Should the Benefit of Adjuvant Chemotherapy in Colon Cancer Be Re-Evaluated?

Abstract

Because favorable effects on survival were seen in randomized trials conducted during the 1980s, adjuvant chemotherapy in colon cancer was established as routine therapy in stage III disease in the United States in 1990. Follow-up trials in the United States, Asia, and Europe soon meant that it became recommended therapy worldwide, not only in stage III but in stage II disease as well, if risk factors for recurrence were present. Additional trials established the combination of a fluoropyrimidine and oxaliplatin as reference treatment for patients with stage II disease with risk factors who are fit for therapy and for those with stage III disease. The addition of oxaliplatin in the treatment of elderly patients has been questioned. Here we present arguments questioning not only the addition of oxaliplatin in the treatment of some younger patients as well but also the offering of adjuvant chemotherapy at all to some of these patients. Medical care continuously develops, and as a consequence, treatment results improve. This development has also been seen in colon (and rectal) cancer, and the improvements actually challenge the established benefit of adjuvant chemotherapy in colon (and rectal) cancer. We question whether the risk of recurrence is sufficiently high for most patients with stage II disease, even when risk factors are present, and for some patients with stage III disease in the presence of high-quality, modern, multidisciplinary team care to motivate adjuvant chemotherapy. In colorectal cancer, there has been a marked change during the past decades regarding surgery. It started with the total mesorectal excision (TME) technique for rectal cancer. This technique has now spread around the world; the majority of surgeons have learned how to operate effectively on rectal cancer, and many centers report low local recurrence rates. Population-based data from national quality registers also show that the local recurrence rate can today reach approximately 5%, equaling the rates achieved in dedicated centers. Surgery for colon cancer may also be about to change, with complete mesocolic excision dissection and the concept of central ligation. These techniques have started to spread among surgeons, and population data already indicate that there may be an overall survival benefit, in addition to improvements reflecting stage migration, if colonic surgery is performed in accordance with such procedures. Preoperative staging of colorectal cancer has also improved, and up-to-date contrast-enhanced computed tomography of the thorax and abdomen, completed with ultrasonography or magnetic resonance imaging with contrast agents in the case of equivocal liver lesions or positron emission tomography– computed tomography in the case of equivocal findings outside the liver, has also resulted in fewer recurrences in those undergoing surgery (ie, the target patients for adjuvant therapy). The scenario has changed from fewer metachronous to more synchronous metastases. Furthermore, although pathologists cannot reduce recurrence risks per se, better pathologic staging results in lower stage-specific recurrence rates, often referred to as stage migration. The rectal cancer radiotherapy story illustrates the same kind of problem the medical community is facing when one or several aspects of multidisciplinary care are improved. The story is well known from literature. The reduction in local recurrence rates seen after preoperative radiotherapy was questioned when surgery was improved (ie, when TME was introduced). The two trials then initiated—the Dutch–Swedish TME trial and the Medical Research Council CR07 trial in the United Kingdom, in which preoperative radiotherapy using the 5 3 5 Gy schedule was tested against selective postoperative (chemo)radiotherapy—showed that preoperative radiotherapy significantly reduced local recurrence rates. Actually, the relative reduction may have been slightly larger with TME (hazard ratio, 0.38; absolute difference, 11% v 4%) than with the older, suboptimal surgery (hazard ratio, 0.46; absolute difference, 27% v 13%). The overall survival gain seen previously in the Swedish Rectal Cancer Trial could not be reproduced; the absolute gain in local recurrences was likely too small to show up in the trials in which TME was used. The gains from postoperative chemoradiotherapy in local recurrence rates and survival have not been tested using TME. In a German trial testing preversus postoperative chemoradiotherapy, it was shown that preoperative chemoradiotherapy was better than postoperative in reducing the local recurrence rate, approximately 10% after postoperative treatment versus 7% after preoperative irradiation. The TME technique was used for most patients in the trial, but no difference in survival could be seen even after long-term follow-up. On the basis of this knowledge, there is an ongoing debate over whether radiotherapy is needed in the majority of rectal cancers because of the low recurrence rates seen today without