Originally published as JCO Early Release 10.1200/JCO.2003.07.941 on September 8 2003

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Therapeutic Strategies for Metastatic Colorectal Cancer: Simultaneous, Sequential, or Specific?

Vanderbilt-Ingram Cancer Center, Nashville, TN

"The more alternatives, the more difficult the choice."
Abbé D’Allanival

DURING THE past 3 years, multiagent chemotherapy, consisting of either irinotecan or oxaliplatin combined with fluorouracil and leucovorin, has largely supplanted single-agent chemotherapy (fluorouracil with leucovorin modulation) as first-line treatment for metastatic colorectal cancer. This shift occurred as a result of randomized, controlled trials demonstrating significant improvements (compared with fluorouracil and leucovorin) in objective response rates, time-to-tumor progression, and, for irinotecan, survival using multiagent chemotherapy.^1–5 These compelling clinical data, combined with the distinct molecular targets, mechanisms of action, and purported mechanisms of resistance for each of these drugs, set the stage for the development of drug treatments in which all three agents were combined into a single regimen. In this issue of the Journal of Clinical Oncology, Goetz et al⁶ report the results of a phase I trial evaluating two different schedules of drug administration for irinotecan, oxaliplatin, fluorouracil, and leucovorin. The most common toxicities were diarrhea and neutropenia, which were dose-limiting for both cohorts. This is consistent with the patterns of toxicity reported by others who have used different schedules.^7,8 What distinguishes this report from others is the detailed neurological symptom evaluation that was conducted as part of the study. Oxaliplatin induces two types of peripheral neuropathy. While the acute, cold-induced neuropathy is usually no more than an inconvenience, it is the cumulative neuropathy that can progress to the point of interfering with activities of daily living. In a cohort of 10 patients treated at the maximum-tolerated dose (MTD), Goetz et al reported no functional neurological impairment at 3 months’ follow-up testing. In a subset of patients with baseline neurologic deficits, none of the six patients treated at the MTD of cohort 2 experienced worsening of their symptoms. Although this experience, covering a cumulative dose of only 170 to 340 mg/m², may not represent a long enough course or a high enough cumulative dose of oxaliplatin for thorough assessment of cumulative neurotoxicity, these results suggest that patients with pre-existing neuropathy can be considered for oxaliplatin treatment without apparent increased risk of an acute or severe exacerbation of this problem.

In a broader context, this study raises many important questions regarding strategies for the rational integration of effective drugs in advanced-stage colorectal cancer. First, is there a strong rationale for incorporating all drugs into a single therapy? The preclinical evidence for combining irinotecan, oxaliplatin, and fluorouracil is not strong, with SN-38 adding little, if any, cytotoxic effect to fluoropyrimidines, compared with the strong synergy observed with oxaliplatin and fluorouracil in two colon cancer cell lines.⁹ Second, are there established guidelines for selecting the starting doses of drugs used in combination phase I trials? An approach that incorporates overlapping patterns of toxicity into a "tolerable-dose diagram" has been proposed.¹⁰ Unfortunately, this model would not have predicted the ease with which irinotecan and oxaliplatin can each be combined in full doses with fluorouracil and leucovorin despite overlapping patterns of toxicity. Therefore, it could not have been relied on to predict toxicities associated with the three-drug combination. Third, are these drugs most effective when used simultaneously, as described by Goetz et al, or sequentially, in a manner described by Tournigand et al?¹¹ Tournigand et al randomized patients with advanced stage colorectal cancer to irinotecan, fluorouracil, and leucovorin (FOLFIRI), or to oxaliplatin, fluoruracil, and leucovorin (FOLFOX).¹¹ Patients developing progressive disease on one regimen crossed over to the alternative regimen. The median survival associated with this sequential approach was excellent, exceeding 20 months in both arms of the study. This should be considered the benchmark against which any new therapy, including the simultaneous approach outlined by Goetz et al, should be compared. A variation of the approach taken by Tournigand, in which the treatment regimen was switched only at the time of tumor progression, would be one in which both regimens are administered in planned sequence prior to disease progression. This approach is similar to the simultaneous approach in that it exposes the patient to all three drugs as part of first-line therapy, before the emergence of clinical drug resistance. However, it differs in that it permits higher doses of each drug to be used as part of sequential two-drug regimens.¹² This approach may also be worthy of prospective evaluation in comparison to a simultaneous, three-drug regimen. Fourth, is there any way to select the "best" treatment for an individual patient with colorectal cancer? The rational selection of therapy has been an elusive goal in cancer treatment. Until recently, this was a moot point due to the lack of therapeutic options beyond fluorouracil. There is now a growing body of evidence demonstrating that specific genetic characteristics can predict for clinical outcome. In the most extensive evaluation reported to date of genetic polymorphisms and their relationship to drug effect in patients with colorectal cancer, McCleod et al¹³ confirmed the associations between UGT1A1 genotype and neutropenia in those patients treated with irinotecan-containing regimens, and the relationship between the ERCC2 (also known as XPD) genotype and response to oxaliplatin-containing regimens. Studies are now being designed that will prospectively assign patients to therapy based on genotype.

The emergence of irinotecan and oxaliplatin as key components of multidrug chemotherapy for colorectal cancer has challenged our ability to integrate both of these new agents into therapeutic regimens in a rational, yet expeditious fashion. It may be impossible to know whether it is better to administer these drugs in a simultaneous or a sequential fashion without performing a phase III trial. But even before this can be done, the landscape of therapeutic options for advanced colorectal cancer is likely to change with the addition of cetuximab, bevacizumab, and other growth factor and receptor antagonists.^14,15 This will exponentially increase the complexity of clinical trials in advanced colorectal cancer. With so many agents, regimens, and designs vying for definitive clinical evaluation, it is therefore incumbent on us to focus on the questions of "which drugs? In what combination? Administered to whom?" in order to develop even better treatment for advanced colorectal cancer.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the past two years: Mace L. Rothenberg, Sanofi-Synthelabo, Pharmacia, Roche; Jordan D. Berlin, Sanofi-Synthelabo, Pharmacia, Roche. Received more than $2,000 a year from a company for either of the past two years: Mace L. Rothenberg, Sanofi-Synthelabo, Pharmacia, Roche; Jordan D. Berlin, Sanofi-Synthelabo, Pharmacia, Roche.

ACKNOWLEDGMENTS

This work was supported by Grant 5K24CA82301 from the National Institutes of Health, Bethesda, MD (M.L.R.), and the Ingram Charitable Trust, Nashville, TN (M.L.R.).

REFERENCES

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12. Van Cutsem E, Pozzo C, Starkhammar H, et al: A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer. Ann Oncol 9:1199–1204, 1998[Abstract/Free Full Text]

13. McLeod HL, Sargent DJ, Marsh S, et al: Pharmacogenetic analysis of systemic toxicity and response after 5FU/CPT-11, 5FU/oxaliplatin, or CPT-11/oxaliplatin therapy for advanced colorectal cancer: Results from an intergroup trial. Proc Am Soc Clin Oncol 22:253, 2003 (abstr 1013)

14. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Results of a phase III trial of bevacizumab in combination with bolus irinotecan, 5-fluourouracil, leucovorin as first-line therapy in subjects with metastatic CRC. Proc Am Soc Clin Oncol 22: 2003 (abstr 3646)

15. Cunningham D, Humblet Y, Siena S, et al: Cetuximab (C225) alone or in combination with irinotecan in patients with epidermal growth factor receptor-positive, irinotecan-refractory metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:252, 2003 (abstr 1012)

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