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New Lessons From "Old" Chemotherapy in Colorectal Cancer

Mayo Clinic, Rochester, MN

The standard of care in the treatment of metastatic colorectal cancer has seen a rapid evolution over the past 10 years. In clinical practice, combination regimens consisting of a fluoropyrimidine plus either irinotecan or oxaliplatin now commonly form the backbone for the addition of a biologic agent.¹ In the first-line setting, this biologic agent is routinely bevacizumab; in subsequent lines of therapy, antibodies against the epidermal growth factor receptor (EGFR) are introduced, again mainly in combination with conventional cytotoxic chemotherapy. Presently ongoing clinical trials focus almost exclusively on defining the best strategy to integrate these biologic agents into palliative (or adjuvant) treatment algorithms, or on biomarker-driven patient selection (eg, by using KRAS mutations to select a patient population with a greater likelihood of responding to EGFR-targeted approaches).²

Based on this current generation of ongoing trials, one might think that all pertinent questions related to conventional chemotherapy in colorectal cancer have been solved, and that it is time to move on beyond the nonselective, one-size-fits-all treatment decisions to a more sophisticated approach toward colorectal cancer. Indeed, the past 10 years have seen a plethora of definitive results from clinical trials which have shaped our current standard treatment approaches. We have learned that infusional fluorouracil (FU) is a much more appropriate backbone for the addition of irinotecan and/or oxaliplatin than bolus FU.³ We have seen that capecitabine can serve as substitute for FU in combination regimens with oxaliplatin, but that combinations with irinotecan can be problematic.^4,5 Eventually, we have recognized that with all treatment options available, one particular treatment sequence is not superior to another, but that within clinical trials, the overall survival of patients with metastatic colorectal cancer is tightly correlated with the percentage of patients who are treated with all three active agents, fluoropyrimidine, irinotecan, and oxaliplatin.⁶

In view of all this knowledge on conventional chemotherapy, what could a trial of second-line irinotecan alone versus irinotecan plus oxaliplatin (IROX) after failure of FU/leucovorin (LV) tell us about palliative treatment algorithms in colorectal cancer in 2008? Currently, at least in the United States, few patients are treated with FU/LV alone as first-line therapy, and definitive first-line results with IROX are available from the pivotal phase III N9741 trial in which it was found to be inferior to FOLFOX4, but superior to IFL (bolus FU/LV plus irinotecan).³

In this issue of Journal of Clinical Oncology, Haller et al⁷ present the results of a phase III trial in advanced colorectal cancer which 628 patients who had shown tumor progression FU/LV were randomly assigned to either irinotecan or IROX. It is important to note that the time of patient accrual (January 2001 to April 2004) largely predates the era of biologics in colorectal cancer, and even oxaliplatin was not routinely available everywhere during that time. Haller et al report that IROX was found to be the superior second-line therapy with regard to overall survival, time to tumor progression, response rate, and improvement in tumor-related symptoms. In fact, the median overall survival for both arms was in the upper range of expectation, with 11.1 months and 13.4 months for irinotecan and IROX, respectively. The incremental gain in median progression-free survival (2.5 months) achieved with IROX over irinotecan alone translated almost exactly into the same incremental gain in overall survival. This finding is notable given the relatively high percentage of patients (46%) in the irinotecan arm who subsequently received an oxaliplatin-based therapy, although almost half of these patients received oxaliplatin as single agent in third-line therapy which is know to have very limited activity.⁸

The results of the Haller et al trial are very similar to the findings of N9841, a phase III trial which randomly assigned 491 patients in second-line after FU/LV failure to either irinotecan or FOLFOX4 with optional cross-over in third-line therapy.⁹ The overall survival for both arms was remarkably long but not statistically different (14.7 months for irinotecan, 13.5 months for FOLFOX4), conceivably due to the high rate of cross-over (51% for FOLFOX4, 38% for irinotecan). These results again highlight the sequence-independent overall survival effect of utilizing all three active cytotoxic agents in the course of therapy.

The clinical relevance of the findings of Haller et al are strengthened by their inclusion of a standardized assessment of tumor-related symptoms (TRS) in their study to provide information on patient benefit. This assessment recorded a combined metric of patient-reported variables (self-assessed pain intensity, patient-assessed performance status), objectives measures (weight, analgesic use by diaries), and investigator-assessed performance status. Patients on IROX experienced an improvement in TRS compared with irinotecan alone, a result which nicely complements—and goes beyond— the tumor-related parameters demonstrating superiority of IROX. The trial convincingly shows the feasibility and added value by using patient-reported outcome measures in study designs.

The trial results raise the question of whether IROX should now be considered the optimal second-line therapy after FU/LV failure, as opposed to sequentially using irinotecan (or FOLFIRI) followed by FOLFOX (or vice versa) after FU/LV. Based on the premise that access to all three active agents is a critical factor in extending patient survival, an argument could be made that IROX after FU failure makes more sense than continuing FU and adding irinotecan (to form FOLFIRI) or oxaliplatin (to form FOLFOX).

A definitive trial testing these two approaches (IROX v a sequential approach FOLFOX the FOLFIRI or visa versa) as second-line therapy in advanced colorectal cancer is not likely to be conducted as first-line therapy now standardly includes both combination therapy and a biologic. In our opinion, though, it is unlikely that IROX as second-line therapy would be superior to a strategic, sequential approach with FOLFOX followed by FOLFIRI (or vice versa). In the Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS) trial,¹⁰ both FOLFOX and FOLFIRI provided a nonsignificant overall survival benefit (about 1-month median) from the beginning of initial therapy compared with irinotecan alone after FU failure, in the setting where only a very small number of patients had access to the other cytotoxic agent after second-line treatment failure. The difference in second-line strategy in FOCUS is also reduced by including the approximately 35% of patients who received no second-line therapy at all, which was the appropriate analysis for the strategy question in FOCUS but limits the ability for that trial to address a specific second line question in those patients who are able to continue therapy past first-line treatment failure. In our estimation, the planned use of all three drugs via a FOLFOX then FOLFIRI or opposite strategy would provide results indistinguishable from second-line IROX.

How then does one arrive at a preferred strategy? FOLFOX and FOLFIRI are both effective and equally tolerable regimens, whereas IROX has demonstrated an increased toxicity profile compared with FOLFOX, both in N9741³ and in the current report (the grade 3/4 toxicity profile of IROX in N9741 and the Haller et al study are virtually identical, in particular with regard to the relatively high rate of severe diarrhea [28%]).¹¹ Unfortunately, data on IROX in combination with biologics are currently missing, a fact which might further prevent a more frequent use of this interesting regimen.

Could IROX evolve as a treatment regimen specifically used for tumors with defective mismatch repair systems (dMMR)? A recent pooled-analysis of adjuvant, FU-based trials demonstrated no treatment benefit for patients with dMMR colon cancer.¹² In fact, for patients with stage II disease, the use of FU in dMMR tumors was associated with a significant detrimental effect on overall survival. Though these still largely unexplained findings are intriguing, it has to be kept in mind that they were generated from adjuvant trials using FU alone, and preliminary reports have suggested that adding either irinotecan or oxaliplatin to FU may reverse the FU resistance in patients with dMMR tumors.^13,14

Consequently, for current clinical practice, FOLFOX, XELOX, and FOLFIRI should be considered the optimal chemotherapy-doublets in the treatment algorithm of advanced colorectal cancer, both in the first-line setting, and as second-line therapy in patients who received FU alone as initial treatment. IROX has well-documented activity and a predictable side effect profile which makes it a very valid alternative in those patients who cannot tolerate fluoropyrimidines, in either the first- or second-line setting.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Axel Grothey, Sanofi-aventis (C), Genentech (C), Pfizer (C); Daniel J. Sargent, Sanofi-aventis (C), Pfizer (C), Genentech (C) Stock Ownership: None Honoraria: Axel Grothey, Roche; Daniel J. Sargent, Sanofi-aventis, Genentech, Pfizer Research Funding: Axel Grothey, Sanofi-aventis, Genentech Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Axel Grothey, Daniel J. Sargent

Collection and assembly of data: Axel Grothey, Daniel J. Sargent

Data analysis and interpretation: Axel Grothey, Daniel J. Sargent

Manuscript writing: Axel Grothey, Daniel J. Sargent

Final approval of manuscript: Axel Grothey, Daniel J. Sargent

REFERENCES

1. NCCN: Clinical practice guidelines in oncology: Colon cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp?button=I+Agree

2. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-1634, 2008[Abstract/Free Full Text]

3. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004[Abstract/Free Full Text]

4. Fuchs CS, Marshall J, Mitchell E, et al: Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: Results from the BICC-C Study. J Clin Oncol 25:4779-4786, 2007[Abstract/Free Full Text]

5. Cassidy J, Clarke S, Diaz-Rubio E, et al: Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006-2012, 2008[Abstract/Free Full Text]

6. Grothey A, Sargent D, Goldberg RM, et al: Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 22:1209-1214, 2004[Abstract/Free Full Text]

7. Haller D, Rothenberg M, Wong A, et al: Oxaliplatin plus irinotecan compared to irinotecan alone as second-line treatment after single-agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol 26:4544-4550, 2008[Abstract/Free Full Text]

8. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003[Abstract/Free Full Text]

9. Pitot HC, Rowland KM, Sargent DJ, et al: N9841: A randomized phase III equivalence trial of irinotecan (CPT-11) versus oxaliplatin/5-fluorouracil (5FU)/leucovorin (FOLFOX4) in patients (pts) with advanced colorectal cancer (CRC) previously treated with 5FU. J Clin Oncol 23:247s, 2005 (suppl; abstr 3506)[CrossRef]

10. Seymour MT, Maughan TS, Ledermann JA, et al: Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): A randomised controlled trial. Lancet 370:143-152, 2007[CrossRef][Medline]

11. Ashley AC, Sargent DJ, Alberts SR, et al: Updated efficacy and toxicity analysis of irinotecan and oxaliplatin (IROX): Intergroup trial N9741 in first-line treatment of metastatic colorectal cancer. Cancer 110:670-677, 2007[Medline]

12. Sargent DJ, Marsoni S, Thibodeau SN, et al: Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials. J Clin Oncol 26:180s, 2008 (suppl; abstr 4008)

13. Bertagnolli MM, Compton CC, Niedzwiecki D, et al: Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer. ASCO Meeting Abstracts 24:541s, 2006 (suppl; abstr 10003)

14. Zaanan A, Cuilliere-Dartigues P, Parc Y, et al: Impact of microsatellite instability and p53 expression on stage III colon cancer disease-free survival in patients treated by fluorouracil and leucovorin with or without oxaliplatin. J Clin Oncol 26:645s, 2008 (suppl; abstr 15017)

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