for the
single-agent arm, and 3.6 months for the combination cohorts). Partial
remissions and stabilization of metastatic disease were observed.
For patients with metastatic colorectal cancer and disease
progression after treatment with 5-FU and irinotecan chemotherapy, oxaliplatin
offers an alternative treatment strategy. The agent is well tolerated and
exhibits a manageable toxicity profile. This compassionate-use study is ongoing
and data are still being collected.
1. de Gramont A, Bosset JF, Milan C, et al: Randomized trial
comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly
high-dose leucovorin and fluorouracil bolus plus continuous infusion for
advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815,
2. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan
(CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily × 5 LV/FU
in 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: Two
consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who
were resistant to previous treatment with fluoropyrimidines. Ann Oncol 7:95-98,
4. Lévi F, Perpoint B, Garufi C, et al: Oxaliplatin activity
against metastatic colorectal cancer: A phase II study of 5-day continuous
venous infusion at circadian-rhythm modulated rate. Eur J Cancer 29A:1280-1284,
5. Becouarn Y, Ychou M, Ducreux M, et al: Phase II trial of
oxaliplatin 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 as
single agent in previously untreated colorectal carcinoma patients: A phase II
multicentric study. Ann Oncol 9:105-108, 1998.
7. André T, Louvet C, Raymond E, et al: Bimonthly high-dose
leucovorin and 5-fluorouracil infusion and oxaliplatin (FOLFOX3) for metastatic
colorectal 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 platinum
resistance 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: Correlation
with replicative bypass of platinum-DNA adducts. Cancer Res 58:3579-3585, 1998.
10. Page JD, Husain I, Sancar A, et al: Effect of the
diaminocyclohexane carrier ligand on platinum adduct formation, repair, and
lethality. Biochemistry 29:1016-1024, 1990.
11. Mitchell EP, LoRusso P, Gococo K, et al: Safety profile of
oxaliplatin (single agent or with 5-FU) from the large North American
compassionate use experience in advanced colorectal cancer (ACC) (abstract
1259). Proc Am Soc Clin Oncol 19:319a, 2000.