Therapy for Early-Stage Colorectal Cancer

The article by Drs. Peeters and Haller provides the details of 20 years of investigation into the adjuvant therapy of colorectal cancer. The authors describe pivotal trials through which an international cast of investigators have identified adjuvant interventions—ie, chemotherapy or chemotherapy plus radiation—that have improved the odds of cure for patients with colorectal cancers, as compared with surgery alone. The choice of two authors, one North American and the other European, offers the perspectives of both oncology communities on stages II and III disease. The authors also identify areas of future investigation and issues for which controversy prevails.

In adjuvant therapy for colon cancer, the treatment approach for patients not enrolled in clinical trials is similar around the globe: Stage III patients are usually treated, stage II patients often are not. For treatment of operable rectal cancer, preoperative combined-modality therapy is preferred in Europe, while many North American oncologists favor postoperative therapy. The potential advantages and drawbacks of both approaches are enumerated.

New Drugs in the Next Decade

The major research questions that have been addressed worldwide during the last 2 decades have focused on optimizing drug administration, drug modulation, and integration of radiation with fluorouracil(Drug information on fluorouracil) (5-FU) in colon and rectal cancer treatment. Trials have discerned and confirmed effective strategies. Virtually all reported regimens have been 5-FU–based.

Although some refinements in 5-FU treatment will continue to occur, the authors correctly predict that the research agenda of the next decade will be different. The task facing the international oncology community is the need to delineate the roles of the promising array of new drugs currently under investigation. These include fluoropyrimidines, which can be administered orally; topoisomerase I inhibitors; platinum analogs; immunomodulators; and agents that interrupt signaling pathways or inhibit the formation of the peritumoral extracellular matrix that supports tumor growth and metastasis.

Staging Systems and Prognostic Determinants

The authors argue, as do most investigators in this field, for universal adoption of the TNM staging system. This taxonomy requires continuing refinement to allow for consistent tumor classification and to reflect factors known to affect outcomes.

The current TNM system does not account for the adverse prognostic implications associated with bowel obstruction and tumor adherence. The classification of N3 disease—ie, positive lymph nodes along a named vascular trunk—remains controversial, as such nodes are infrequently included in standard resection specimens.

It is still unclear whether tumor characteristics other than stage and grade, such as immunohistochemical staining for the p53 or DCC (deleted in colon cancer) genes, levels of thymidylate

synthase, flow cytometry, and markers of apoptosis (eg, Bax and Bcl-2), will have a practical use in the clinic. Within stages II and III disease, there is a pressing need to identify and subdivide patients with better and worse prognoses in order to allow for more individually tailored prescriptions.

Long-Term Toxicity

While issues of 5-FU modulation are still under investigation, investigators are now adding new cytotoxic drugs, such as irinotecan(Drug information on irinotecan) (CPT-11 [Camptosar]) and oxaliplatin(Drug information on oxaliplatin), to the adjuvant therapy armamentarium. With the exception of the potential leukemogenic effects of semustine (methyl-CCNU), long-term toxicity of adjuvant colorectal cancer chemotherapy generally has not been an important consideration.[1]

Fluorouracil has not been implicated as either a human or an animal carcinogen. With the integration of topoisomerase inhibitors and platinum analogs into adjuvant therapy, survivors will need careful surveillance for late toxicity, such as myelodysplasia and leukemia, as well as for neuropathy.

Multimodality Therapy for Rectal Cancer

The optimal program of radiation, chemotherapy, and surgery remains a subject for ongoing studies in rectal cancer. Currently, surgery is the primary determinant of outcome for patients with stage II or III rectal cancer. In an age in which the pursuit of the highest product quality has emerged as an industrial agenda, it is not surprising that health care purchasers, providers, and patients have challenged the medical community to identify and provide the best outcomes.

Recently, surgeon-related variability has come under scrutiny, piqued by promising reports of improved outcomes after total mesorectal excision.[2,3] Proponents of total mesorectal excision note that 16.3% and 28.6% of patients with Dukes’ stage B and C rectal cancer, respectively, will develop a local recurrence, most commonly in the mesorectum.[4]

Heald and others suggest that total mesorectal excision can reduce the local recurrence rate to £ 10%.[5] Given this low recurrence rate, some have questioned the need for postoperative therapy, with its attendant risk of long-term morbidity, except among patients with N2 disease or those felt to be at high risk of distant failure. Several European trials are underway to help elucidate the roles of either neoadjuvant or adjuvant therapy.

Radiation therapy continues to be an important component of therapy for patients with rectal cancer in the United States. A recent survey of US patterns of care showed that 75% of patients received postoperative radiation therapy and 22%, preoperative therapy.[6] Moreover, 90% of patients also received chemotherapy.

Preoperative radiation therapy has been employed as a means of providing local control and improving the odds of sphincter preservation by downstaging the tumor prior to surgery. A recent paper described 36 patients who underwent preoperative radiation therapy and who were felt at presentation to require an abdominoperineal resection.[7] Subsequently, 77% of these patients had a sphincter-sparing procedure.

As reported by Drs. Peeters and Haller, a clinical trial (National Surgical Adjuvant Breast and Bowel Project [NSABP] R-03) is currently underway in North America, the goal of which is to better define the benefits and complications of preoperative vs postoperative radiation therapy. An interim report from this trial suggests that there is no increased or unexpected toxicity with preoperative therapy.[8] The group of patients assigned to the preoperative arm also exhibited a trend toward tumor downstaging and a higher rate of sphincter preservation.

Future Studies

Beyond the current studies aimed at determining the most effective concomitant 5-FU regimen to be given with radiation therapy, future studies will need to address the role of newer chemotherapy agents and biological response modifiers in decreasing the risk of recurrent rectal cancer. As noted in the article, this will include the evaluation of agents that act as radiation sensitizers, as well as agents that are more effective in eliminating residual micrometastatic disease.

In this fine review, Drs. Peeters and Haller have nicely catalogued past and present studies in the adjuvant therapy of colorectal cancer and have projected the direction of future investigations.