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

In this article, Dr. Rich traces the evolution of chemoradiation incancer of the rectum from its role as adjuvant therapy to its role in neoadjuvanttherapy and its potential as definitive therapy. The efficacy of irradiationand fluorouracil (5-FU)-based chemotherapy as adjuvant therapy for resectedhigh-risk rectal cancer (stage II or III disease) was first establishedin a series of prospective randomized trials conducted in the 1980s and'90s in the United States.[1-4] These studies demonstrated that patientsreceiving postoperative irradiation with concurrent and maintenance 5-FU-basedchemotherapy had improved local control and survival, as compared withpatients receiving no adjuvant therapy, postoperative irradiation only,or chemotherapy only.

Recent phase III studies have documented the merits of 5-FU administeredas a continuous peripheral venous infusion throughout the 5- to 6-weekcourse of irradiation--an approach first pioneered by Dr. Rich and colleaguesin the early 1980s. Current adjuvant trials in rectal cancer are investigatingvarious combinations of 5-FU with leucovorin and levamisole (Ergamisol),as well as different methods of 5-FU administration.

Neoadjuvant Chemoradiation

Because of the success of combined-modality treatment in the postoperativesetting, there has been intense interest in utilizing this approach neoadjuvantly.Numerous phase II studies have demonstrated the safety of this program,and preliminary analyses indicate satisfactory local control and survivalrates.

These studies also show higher rates of complete pathologic responsefollowing treatment with chemoradiation than after irradiation alone. Completepathologic responses occur in only 6% to 12% of patients following moderate-to high-dose (45- to 50-Gy) preoperative irradiation (Table1).[5-9] Continuous-infusion 5-FU programs or various 5-FU-based regimenswith irradiation have increased these complete pathologic response ratesto 20% to 29% (Table 1).

Although the primary goals of neoadjuvant therapy are improved localcontrol and improved survival, there is an additional important benefitto this approach for tumors in the distal rectum--sphincter preservation.Chemoradiation programs have been utilized to promote tumor regression,thus facilitating a resection that spares the sphincter and insetting theleft colon as a coloanal anastomosis. The sphincter is disturbed by thissurgery, and many patients experience initial difficulty with control,a sense of urgency, and stool frequency, although most patients eventuallyhave acceptable functional results. Table2 summarizes the results of three studies utilizing this approach ofneoadjuvant treatment and resection with coloanal anastomosis.[10-12]

The data demonstrate that approximately 80% of patients with distalrectal cancers can undergo a resection, with a coloanal anastomosis asan alternative to abdominoperineal resection with satisfactory results.Investigators from Thomas Jefferson University Hospital have used preoperativeirradiation (45 to 55 Gy) and local excision as an alternative to a resectionwith coloanal anastomosis in 48 patients with distal rectal cancer.[13]Of these patients, 30 were judged to have transmural tumors (T3) priorto irradiation.

The 5-year actuarial survival was 83.5% and the local recurrence ratewas 10%. Surgical complications occurred in 10% of patients. Sphincterfunction was described as good to excellent in 88% of patients. As thedata from this study and other investigations show, neoadjuvant chemoradiationpromotes regression of rectal cancer and facilitates sphincter-sparingprocedures. Preliminary local control and survival rates, as well as bowelfunction, appear to be encouraging.

Current Indications for Definitive Infusional Chemoradiation

The indications for infusional chemoradiation as definitive therapyof rectal cancer without surgical intervention are limited at present.With residual disease present in over 70% to 80% of resection specimensafter standard neoadjuvant chemoradiation and surgery, it is unlikely thatthis approach, by itself, will offer satisfactory long-term local controland survival rates. As pointed out by Dr. Rich, efforts to select patientsfor definitive infusional chemoradiation according to kinetic and geneticmarkers, as well as further investigations of fractionation and new drugs,may make this a possibility in the future.

References:

1. Gastrointestinal Tumor Study Group: Survival after postoperativecombination treatment of rectal cancer. N Engl J Med 315:1294-1295, 1986.

2. Fisher B, Wolmark N, Rockette H, et al: Postoperative adjuvant chemotherapyor radiation therapy for rectal cancer: Results from NSABP Protocol R-01.J Natl Cancer Inst 80:21-29, 1988.

3. Krook JE, Moertel CG, Gunderson LL, et al: Effective surgical adjuvanttherapy for high-risk rectal carcinoma. N Engl J Med 324:709-715, 1991.

4. O'Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvanttherapy for rectal cancer by combining protracted-infusion fluorouracilwith radiation therapy after curative surgery. N Engl J Med 331:502-507,1994.

5. Mendenhall WM, Bland KI, Copeland EM, et al: Does preoperative radiationtherapy enhance the probability of local control and survival in high-riskdistal rectal cancer? Ann Surg 215:696-706, 1992.

6. Myerson RJ, Michalski JM, King ML, et al: Adjuvant radiation therapyfor rectal carcinoma: Predictors of outcome. Int J Radiat Oncol Biol Phys32:41-50, 1995.

7. Rich TA, Skibber JM, Ajani JA, et al: Preoperative infusional chemoradiationtherapy for stage T3 rectal cancer. Int J Radiat Oncol Biol Phys 32:1025-1029,1995.

8. Chan RS, Tyler DS, Anscher MS, et al: Preoperative radiation andchemotherapy in the treatment of adenocarcinoma of the rectum. Ann Surg221:779-787, 1995.

9. Minsky BD, Cohen AM, Kemeny N, et al: Enhancement of radiation-induceddownstaging of rectal cancer by fluorouracil and high-dose leucovorin chemotherapy.J Clin Oncol 10:79-84, 1992.

10. Minsky BD, Cohen AM, Enker WE, et al: Sphincter preservation withpreoperative radiation therapy and coloanal anastomosis. Int J Radiat OncolBiol Phys 31:553-559, 1995.

11. Rouanet P, Fabre JM, Dubois JB, et al: Conservative surgery forlow rectal carcinoma after high-dose radiation: Functional and oncologicresults. Ann Surg 221:67-73, 1995.

12. Marks G, Mohiuddin M, Masoni L: The realty of sphincter preservationsurgery for cancer of the distal 3 cm of rectum following high dose radiation.Int J Radiat Oncol Biol Phys 27:779-783, 1993.

13. Mohiuddin M, Marks G, Bannon J: High-dose preoperative and fullthickness local excision: A new option for selected T3 distal rectal cancers.Int J Radiat Oncol Biol Phys 30:845-849, 1994.