“If you don’t know where you are going, any road will take you there.”
—Lewis Carroll (1832–1898)
The complexity of treatment options that now exist for patients with newly diagnosed metastatic colorectal cancer has increased dramatically over the past decade. The use of these new agents has led to marked improvements in the lives of patients, with median overall survivals now exceeding 2 years. Yet as the treatment options have increased, the complexity of combining and sequencing agents has also grown. Drs. Davies and Goldberg clearly delineate the various treatment options available and their comments regarding K-ras mutational status and combined biologic therapy are of great clinical relevance. Given these complexities, it is now more important that ever to define the goals of therapy prior to selection of a first-line chemotherapy regimen.
Consistently, large series of liver metastasectomies have demonstrated 5-year survival rates of 30% to 50%, and similar outcomes may be derived for patients with limited pulmonary involvement. Given such a potential benefit, identification of possible surgical candidates is the most critical component of initial chemotherapy planning. With this in mind, what is the proper endpoint with which to evaluate an appropriate first-line chemotherapy regimen?
Goal of Treatment: Resection of Limited Metastatic Disease
For patients with potentially resectable disease, other clinical endpoints besides progression-free survival may be more appropriate when selecting regimens. For example, aggressive combination chemotherapy is able to increase the rate of successful margin-negative (R0) metastasectomies. As an example, for patients with liver metastases only, FOLFOXIRI (leucovorin [folinic acid], fluorouracil [5-FU], oxaliplatin [Eloxatin], irinotecan) resulted in an R0 resection rate of 36% compared to 12% for FOLFIRI (leucovorin, 5-FU, irinotecan). Likewise, the addition of cetuximab (Erbitux) to FOLFIRI resulted in an increase in the R0 resection rate from 4.5% to 9.8% in unselected patients with liver-limited disease.
In these potentially resectable patients, the added toxicities associated with these regimens may be acceptable. In addition, response rates appear to be appropriate surrogates for resection rates in a pooled analysis of trials. It is in this potentially resectable subset of metastatic colorectal cancer patients where response rate is a useful endpoint in assessing a chemotherapy regimen.
One of the most useful new biomarkers for treatment selection has been the demonstration that patients with activating mutations in the K-ras oncogene do not respond to anti–epidermal growth factor receptor (EGFR) therapy. By properly selecting patients, several studies have demonstrated an increased response rate to anti-EGFR therapy. In the K-ras wild type patients from the CRYSTAL trial, the addition of cetuximab to FOLFIRI increased response rates from 43% to 59%. Likewise, in the K-ras wild type subset of the OPUS trial, response rates increased from 37% with FOLFOX (leucovorin, 5-FU, oxaliplatin [Eloxatin]) alone to 61% with the addition of cetuximab. This approach is being adopted in a planned National Surgical Adjuvant Breast and Bowel Project/American College of Surgeons Oncology Group (NSABP/ACOSOG) neoadjuvant trial, where K-ras wild type patients with resectable liver metastases will be treated with perioperative or adjuvant FOLFOX and cetuximab.
As noted by Davies and Goldberg, recent studies have added a word of caution to our attempts to improve outcomes by adding more agents to first-line regimens. In the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) and CApecitabine, IRinotecan, Oxaliplatin (CAIRO) II studies, the addition of anti-EGFR therapy to a bevacizumab (Avastin)/chemotherapy backbone did not improve outcomes for either the entire population or the K-ras wildtype subgroup. These results have challenged our understanding of both the EGFR and vascular endothelial growth factor (VEGF) pathways and indicated that combined biologic therapy should be limited to the clinical trial setting.
Goal of Treatment: Palliation
For patients where palliative treatment without the possibility of surgical intervention is the goal, progression-free survival remains the best surrogate for overall survival. Equally important for this group of patients is the toxicity profile of each therapy.
Drs. Davies and Goldberg discuss the use of the OPTIMOX1 approach as one method of minimizing toxicity. Although the clinical trial dictated reintroduction of oxaliplatin at the time of disease progression, this was rarely done. Likewise, in clinical practice, reintroduction of oxaliplatin at some point in the disease course is often overlooked, even in patients with resolution of their neuropathy. This may represent a missed opportunity to treat refractory patients with an active chemothepeutic agent. Irinotecan-based therapy, such as FOLFIRI/bevacizumab, has demonstrated benefits in progression-free survival similar to those of oxaliplatin-based regimens, and given the lack of dose-limiting neurotoxicity, these strategies should also be considered viable first-line treatment options.
Given the large number of colorectal cancer patients who are older than 70 years, the applicability of aggressive combination chemotherapy to this elderly population deserves mention. A pooled analysis including 3,742 colorectal cancer patients treated with FOLFOX demonstrated equivalent benefit with regard to response rate, progression free-survival, and overall survival between those who were < 70 and those ≥ 70 years old. Toxicities between the two groups were similar, with the exception of slightly higher neutropenia and thrombocytopenia in the elderly patients. A similar analysis for 2,691 patients treated with irinotecan and 5-FU demonstrated similar benefits and toxicities between the two age groups. Therefore, even in a palliative setting, chronologic age alone should not dissuade the use of a first-line combination regimen.
As discussed in the review, the FOCUS (Fluorouracil, Oxaliplatin, and CPT-11 [irinotecan] Use and Sequencing) and CAIRO studies have suggested that sequential single-agent chemotherapy provides similar outcomes to a combination chemotherapy approach. However, the chemotherapy combinations used in these studies and the low utilization of second-line chemotherapy bring into question the applicability of these data. A single-agent approach should not be applied to all patients, but for whom this strategy is most appropriate is not yet clearly delineated.
We are fortunate to have a number of active agents with which to treat metastatic colorectal cancer. However, further research is needed to find better positive and negative predictive biomarkers. Clinical practitioners must be cognizant of the goals of front-line therapy and help place patients on the right road to obtaining those goals.
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