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Adjuvant Therapy for Rectal Cancer: Results and Controversies

Adjuvant Therapy for Rectal Cancer: Results and Controversies

Dr. Minsky provides an excellent overview of the current status of adjuvant therapy for patients with rectal cancer. The article includes not only the results of completed randomized and phase II trials but also some of the early toxicity data from ongoing and maturing neoadjuvant trials. Although it would appear that Dr. Minsky’s personal bias favors neoadjuvant combined-modality therapy, he clearly defines gaps in our existing knowledge that will need to be filled in by randomized trials.

Is a Sphincter-Sparing Procedure Oncologically Appropriate?

There is an implication in Dr Minsky’s review that downstaging, as a result of neoadjuvant radiation with or without chemotherapy, may permit the surgeon to perform a sphincter-saving procedure that would not otherwise have been possible. Although this modification of the surgical procedure is technically feasible, there are no long-term rigorous follow-up data showing that it is oncologically appropriate. Certainly, this is one question for which a randomized trial could provide morbidity and perineal recurrence data. However, such a trial will probably never be instituted.

The criteria determining which rectal cancers cannot be resected without an abdominoperineal resection must be more clearly defined,[1] since some surgeons will resect cancers that have a lower margin 4 cm or more from the anal verge, provided that at least a 2-cm cancer-free distal resection can be attained.

For cancers in the lower rectum (eg, lower margin of the tumor within 5 cm of the dentate line), radiation should always include the perineum and obturator lymph nodes, since lymphatic drainage in this area does not proceed uniformly upward through the mesorectum. Approximately 3% to 19% of patients can be expected to develop a perineal recurrence,[2,3] with higher recurrence rates anticipated in patients in whom the distal cancer-free margin of resection is less than 2 cm.[3]

Neoadjuvant Therapy--Still Experimental

Although widely used throughout the United States, neoadjuvant therapy must still be considered experimental. The accuracy of staging of rectal cancers has improved. Computed tomography can identify most patients with metastatic disease, while rectal ultrasound can identify and assess the T-stage of the ever-increasing number of early

T1-2 N0 cancers, for which neoadjuvant therapy has questionable additional value. Further testing adds to the cost of medical care without significantly increasing its quality.

Neoadjuvant approaches are still associated with too many unknowns, most, if not all, of which will require randomized trials to resolve. Some of these unknowns include:

  1. The optimal radiotherapeutic equivalent dose (a question not clearly established for postoperative therapy) and the time interval over which radiation therapy should be administered. This includes the manner in which the dose-time ratio affects acute (immediate) and chronic (6 to 12 months posttreatment) toxicities.

  2. The optimal interval between radiation therapy and surgery.

  3. The optimal radiosensitizing agent (including new agents, such as gemcitabine [Gemzar] and hypoxic radiosensitizers, such as mitomycin [Mutamycin]), as well as the dose of this agent and the method by which it should be administered (eg, continuous infusion, bolus injection, oral route).

Most recurrences in patients with rectal cancer do not occur within 1 year of treatment. In half of the patients who participated in the Gastrointestinal Tumor Study Group (GITSG) trial (GI 8180) of radiation plus escalating doses of fluorouracil (5-FU), recurrences did not begin to occur until almost 3 years after postoperative randomization to treatment.[4] More than half of the patients in the escalating 5-FU arm of this trial were still disease-free at 6 years. Thus, long-term follow-up (of 5 years or more) of patients receiving neoadjuvant therapy is necessary before reliable results of treatment will be known.

Combined-Modality Adjuvant Therapy

The GITSG completed two trials of postoperative adjuvant combined-modality therapy. The first, GI 7175, demonstrated the advantages of combined- modality therapy (5-FU and semustine plus radiation therapy) over no postoperative therapy or single-modality (radiation or chemotherapy) postoperative adjuvants.[5] This trial and its successor (GI 7180)[4] provided the first hints that a significant proportion of patients who survived semustine treatment might develop preleukemic syndromes 2 to 6 years later. Fortunately, GI 7180 also proved that semustine, a leukemogenic agent,[6] was not an essential component of the chemotherapy regimen.[4] Indeed, the results of radiation and the escalating 5-FU regimen were superior to those of 5-FU and semustine, although this difference was not statistically significant (P = .20). These data were presented at the 1990 National Cancer Institute Consensus Conference.

The GI 7180 trial admitted only patients with T3 N0 or T2-3 N1-2 rectal cancers, with patients stratified by stage. Subset analysis suggested that patients treated by low anterior resection with margins greater than 3 cm had an overall 6-year survival of 70%. This subset analysis should be viewed with caution, since it did not involve pretreatment stratification. Like any subset analysis, its value relates only to the planning of future treatment programs and should not be utilized for treatment decisions without confirmation of the results. Reproducibility cannot be guaranteed. As with many subset analyses, these results have been transferred into clinical practice without further confirmation. Fortunately, they seem to have survived the test of time.

Summary

Neoadjuvant therapy must still be considered experimental even though its use has become a common clinical practice. To date, no data from a randomized study have shown that neoadjuvant therapy is even equivalent, let alone superior, to postoperative therapy. The question of whether preoperative therapy is an oncologically sound approach to facilitating sphincter preservation when such a procedure is otherwise impossible remains unanswered by randomized studies.

In the absence of a randomized trial, clinical experience over the next decade may determine whether this approach is appropriate. It is unfortunate that the National Cancer Institute has not persisted with its randomized trial of neoadjuvant therapy, INT 0147, in spite of poor accrual. Hopefully, the National Surgical Adjuvant Project for Breast and Bowel Cancers (NSABP) will complete its trial of neoadjuvant therapy, R0-3.

References

1. Wagman R, Minsky BD, Cohen AM, et al: Sphincter preservation with preoperative radiation therapy (RT) and coloanal anastomosis: Long-term follow-up. Int J Radiat Oncol Biol Phys, 1998 (in press).

2. Wilking N, Herrera L, Petrelli NJ, et al: Pelvic and perineal recurrences after abdominoperineal resection for adenocarcinoma of the rectum. Am J Surg 150:561-563, 1985.

3. Warneke J, Petrelli NJ, Herrera L: Local recurrence after sphincter saving resection for rectal adenocarcinoma. Am J Surg 158:3-5, 1989.

4. Gastrointestinal Tumor Study Group: Radiation therapy and fluorouracil with or without semustine for the treatment of patients with surgical adjuvant adenocarcinoma of the rectum.J Clin Oncol 10:549-557, 1992.

5. Gastrointestinal Tumor Study Group: Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med 312:1465-1472, 1985.

6. Boice JD Jr, Greene MH, Killen JY Jr, et al: Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with methyl-CCNU. N Engl J Med 309:1079-1084, 1983.

 
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