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Infusional Chemoradiation for Operable Rectal Cancer: Post-, Pre-, or Nonoperative Management?

Infusional Chemoradiation for Operable Rectal Cancer: Post-, Pre-, or Nonoperative Management?

Dr. Rich presents a comprehensive overview of adjuvant therapy for advanced operable rectal cancer. He emphasizes the roles of infusional chemoradiation in both the adjuvant setting and as sole therapy. Unless otherwise specified, the following comments pertain to clinically resectable B2-C (T3, N0-N1) adenocarcinoma of the rectum.

What Do We Know?

Based on Dr. Rich's review, it is apparent that:

  1. Surgery alone results in a high local recurrence rate.[1]
  2. Moderate-dose postoperative irradiation (45 to 50 Gy at 1.8 Gy/fraction) reduces the risk of local recurrence but does not improve survival rates.[2-4]
  3. Postoperative radiotherapy and fluorouracil(5-FU)/semustine-based chemotherapy improve local control and survival rates, compared with surgery alone, surgery plus chemotherapy, and surgery plus postoperative radiotherapy.[2-4]
  4. Low-dose preoperative irradiation is ineffective.[5,6]
  5. Moderate-dose preoperative radiotherapy reduces the incidence of local recurrence and may improve survival rates.[7,8]
  6. Compared with postoperative radiotherapy, moderate-dose preoperative radiotherapy is more likely to be completed as planned, is less morbid, and is more efficacious.[9]

Unanswered Questions

It is also apparent from Dr. Rich's review that several questions remain to be answered:

What Is the Optimal Chemotherapy Regimen?--The observation that postoperative chemoradiation, using 5-FU/semustine-based chemotherapy, improves survival rates produced a wave of enthusiasm for the use of adjuvant chemotherapy in rectal adenocarcinoma. Because semustine is not commercially available due to its leukemogenic potential, initial attention focused on whether it was a necessary component of a 5-FU-based chemotherapy regimen. Comparison of adjuvant 5-FU, with or without semustine, in a large randomized trial showed no survival advantage associated with semustine.[10] Therefore, although 5-FU-based adjuvant chemotherapy without semustine has not been shown to improve survival rates when compared "head-to-head" with a non-chemotherapy-treated control arm, it is currently considered to be part of the "standard of care" for advanced, operable rectal cancer.

The optimal chemotherapy regimen remains to be defined. Questions relating to adjuvant chemotherapy include: (1) Is the dose intensity of the 5-FU infusion important? (2) What is the role of 5-FU enhancers, such as leucovorin, levamisole (Ergamisol), methotrexate, interferon, and N-phosphonacetyl-L-asparate (PALA)? (3) How many courses of adjuvant chemotherapy are optimal? Chemotherapy protocols under investigation include bolus 5-FU, continuous-infusion 5-FU, protracted continuous-infusion 5-FU, 5-FU with levamisole, and 5-FU plus leucovorin. As suggested by Rich, protracted-infusion 5-FU combined with radiotherapy may be the optimal adjuvant chemoradiation schedule.

Is Preoperative Chemoradiation Better Than Postoperative Chemoradiation?--It is unclear whether postoperative chemoradiation is better than preoperative radiotherapy alone or combined with concomitant chemotherapy. Potential advantages of preoperative radiotherapy include the following: (1) It may be more effective in reducing the risk of local recurrence. (2) It may be less morbid, both in terms of acute effects and the risk of late small bowel obstruction. (3) It may increase the likelihood of sphincter preservation. (4) The likelihood of completing treatment as planned is probably higher.

The main disadvantage of preoperative chemoradiation is that patients with early-stage, A-B1 (T1-T2, N0) tumors who do not need adjuvant therapy could potentially receive unnecessary treatment. However, the likelihood of including patients with early cancers is remote if preoperative chemoradiation is restricted to patients with annular and/or tethered tumors and those with transmural invasion and/or positive nodes observed on transrectal ultrasound or MRI.

It is highly unlikely that preoperative irradiation will be compared with postoperative chemoradiation in a randomized trial in the United States. However, two ongoing randomized trials (ie, the intergroup trial and the National Surgical Adjuvant Project for Bowel and Breast Cancers [NSABP] R-03 trial) are comparing preoperative with postoperative chemoradiation.

Can We Predict Whether an Individual Patient Will Respond to Preoperative Chemoradiation?--Willett and colleagues found that tumor regression following preoperative irradiation alone or combined with two 3-day courses of 5-FU (500 mg/m2/d) during the first and last weeks of radiotherapy was associated with smaller tumor size and high proliferative activity.[11] When stratified by tumor size, tumor regression occurred most often in lesions with high Ki-67, proliferating cell nuclear antigen (PCNA), and mitotic activity, all of which are indicators of proliferative activity. It is likely that other biologic markers may be useful in predicting tumor response to preoperative therapy.

Current University of Florida Guidelines

Currently, at the University of Florida, patients with clinically resectable B2-C rectal adenocarcinoma are treated with preoperative radiotherapy (45 to 50.4 Gy at 1.8 Gy/fraction) combined with a concomitant, protracted, continuous, chronobiologically shaped 5-FU infusion administered with a portable, programmable pump.[12] The dose rate varies from approximately 250 to 275 mg/m2/d. The potential advantages of a circadian-shaped, protracted 5-FU infusion include increased dose intensity and reduced toxicity.[12] Patients who are found to have pathologically positive nodes are given postoperative adjuvant 5-FU and leucovorin for 6 months.

Radical Infusional Chemoradiation Without Surgery

Although aggressive chemoradiation may result in impressive response rates, elimination of surgery from the treatment scheme currently results in an unacceptably high likelihood of local recurrence. Therefore, except for the small subset of patients with very favorable tumors who are suitable candidates for endocavitary irradiation, the use of radical chemoradiation should be restricted to patients with unresectable cancer, those who cannot be rendered operable by aggressive preoperative chemoradiation, and those who are medically unsuitable for or refuse to undergo surgery. As described by Papillon and Berard, interstitial brachytherapy and/or endocavitary irradiation may be used in suitable patients to boost the dose of radiation given to the primary tumor after chemoradiation, and probably results in improved local control rates.[13]

References

1. Mendenhall WM, Bland KI, Copeland EM, III, et al: Does preoperative radiation therapy enhance the probability of local control and survival in high-risk distal rectal cancer? Ann Surg 215(6):696-705, 1992.

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

3. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 80(1):21-29, 1988.

4. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324(11):709-715, 1991.

5. Roswit B, Higgins GA, Jr., Keehn RJ: Preoperative irradiation for carcinoma of the rectum and rectosigmoid colon: Report of a National Veterans Administration randomized study. Cancer 35:1597-1602, 1975.

6. Higgins GA, Humphrey EW, Dwight RW, et al: Preoperative radiation and surgery for cancer of the rectum: Veterans Administration Surgical Oncology Group Trial II. Cancer 58:352-359, 1986.

7. Gerard A, Buyse M, Nordlinger B, et al: Preoperative radiotherapy as adjuvant treatment in rectal cancer: Final results of a randomized study of the European Organization for Research and Treatment of Cancer (EORTC). Ann Surg 208(5):606-614, 1988.

8. Cedermark B, Johansson H, Rutqvist LE, et al: The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma: A prospective randomized trial. Cancer 75:2269-2275, 1995.

9. Frykholm GJ, Glimelius B, Pahlman L: Preoperative or postoperative irradiation in adenocarcinoma of the rectum: Final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 36:564-572, 1993.

10. 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.

11. Willett CG, Warland G, Coen J, et al: Rectal cancer: The influence of tumor proliferation on response to preoperative irradiation. Int J Radiat Oncol Biol Phys 32(1):57-61, 1995.

12. Marsh RD, Chu NM, Vauthey JN, et al: Preoperative treatment of patients with locally advanced unresectable rectal adenocarcinoma utilizing continuous chronobiologically shaped 5-fluorouracil infusion and radiation therapy. Cancer 78:217-225, 1996.

13. Papillon J, Berard P: Endocavitary irradiation in the conservative treatment of adenocarcinoma of the low rectum. World J Surg 16:451-457, 1992.

 
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