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Editorial |
Department of Radiation Oncology, Gastrointestinal Section, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 97, Houston, Texas 77030
Correspondence: Address correspondence and reprint requests to: Christopher H. Crane, MD; E-mail: ccrane{at}mdanderson.org.
Two steps ahead, you are a leader; 10 steps ahead, you are a target. I wonder which Norm Nigro felt like when he first argued that abdominoperineal resection should be used only as a salvage operation for anal cancer >30 years ago.1 Because of his efforts, organ preservation became the standard for anal cancer without a randomized trial. What is different about rectal cancer? Several things. Most importantly, the intrinsic radiosensitivity is dramatically different. Durable complete responses to chemoradiation combinations for anal cancer vary from 60% to 90%, depending on patient selection, the radiation dose, and possibly the chemotherapeutic agents that are used,2,3 compared with pathologic complete response rates that usually range from 10% to 20% with neoadjuvant chemoradiation in rectal tumors. Second, differences in anatomical location and tumor biology contribute to higher salvage rates for recurrent anal cancer than for rectal cancer. Anal cancer recurrences produce symptoms (tumor mass, anal canal pain, or bleeding) early and are accessible for physical examination, resulting in detection most often when they are localized and resectable. In contrast, recurrent rectal cancer is a devastating problem with frequent infiltration of the sacrum, low resectability, low 5-year overall survival rates, and significant morbidity even when resected. Biologically, anal cancers also tend to remain locoregionally confined much longer than rectal cancers. The greater tendency of rectal tumors to metastasize makes giving them a second chance to do so undesirable. Therefore, the intrinsic radiosensitivity, resectability rates, and propensity for distant metastasis distinguish anal and rectal cancers.
On the other hand, uncomplicated radical rectal surgery commonly results in incontinence, impotence, retrograde ejaculation, permanent colostomy, and permanent alteration of bowel function. Patients nearly always have alterations of their lifestyle because of increased stooling frequency, increased fecal urgency, or encopresis. A safe alternative to these problems, such as full-thickness local excision, would be welcomed, but the appropriate concern has been that a more limited surgical procedure such as full-thickness local excision would probably result in a survival disadvantage in locally advanced rectal cancer patients. But is that true in all patients? Is there a way to be reasonably assured that reducing the extent of surgery will be safe to investigate? The answer probably lies in patient selection based on clinicopathologic features and the pathologic response of the primary tumor to neoadjuvant chemoradiation.
On the basis of somewhat limited evidence, the complete pathologic response of the primary tumor after chemoradiation (ypT0) for locally advanced rectal cancer correlates very highly with microscopic disease sterilization in the pelvis. Patients undergoing full-thickness local excision4–7 or even observation8 after neoadjuvant chemoradiation for T3N0 rectal cancer have had pelvic control rates that are as high as or higher than what is expected with radical surgery. Five studies have reported rare tumor recurrence in patients undergoing full-thickness local excision or observation instead of radical surgery, but the majority of patients in these series had excellent responses to chemoradiation. In the first report, in 15 of 15 of tumors treated with radiotherapy alone, 15 of 15 had T-stage downstaging.5 In the more recent reports, a pathologic complete response or microscopic residual disease was seen in 17 of 17,4 11 of 11,7 and 23 of 266 tumors. Collectively, only 2 of the total 69 patients have been reported to have local tumor recurrence, both in the series from the University of Texas M. D. Anderson Cancer Center. Both patients had unfavorable characteristics; one had a clinically positive lymph node at presentation (radical surgery was not advised because of metachronous poor-prognosis breast cancer), and the other had gross residual disease after chemoradiation.6 The most interesting example of an organ-preserving strategy in T3 rectal cancer comes from a prospective experience reported by Habr-Gama et al.8 They treated patients with neoadjuvant chemoradiation followed by observation in 71 patients with a complete clinical response and have reported no deaths due to rectal cancer in that group with a median of 57.3 months’ follow-up. Two patients have undergone salvage abdominoperineal resection, but all are alive. Although these data are provocative, it is important to realize that this experience has not been duplicated. However, it does appear that that radical surgery would not have improved outcomes in these highly selected groups of patients (collectively, 5 studies with 140 patients).
As reported by Tulchinsky et al.9 in this issue of the Annals of Surgical Oncology, ypT0 has also been reported to correlate with a low probability of positive lymph nodes after mesorectal excision. In a report from M. D. Anderson of patients with ypT0 disease, mesorectal lymph nodes were positive in 9% (4 of 45). When poorly differentiated tumors were excluded, the percentage was reduced to 5% (2 of 41).10 Another analysis of only clinically node-negative patients from M. D. Anderson, combined with data from 2 other institutions, revealed a 1% (1 in 84) incidence of mesorectal nodal involvement among patients with cT3N0 tumors who had ypT0 disease after chemoradiation.11 Thus, it appears that exclusion of patients with poorly differentiated histology and particularly clinically enlarged lymph nodes leads to a very high correlation between ypT0 and sterilization of microscopic disease in the mesorectum.
I agree with the authors’ conclusion9 that full-thickness transanal excision should be investigated further in clinical trials and that it should be done in highly selected patients. Since pathologic evaluation of the primary tumor provides a potential in vivo response assay that appears to be predictive of sterilization of microscopic disease control in mesorectal lymph nodes, patients with clinically staged T2 or T3 disease who are clinically node negative seem to be optimal for consideration of an organ-preserving approach. A reasonable approach for a clinical trial would be to select patients with endoscopic transrectal ultrasonographically and computed tomographically node-negative disease, regardless of histology. Six to 12 weeks after chemoradiation, patients with an endoscopically suspected complete clinical response would then undergo proctoscopy with biopsy to evaluate for a complete clinical response. (Note that false-positive biopsy results of regressing tumors are possible up to 12 weeks after chemoradiation.)
Since endoscopic transrectal ultrasonography is difficult to interpret after chemoradiation, it should be optional. Patients with negative biopsy results would then undergo a full-thickness excisional biopsy of the entire tumor bed in order to determine the pathologic response, looking for patients with ypT0 or microscopic residual disease, which is key prognostic information. Patients with gross residual tumor in the specimen after chemoradiation and full-thickness local excision have a high-enough probability of mesorectal disease to warrant radical surgery, and patients with no residual disease appear to have a low-enough risk of mesorectal involvement to offer observation in the setting of a clinical trial. Patients with only microscopic residual disease probably have a low to intermediate risk and may also be candidates for observation. Notice that positron emission tomography (PET) and molecular markers predictive of response are not a part of this algorithm. PET is not sensitive enough to have any role in the evaluation of the presence of microscopic residual disease in the mesorectum, and although PET and molecular markers may have some role in the future of predicting tumor response, we do not need to predict response—only to observe if it has occurred pathologically. The surgeon and pathologist can provide all of the necessary prognostic information. As "low tech" as it may be, proctoscopy, biopsy, and light microscopy are all that is needed. This concept should move forward within single-institutional multidisciplinary teams with an interest in rectal cancer and perhaps multi-institutional trials under the leadership of the surgical oncology community. Such trials would complement the current studies looking at novel chemoradiation regimens incorporating molecular targeted agents. If these regimens become more effective in the future as anticipated and the ypT0 rates approach what we currently see with anal cancer, the oncology community will need another Norm Nigro.
Received for publication October 13, 2005. Accepted for publication October 26, 2005.
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