Interest in preoperative irradiation of operable rectal cancer is not new, as this approach reduces the tumor bulk prior to surgery, making it easier to obtain safe resection margins around low-lying cancers. Randomized studies have shown that preoperative irradiation can significantly reduce local recurrence, most likely because of the sterilization of the "tangential margin" of resection.[35,36] Although an argument can be made for continued study of preoperative irradiation alone, infusional chemoradiation given before surgery for patients with both operable and locally advanced rectal cancer is under intense phase II study.[37-39]
Preoperative infusional chemoradiation has also been used in conservation therapy for the anal-rectal complex according to the "Nigro" protocol. From the anal cancer trials, as well as the results of infusional chemoradiation in the treatment of esophageal cancer, several important observations about infusional chemoradiation have been made. For example, in the Radiation Therapy Oncology Group's (RTOG) trial in patients with unresectable esophageal cancers, 50 Gy of radiation plus short-term1111 5-FU infusion and bolus cisplatin(Drug information on cisplatin) (Platinol; 75 mg/m2) was superior to 64 Gy of radiation alone even though the total radiation dose was 22% lower in the chemoradiation arm. The actuarial survival rate after chemoradiation was ~25% at 5 years, whereas there were no survivors in the group treated with irradiation alone.
Although a sixfold increase in acute toxicity was associated with chemoradiation, late normal tissue morbidity was equal in the two arms. The latter observation suggests that infusional chemoradiation given in this way may produce significant late normal tissue injury; this could be a relative disadvantage of this technique compared to protracted 5-FU infusional chemoradiation.
M. D. Anderson Experience
Although the optimal preoperative chemoradiation schedule for rectal cancer patients is unknown, acute and late toxic effects are key outcome measures that need to be examined carefully with the newer treatment schedules. One large experience with preoperative protracted infusional 5-FU chemoradiation for various stages of rectal cancers (stages T3, T4, and recurrent disease) has been reported from the University of Texas M. D. Anderson Cancer Center (Table 1). Over 130 patients were treated with intermittent protracted 5-FU infusional chemoradiation in dosages of 300 mg/m2 for 5 days per week; with this schedule, 5-FU was administered with each irradiation dose.[37,39] All patients received 45 Gy of radiation in 25 fractions over 5 weeks, and boost doses were given only to nonresponding patients when there was major operative adherence or residual disease documented at the time of resection.
T3 Disease--Among the 77 patients with clinically operable T3 rectal cancer, endoscopic ultrasound staging confirmed the clinical diagnosis in 58 (75%). All patients completed infusional chemoradiation without interruption; three patients needed a brief hospital admission for the management of acute toxicity (dehydration associated with diarrhea). Treatment response was scored histopathologically; 47 patients (61%) had either complete responses or microscopic residual disease. Although this clinical complete response rate is high, up to 50% of complete clinical responders can have microscopic residual disease in the resected specimen, therefore surgical resection was routinely performed.
Conservation surgery that spared the anal/rectal complex was performed in two-thirds of the 77 patients. Local control was obtained in 96% of patients after preoperative infusional chemoradiation; surgery was performed in two of three patients who suffered a local failure. This resulted in an overall local control rate of 99% (76 of 77).
Survival was better in those with a good treatment response than in those with residual disease. Patients with node-negative specimens did only slightly better than those with involved lymph nodes.
These data suggest that preoperative 5-FU infusional chemoradiation is highly effective in downstaging tumors, and that responders have a better outcome. The toxicity of this treatment approach was also found to be very acceptable. Only 3% to 4% of patients suffered severe acute effects or late effects.
In comparison to preoperative biomodulated bolus 5-FU regimens, higher complete responses have been found in those treated with infusional chemoradiation, despite the use in the infusional program of a radiotherapy dose of 45 Gy, which is ~10% lower than the dose used in other chemoradiation approaches.
Tethered T3-T4 Tumors and Pelvic Recurrences--The same infusional 5-FU chemoradiation protocol was used in 79 patients with tethered T3 or fixed tumors (T4) or with pelvic recurrence after surgery (Table 1). In addition, all patients had surgery performed in a dedicated electron beam-intraoperative radiation therapy facility, where a boost dose was administered to those with poor treatment response (Figure 2). Local control was obtained in more than 96% of the patients with primary disease but in only ~ 70% of those with recurrent tumors.
Treatment response to infusional chemoradiation was again found to predict overall survival. Since intraoperative radiation therapy was used selectively in patients with poor treatment response, it was associated with poor survival.[38,39] Another interesting finding was that in about half of the patients with recurrent disease, the surgeon performed a sphincter-saving procedure, which did not compromise survival.
These data suggest that preoperative infusional chemoradiation is highly effective in patients with advanced rectal cancer.
Based on the postoperative adjuvant trials, there is clear evidence that these pelvic volumes can tolerate up to 55 Gy of radiation. An interesting question for the future is, what total irradiation dose is optimal for this group? Also, which patients should have more aggressive therapy (with both local and systemic therapy) in order to improve survival? The results of new studies with kinetic and genetic markers are becoming available that may help make this selection.
The successes achieved with infusional chemoradiation in the organ-preserving treatment of anal and esophageal cancers and the high activity seen with 5-FU infusional chemoradiation in the preoperative treatment of rectal cancer patients (described above) suggest that nonsurgical management may be possible for adenocarcinoma of the distal rectum.
Preliminary data on the use of radical external-beam irradiation alone for rectal cancer patients has been reported; this study employed an accelerated irradiation schedule of 52 Gy (axis dose) in 20 fractions over 4 weeks. Local control was achieved in 31% of patients with mobile tumors, but in only 13% of those with partially fixed cancers and 3% of those with fixed tumors. In the majority of patients, regression of rectal cancer was maintained for 3 to 5 months after irradiation.
Tumor radio-responsiveness did not necessarily translate into cure, since in 31% (18/48) of the complete responders with mobile cancers, disease subsequently recurred. However, a correlation between the time for a tumor to regress completely and the interval to local relapse was found, indicating that these patients require very close follow-up by both the radiation oncologist and surgeon.
About one-third of patients with mobile rectal cancers are cured with irradiation alone. The value of additional therapy in improving local control may thus depend on timing, as well as the type of treatment chosen.[44,45] In the future, could even more patients who refuse surgery or whose medical status is marginal for anesthesia be cured with infusional chemoradiation?
A Potentially Interesting Hypothesis
In the studies with infusional 5-FU chemoradiation at M. D. Anderson Cancer Center, a few patients were treated with nonoperative infusional chemoradiation. The results of this approach in one such patient are illustrated in Figure 3. Briefly, this patient had an excellent clinical response to infusional chemoradiation and refused a surgical procedure that would have required a permanent colostomy. After radical chemoradiation, there has been no evidence of either local or distant disease.
This anecdotal case and the finding of a complete clinical response rate of ~ 30% with chemoradiation suggest a potentially interesting hypothesis regarding a new nonoperative approach for operable rectal cancer patients: Are there selected rectal cancer patients who could be treated with infusional chemoradiation and thereby avoid a permanent colostomy, just as has been found in anal cancer patients?
Further evidence favoring the use of radical (nonoperative) infusional chemoradiation in selected rectal cancer patients is the observation that the incidence of late complications after this therapy is very low. This finding also has biologic support: Use of a small daily doses of cytotoxic therapy with both conventionally fractionated irradiation and infusional chemoradiation should result in low levels of late effects, suggesting that late effects are avoided with protracted treatment. This is also consistent with observations from the last randomized postoperative rectal adjuvant trial, in which late effects were the lowest of any reported trial.
These findings suggest that radical infusional chemoradiation may someday be a viable alternative to treatment schemes that include surgery for patients with operable rectal cancer. These results indicate that further study of the best "fractionation" patterns of both modalities in combined-modality programs may be important, especially with regard to the functional integrity of the anus, rectum, and sexual organs, as well as the quality of life after standard and alternative management.
Adjuvant therapy has improved the management of rectal cancer. In many patients, adjuvant treatment is administered after surgery because this allows for pathologic staging. With the use of newer diagnostic modalities to stage tumors, more attention has been directed toward the use of preoperative adjuvant treatment. One preoperative treatment regimen that produces a high rate of tumor shrinkage is infusional chemoradiation. This approach is based on both clinical and basic science observations made over the last several decades.
As in much of medicine, many therapeutic alternatives exist for rectal cancer. In an illness such as low-lying rectal cancer that has potentially devastating effects on lifestyle, future studies should continue to examine promising treatment strategies, such as the use of conservation surgery after infusional chemoradiation, as well as the selected use of radical infusional chemoradiation in"responders."