During the 1980s, the only drug routinely used to treat colorectal carcinoma was single-agent fluorouracil (5-FU), a drug that had shown no proven benefit in the adjuvant setting. Since then, significant improvements in the overall management of colorectal cancer have been made. This review will compare today's standard of care for adjuvant colorectal carcinoma to that practiced 20 years ago. The authors examine key questions asked about adjuvant therapy and the answers that ultimately changed clinical practice standards and improved overall survival for patients diagnosed with this disease. In addition, this review explores whether 5-FU should be given as part of a multidrug regimen and which route of administration is best when this drug is given. Further, the authors delve into both the use of locally directed therapies to the liver or peritoneum to improve outcomes and the selection of patients to receive adjuvant chemotherapy. Finally, a look to the future shows monoclonal antibodies to be an avenue of great promise in fighting colorectal cancer.
Over the past 20 years, death rates from colorectal cancer have declined progressively in the United States. This improvement in outcome can be attributed, at least in part, to detection of disease at an earlier stage and more effective treatments, particularly adjuvant therapy. In this same time period, adjuvant therapy for colon cancer has evolved from single-agent fluorouracil (5-FU)-initially thought from small, nondefinitive trials to have no proven benefit-to therapy that decreases mortality in patients with stage III disease by a relative risk of 20% to 30%.[2,3] While 5-FU continues to be the foundation of treatment for colon cancer, its administration, both as a single agent and in conjunction with modulators, has undergone considerable change over the past 2 decades. In the past decade, we have also discovered that this drug's toxicity and activity varies considerably depending on the method of administration (whether by bolus or infusion).
Since publication of the MOSAIC trial in 2002, and with confirmation by the preliminary data from National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07, oxaliplatin (Eloxatin) has added to the adjuvant therapy arsenal in a statistically significant and clinically relevant manner and is now an important drug for the adjuvant treatment of colon cancer. While it is exciting to consider the advancements that have been made in colon cancer treatment, this success leads to new and complex questions that will need to be addressed over the next 20 years.
Role of Adjuvant Therapy
One issue that needs be explored further is the role of adjuvant therapy in patients with high-risk stage II colon cancer. While there is a clear benefit to patients with stage III disease, this benefit has not been proven with stage II disease. Part of the problem is the heterogeneity of patients classified as having stage II colon cancer. The 5-year survival rate of patients with stage IIA disease is 85%, compared to 72% among those with stage IIB disease, which is actually worse than those patients with node-positive, stage IIIA disease. Current American Society of Clinical Oncology (ASCO) guidelines suggest a course of 5-FU-based adjuvant chemotherapy for stage II patients with at least one poor prognostic indicator including incomplete lymph node sampling, perforation, T4 lesions, or poorly differentiated histology. Whether oxaliplatin-based regimens should be used in stage II disease over 5-FU/leucovorin alone is controversial, although results of studies investigating this issue seem to favor the addition of oxaliplatin in early-stage disease.
Another issue deserving attention is the optimal length of adjuvant treatment and timing of treatment, particularly with respect to oxaliplatin. Most commonly, FOLFOX (infusional 5-FU/leucovorin/oxaliplatin) is administered every 2 weeks for a period of 6 months. Cumulative neurotoxicity occurs with oxaliplatin, often necessitating discontinuation of the drug. Administering oxaliplatin for fewer cycles or in a stop-and-go fashion might reduce severe neuropathy, but it also might affect disease recurrence. This strategy has been explored in the OPTIMOX1 trial, in which patients with metastatic disease received the standard regimen of FOLFOX vs FOLFOX administered in six-cycle intervals with 12-week breaks from oxaliplatin. OPTIMOX1 suggests that six cycles of oxaliplatin may be sufficient to achieve the full clinical benefit of oxaliplatin treatment while avoiding significant neurotoxicity related to extended use. This issue is currently being explored further in the metastatic setting and also needs to be examined in the adjuvant setting.
As in all patients with curative resections of colon cancer, we need to move beyond clinicopathologic staging into molecular profiling, as is being done in E5202. In the interim, other markers such as the ratio of metastatic to examined lymph nodes (or lymph node ratio) may also serve as an important prognostic factor. As previously shown, in patients with 10 or more lymph nodes removed, the lymph node ratio is the most significant prognostic factor for both overall survival and disease-free survival.
Once patients complete adjuvant therapy, they undergo surveillance for a period of time. Current ASCO guidelines recommend annual computed tomography of the chest and abdomen for 3 years after primary therapy and carcinoembryonic antigen testing every 3 months postoperatively for at least 3 years. The improvement in disease-free survival seen with our newer treatment regimens may indicate that we are simply delaying the time to disease recurrence. We may need to reconsider our surveillance guidelines-ie, close surveillance beyond 3 years may be warranted.
As noted in Beaven and Goldberg's comprehensive review, adjuvant trials have traditionally tested agents that have previously shown efficacy in the metastatic setting. This sequence of events is no different with the new biologic agents targeting vascular endothelial growth factor (bevacizumab [Avastin]) and epidermal growth factor receptor (cetuximab [Erbitux]). While we are hopeful these new biologics will prove efficacious in the adjuvant setting, we know from our experience with irinotecan (Camptosar) that benefit in the metastatic setting does not automatically translate to benefit in the adjuvant setting.
One important issue with respect to biologics in the adjuvant setting is the additional and nontrivial toxicities associated with these medications. Bevacizumab is associated with an increased risk of gastrointestinal perforation, as well as venous and arterial thrombotic events. These toxicities are being closely monitored in NSABP C-08 and the AVANT trial, adjuvant studies in which patients receive FOLFOX, with or without bevacizu-mab. While the major side effects associated with cetuximab seem less severe, the rash associated with this therapy has been responsible for treatment cessation in a significant number of patients with metastatic disease.
Even if the trials evaluating these new biologics prove positive, whether or not these toxicities can be justified in patients who have already undergone potentially curative resection is open for debate. It is likely that the incremental gain from the new biologics may be quite small, both relatively and absolutely, in those patients with a high likelihood of cure from surgery and standard chemotherapy alone.
The issue that is on everyone's mind and is impossible to ignore is the substantial cost associated with these new therapies. In the past decade, the treatment of cancer (in particular, colon cancer) has skyrocketed. The 6-month cost of adjuvant treatment for colon cancer has gone from approximately $650 for 5-FU and leucovorin to $47,000 with the addition of oxaliplatin. If bevacizumab is approved for the adjuvant setting, the 6-month cost of FOLFOX plus bevacizumab would be in excess of $67,000. It becomes increasingly difficult to justify the increased costs associated with the addition of these medications if their margin of benefit is low. While cost of treatment was not a great consideration in the past when determining the success of a clinical trial, the economic implications associated with approval for such a common disease are enormous and will likely be a real factor in the future.
The success realized in the adjuvant treatment of colon cancer in the past 20 years has bred a diverse list of challenges to address in the next 2 decades. In addition to continuing the development of more directed therapies, we must also deal with the economic impact of these therapies. Over the next 20 years, as more targeted therapies become available, we will likely be treating colon cancer as an individualized disease and developing more personalized therapies. This is an exciting time for us and for our patients, and we look forward to the next 20 years.
-Maureen R. Hewitt, MD
-Daniel G. Haller, MD
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