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Originally published as JCO Early Release 10.1200/JCO.2004.05.985 on July 12 2004 © 2004 American Society of Clinical Oncology.
Patient Selection, Realism, and Randomized Clinical TrialsDepartment of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, NC Since the introduction of adjuvant chemotherapy for patients with node-positive adenocarcinoma of the colon, the general approaches have not significantly changed in the last decade, although there is now great interest in more aggressive combination chemotherapy regimens than standard bolus fluorouracil (FU). The surgical management of the primary disease has not changed substantially for many decades, though the advent of improved anesthesia and postoperative care has produced a significant decrease in operative mortality, especially for patients with serious comorbidities, and in the elderly. The use of laparoscopic resections may decrease surgical morbidity and hospital length of stay, but the data suggest that the advantages over standard open procedures will not be large. Local recurrence has not been generally perceived to be a major problem for most patients with extrapelvic colon cancer, although a number of series have suggested that it could contribute to lower cure rates in certain subsets of patients.1,2 Studies in rectal cancer have shown an improvement in local control with the use of postoperative radiation therapy and FU chemotherapy for patients with T3 or node-positive disease, though there has not been an impact on survival with postoperative radiation therapy alone.3 This is in contrast to the data for preoperative radiation therapy (especially with chemotherapy) in rectal cancer where there are good data demonstrating a survival advantage compared to surgery alone, as well as improved local control compared with postoperative chemoradiotherapy therapy.4-6 Since many investigators have assumed that there are not major biologic differences between colon and rectal cancer, it appears logical to believe that radiation therapy could have an impact, at least on local control, for certain subsets of colon cancer patients. This question prompted the design of the gastrointestinal Intergroup trial 0130, described in this issue of the Journal of Clinical Oncology by Martenson et al.7 Unfortunately, the data presented by Martenson et al do not support further improvements in the management of colon cancer by routinely adding adjuvant radiation therapy. There were six major issues with the implementation of the study (of which the authors are fully aware), that should be kept in mind: (1) the sample size was small, and the total accrual was only about one-quarter of that planned, so the power of the study to detect a moderate, but potentially clinically important impact, was extremely low; (2) there was a much higher ineligibility rate (15%) than is generally viewed as acceptable in a phase III trial; (3) the eligibility criteria were very broad, allowing in patients who were at relatively low risk of local failure (especially T3N1); (4) the trial was designed to detect a survival difference when, even in rectal cancer, studies have only shown improvement in local control with the use of postoperative radiation therapy; (5) although it was considered appropriate when the trial was designed, the chemotherapy used would now be considered inadequate when given concurrently with radiation therapy; and (6) the inability in many of the patients to determine the proper location of the tumor, without preoperative imaging or surgical clips, which seriously brings into question the adequacy of the delivered radiation treatment. Despite these problems, there are substantial lessons to be learned from this trial. First, there is no justification for the use of routine adjuvant radiation therapy for patients with resected colon cancer with negative surgical margins. This study could not rule out a benefit in selected patients who were at high risk for local recurrence in whom radiation treatment may have contributed to a benefit beyond that achieved with standard chemotherapy, but the data clearly do not justify the routine use of postoperative radiation therapy. Second, the trial does not answer the question about the use of radiation therapy for patients with residual disease, either gross or microscopic. However, it raises the question as to whether consideration should be given to preoperative radiochemotherapy (and perhaps with a boost dose of intraoperative radiation) and aggressive re-resection for those patients with residual disease, followed by additional chemotherapy. Although we do not have proof from this trial or other series that this approach will be effective, it is clear that patients with local residual disease (gross or microscopic) are very unlikely to be cured with chemotherapy alone, and salvage after local or regional recurrence has been demonstrated with similar regimens.8 Aggressive local and systemic therapy is a reasonable approach in this situation, and likely offers a far better chance of cure than treatment with chemotherapy alone. Third, we should not have expected a positive overall survival outcome in this trial, even if it had completed accrual, considering that we have not observed a survival improvement with similar approaches in rectal cancer, where local control is a more frequent problem. However, to the extent that one can extrapolate from rectal cancer data,6 outcomes should be better with preoperative radiochemotherapy than with postoperative therapy. With improved imaging technology it should be possible to identify more precisely the very high-risk patients with extrapelvic colon cancer, such as those in whom the surgeon would have difficulty in obtaining a wide resection because of tumor adherence or fixation to adjacent structures. Consideration should be given to exploring preoperative therapy in these very high-risk patients. It is important to keep in mind that the local recurrence rate in Intergroup Protocol 0130 was at least 16% without routine follow-up computed tomography or magnetic resonance imaging scans to detect local failures, indicating that the true rate would have been even higher if aggressive surveillance were done. Local recurrence is therefore still an issue for selected patients with colon cancer, and it is a failure pattern that cannot be ignored. Preventing local failure alone may not ultimately cure large numbers of additional patients, but patients cannot be cured if local control is not obtained. Fourth, future clinical trials of more aggressive local therapies will be doomed to failure if we try to manage all patients with a single treatment algorithm. We developed long ago the principles of clinical and pathological staging of colon cancer, but often, these simple and very valuable tools are underused. Surgeons often do not describe the true anatomic issues found during an operation. Pathologists often do not fully evaluate the nodal status, but examine only a handful of nodes, even though full nodal evaluation has been shown to be of major prognostic importance. Pathologists often do not examine the radial margins of the resection, even though this may be the single most important prognosticator of local recurrence (and was not usually available in the present study). Clinicians do not always use the information that is available, not reading the full operative note, pathology report or radiology report, even though critical information often resides—or is missing—in those reports.9,10 As we move forward in developing new cancer clinical trials, especially those using more aggressive local modalities, we will likely miss significant effects if we do not properly select patients for entry into those studies. Radiation therapy will only be of benefit in patients who have residual local-regional residual disease (because of margin positivity in which case the treatment is no longer an adjuvant therapy) or who at the highest risk of local recurrence, such as those with T4 tumors where wide surgical margins cannot be obtained. The likelihood of residual disease (gross or microscopic) can be partially determined by the simple approaches described above. Adjuvant radiation therapy will only be of value if we know what volumes need to be treated, requiring proper imaging or clip placement by the surgeon. The lessons for proper selection of patients into trials do not apply just to radiation oncology fields. It is very possible (I believe likely) that the controversy regarding the value of adjuvant chemotherapy in T3N0 colon cancer, and the small value that some studies report for these patients, is due to the fact that analyses of "node-negative" patients include a substantial cohort of node-positive patients, where the pathologist has simply not identified a patient as being at high risk because there has been an inadequate nodal evaluation by the pathologist or the surgeon has performed an inadequate resection. The efforts to develop microarrays and other sophisticated techniques for determining risk of tumor recurrence is of enormous importance. However, these new technologies are unlikely to replace the old approaches, but only to supplement them. If we are to do the best for our patients, it is vitally important that we ensure that surgery and pathology are optimized, and that this information is incorporated into clinical trial design and into routine clinical management. Major resources should be expended on new technology, but the new technology must be added to simple and effective tools that we already have at our disposal. Author’s Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Willett CG, Tepper JE, Cohen AM, et al: Failure patterns following curative resection of colonic carcinoma. Ann Surg 200:685-690, 1984[Medline] 2. Gunderson LL, Sosin H, Levitt S: Extrapelvic colon–areas of failure in a reoperation series: Implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 11:731-741, 1985[Medline] 3. Colorectal Cancer Collaborative Group: Adjuvant radiotherapy for rectal cancer: A systematic overview of 8507 patients from 22 randomised trials. Lancet 358:1291-1304, 2001[CrossRef][Medline]
4. Swedish Rectal Cancer Trial: Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 336:980-987, 1997
5. Camma C, Giunta M, Fiorica F, et al: Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA 284:1008-1015, 2000 6. Sauer R, Group GRC: Adjuvant versus neoadjuvant combined modality treatment for locally advanced rectal cancer: First results of the German Rectal Cancer Study (CAO/ARO/AIO-94). Int J Radiat Oncol Biol Phys 57:S124-S125, 2003 (suppl)[Medline]
7. Martenson JA, Willett CG, Sargent DJ, et al: Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: Results of Intergroup Protocol 0130. J Clin Oncol 22:3277-3283, 2004 8. Haddock MG, Nelson H, Donohue JH, et al: Intraoperative electron radiotherapy as a component of salvage therapy for patients with colorectal cancer and advanced nodal metastases. Int J Radiat Oncol Biol Phys 56:966-973, 2003[Medline]
9. Gunderson L, Sargent D, Tepper J, et al: Impact of T and N stage and treatment on survival and relapse in adjuvant rectal cancer: A pooled analysis. J Clin Oncol 22:1785-1796, 2004
10. Benson III AB, Catalano PJ: A rose, is a rose, is a rose...or not. J Clin Oncol 22:1773-1775, 2004
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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