Current Status of Adjuvant Therapy for Colorectal Cancer

Dr. O'Connell has done a remarkable job of discussing modalities available for patients with intermediate- to high-risk fully resected large bowel malignancies. Indeed, the title "Current Status of Adjuvant Therapy for Colorectal Cancer" is an underestimate of the article's contents, as he nicely details the past development of standard-ofcare adjuvant (and neoadjuvant, when appropriate) treatments as well. As is clearly pointed out in the article, adjuvant therapy works. Adding fluorouracil(Drug information on fluorouracil) (5-FU) with or without radiation to surgery already saves thousands of lives each year, and the enticing possibility of throwing newer chemotherapeutic agents (eg, oxaliplatin(Drug information on oxaliplatin)) and/or targeted therapies (bevacizumab [Avastin]) into the mix makes potential future successes even greater. While it thoroughly reviews the landmark adjuvant trials and reliably discusses the general outcomes by arm (eg, "This study [MOSAIC] demonstrated a significant improvement in 3-year disease-free survival for patients who received...FOLFOX compared to...5-FU plus leucovorin"), space precludes a discussion of the magnitude of benefits in Dr. O'Connell's article. Thus, readers should pull the references and read the original publications themselves. This will likely lead to an even greater appreciation for what has been achieved by investigators over the past 20 or so years. Dose and Schedule of 5-FU and Leucovorin
Dr. O'Connell addresses many of the controversies in adjuvant therapy for colorectal malignancy, such as whether or not to offer treatment to resected stage II colon cancer patients. However, there are several remaining questions. One concerns the appropriate dose of leucovorin. Leucovorin is an excellent 5-FU modulator, and Dr. O'Connell states that the addition of leucovorin to 5-FU improves efficacy (response) in metastatic disease. Indeed, a recent update[1] of the meta analysis he references suggests a survival improvement as well. Currently, 5-FU plus leucovorin is also the standard-of-care colon cancer adjuvant regimen. However, the best dose and schedule of leucovorin following resection of colon cancer are rarely discussed by American authors and editorialists. In general, leucovorin (given with 5-FU) can be given at a low (usually 20 mg/m²) or higher (175 to 500 mg/m²) dose, and it can be administered on a weekly or daily * 5 (usually every 4 to 5 weeks) basis. In metastatic disease, there are no overall survival differences when one uses 5-FU with weekly low-dose leucovorin, weekly high-dose leucovorin (Roswell Park regimen), or daily * 5 low-dose leucovorin (the Mayo regimen). However, due to severe toxicities associated with that dosing schedule, the Mayo regimen is essentially no longer used to treat either metastatic or micrometastatic (ie, adjuvant) disease. There is also no reason to use the Roswell Park regimen for advanced disease, as the higher leucovorin dose is not more efficacious, but it is more expensive; it is also associated with higher rates of severe diarrhea. Strangely, North American cooperative groups have tested Mayo against Roswell Park in adjuvant trials (thus changing both dose and scheduling of the leucovorin), demonstrating equivalent efficacy, but a low-dose weekly leucovorin-containing regimen has not been tested in the United States. The QUASAR (Quick And Simple And Reliable) Group from Birmingham in the United Kingdom has tested the efficacy of low-dose (25 mg/m2) vs higher-dose (175 mg/m²) leucovorin with 5-FU, allowing weekly or daily * 5 administration.[2] There was no efficacy improvement for patients getting high-dose leucovorin on either schedule. Thus, most US oncologists continue to use the Roswell Park regimen even though there are randomized trial data to suggest that using weekly 5-FU with low-dose leucovorin as adjuvant therapy for resected colon cancer is a safe and effective strategy. The Role of Radiation Therapy in Colon Cancer
Dr. O'Connell appropriately states radiation therapy plays a "very limited" role following resection of proximal large bowel cancers. However, local recurrence even of colonic tumors can certainly be problematic, particularly if there are a number of involved regional lymph nodes, or if the primary tumor is deeply invasive (T4 disease). The North Central Cancer Treatment Group performed a phase III randomized trial of 5-FU and levamisole(Drug information on levamisole) (Ergamisol) with or without irradiation in high-risk colon cancers (tumor adherence or invasion of surrounding structures, or T3, N1- 2 disease).[3] This trial closed early due to poor accrual, and its initial publication reported that the radiation therapy did not significantly improve outcome over the chemotherapy alone. Indeed, review of the actual survival data shows patients on the radiation arm had a slightly worse outcome. The updated manuscript for this trial has been submitted, but it is unlikely its conclusions will change. Despite the negative result, this study was not really definitive; the question of whether or not to irradiate these patients (a practice which is frequently offered, at least in T4 disease) may remain forever unanswered. Clinical Trial Design
What is the most expeditious way to do large-scale, randomized, adjuvant clinical trials in colorectal cancer? In general, standard phase III trials, with 5-year survival as their primary objective, require long periods of follow-up. The MOSAIC trial, discussed in detail by Dr. O'Connell, used 3-year disease-free survival as an end point.[4] Certainly several trials with this potential objective could be performed in the time it takes to do one study utilizing 5-year overall survival as its primary end point. Is 3-year disease-free survival a reliable surrogate for 5-year overall survival? A sophisticated statistical analysis aiming to answer that question, using patient data from a number of large trials, is under way. New Chemotherapeutic Agents
What do we do with new chemotherapeutic agents? In the metastatic setting, oxaliplatin (Eloxatin) plus infusional 5-FU and irinotecan(Drug information on irinotecan), in combination with bolus (Saltz) or infusional 5-FU, are all more effective than 5-FU/leucovorin alone. However, the addition of oxaliplatin to infusional 5-FU (FOLFOX4) improves the outcome in adjuvant treatment of colon cancer (MOSAIC, discussed above and by Dr. O'Connell). But surprisingly, adding irinotecan to bolus 5-FU does not improve cure rates. We also know that FOLFOX4 is more effective than the Saltz regimen in metastatic disease, but regimens using irinotecan with infusional 5-FU appear equally effective as FOLFOX.[ 5] Thus, it is possible that using infusional 5-FU with irinotecan, or using capecitabine(Drug information on capecitabine) (Xeloda) with the latter agent, will be better than 5-FU/leucovorin alone in the adjuvant setting. The V307 (infusional 5-FU with or without irinotecan) and QUASAR 2 (irinotecan with capecitabine, 3- or 6-month duration, vs bolus 5-FU plus leucovorin) trials respectively will answer those questions, but data from those studies are not yet available. Radiation in Rectal Cancer
Rectal cancer is slightly simpler. Patients with stage II or III resected tumors need some type of adjuvant therapy. While we now know that neoadjuvant chemoradiotherapy is better than postoperative treatment, at least in terms of toxicity, the question remains whether the irradiation component is always necessary. Dr. O'Connell's article somewhat downplays the National Surgical Adjuvant Breast and Bowel Project's R-02 trial, which compared postoperative adjuvant therapy with 5-FU-based chemotherapy, with or without radiation (5,040 cGy), in patients with resected stage II and III tumors. The radiation added no disease-free or overall survival benefit, but it did decrease the cumulative incidence of local relapse from a relatively low 13% to an even lower 8%. Thus, it seems reasonable to treat patients felt to be at low risk of locoregional relapse (T3, N0 disease) with chemotherapy alone. It is also possible that the results with chemotherapy alone may be even better (both locally and distantly) when oxaliplatin and targeted agents make their way into standard treatment of rectal cancer, as they almost certainly will. Conclusions
This is an extraordinary time to be a colorectal oncologist. No new drugs were approved in this disease between 1962 (5-FU) and 1990/1991 (levamisole/ leucovorin). In the past 8 years, however, five new agents were suddenly registered. However, Dr. O'Connell is correct in saying that we should not be satisfied. Median survival for advanced neoplasms will likely break the 2-year barrier soon, and even incremental gains made in metastatic disease should translate into huge improvements in cure rates when similar regimens are used in adjuvant patients.