Adjuvant radiation therapy for colon cancer.

Minsky BD

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.

Post-operative radiation therapy has been used in selected patients with colon cancer. In contrast with rectal cancer, the primary failure pattern in colon cancer is abdominal. Local failure does occur, but is less frequent and more difficult to detect. Retrospective data suggest a benefit from local/regional radiation therapy on local control and disease-free survival in subsets of patients compared to historical controls. An ongoing phase III intergroup trial (INT 0130) will determine if local/regional radiation therapy improves the results of chemotherapy in subsets of patients with high-risk colon cancer. In general, the results of whole abdominal radiation plus 5-fluorouracil (5-FU) have been disappointing. However, the more recent data from the Southwest Oncology Group pilot trial are encouraging. In contrast to rectal cancer, where adjuvant chemotherapy plus radiation therapy is standard treatment in high-risk patients, the use of radiation therapy (either local/regional or whole abdomen) in colon cancer remains investigational.

Semin Radiat Oncol 1997 Oct;7(4):300-305

The Role of Radiation Therapy and 5-Fluorouracil in Colon and Rectal Cancer.

Willett CG

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 01890, USA

Since the original report improved survival of patients with locally unresectable gastric cancer treated with irradiation and 5-fluorouacil (5-FU) in 1968, there has been extensive investigation of this treatment combination in a variety of gastrointestinal tumors, including colon and rectal cancer. There are now extensive data supporting the use of 5-FU-based chemotherapy with irradiation in the adjuvant treatment of rectal cancer and increasing experience defining its role in negotiant therapy. The value of adjuvant 5-FU-based chemotherapy and irradiation in colonies cancer is controversial, but there may be subsets of patients who benefit from this treatment. Ongoing studies in rectal and colon cancer are evaluating the role of irradiation with various modes of 5-FU adminstration (bolus v short or continuous infusion) as well as its modulation with other agents.

Cancer J Sci Am 1999 Jul-Aug;5(4):242-7

Does postoperative irradiation play a role in the adjuvant therapy of stage T4 colon cancer?

Willett CG, Goldberg S, Shellito PC, Grossbard M, Clark J, Fung C, Proulx G, Daly M, Kaufman DS

Department of Radiation Oncology, Massachusetts General Hospital, Boston 02114, USA.

PURPOSE: This study analyzes the long-term outcome of patients with stage T4 colon cancer who receive postoperative irradiation. The purpose of the study is to define the potential role of this modality with current systemic therapies. PATIENTS AND METHODS: A retrospective analysis was performed of 152 patients undergoing resection of T4 colon cancer followed by moderate- to high-dose postoperative tumor bed irradiation with and without 5-fluorouracil-based chemotherapy. Of the 152 patients, 110 patients (T4N0 or T4N+) were treated adjuvantly, whereas 42 patients received irradiation for the control of gross or microscopic residual local tumor. RESULTS: For 79 adjuvantly treated patients with stage T4N0 or T4N+ cancer with one lymph node metastasis, the 10-year actuarial rates of local control and recurrence-free survival were 88% and 58%, respectively. Results were less satisfactory for patients with more extensive nodal involvement. The 10-year actuarial rates of local control and recurrence-free survival of 39 patients with T4 tumors complicated by perforation or fistulas were 81% and 53%, respectively. For 42 patients with incompletely resected tumors, the 10-year actuarial recurrence-free survival was 19%. CONCLUSIONS: In comparison with historical controls, postoperative tumor bed irradiation improves local control for some subsets of patients. In addition to standard 5-fluorouracil-based chemotherapy, adjuvant tumor bed irradiation should be considered when colon cancers invade adjoining structures, when they are complicated by perforation or fistulas, or when they are incompletely excised at the primary site

Int J Radiat Oncol Biol Phys 2000 Jun 1;47(3):725-33

Phase II trial of adjuvant radiation and intraperitoneal 5-fluorouracil for locally advanced colon cancer: results with 10-year follow-up.

Palermo JA, Richards F, Lohman KK, Lovelace JV, Atkinson J, Case LD, White DR, Blackstock AW

Department of Radiation Oncology, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157, USA.

PURPOSE: To determine the toxicity, disease-free survival, and overall survival for patients with Modified Astler-Coller (MAC) B2-3 or C1-3 colon cancer receiving adjuvant radiation and sequential intraperitoneal 5-fluorouracil (5-FU). METHODS AND MATERIALS: From August 1984 to June 1989, 45 patients were accrued to this Phase II trial and received a 21-week course of intraperitoneal 5-FU (20 mg/kg/d x 5) and external beam radiation. The radiation was delivered to the tumor bed and para-aortic lymph nodes in two split-courses of 22.5 Gy, alternating with the first two cycles of chemotherapy. All patients then received 4 additional cycles of intraperitoneal 5-FU. RESULTS: The therapy was well tolerated with 4 patients experiencing Grade 3 peritonitis. Four patients developed small bowel obstruction requiring surgery; in each instance, recurrent tumor was found at the time of laparotomy. The median and overall survivals at 10 years were 9.3 months and 53% respectively. Local failures were infrequent, occurring in only 11% of patients treated. CONCLUSIONS: Sequential intraperitoneal 5-FU and tumor-bed/para-aortic irradiation is tolerable in patients with resected colon cancer. Although the incidence of local and regional relapse appeared to be lower than anticipated, this did not appear to translate into improved survival.

Int J Radiat Oncol Biol Phys 1997 Feb 1;37(3):615-8

Pilot study of continuous-infusion 5-fluorouracil, oral leucovorin, and upper-abdominal radiation therapy in patients with locally advanced residual or recurrent upper gastrointestinal or extrapelvic colon cancer.

Martenson JA, Swaminathan R, Burch PA, Santala RG, Schroeder G, Pitot HC, Wright K, Kugler JW, Stella PJ, Garton GR

Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.

PURPOSE: The purpose of this study was to develop a satisfactorily tolerated regimen of radiation therapy, continuous infusion 5-fluorouracil, and leucovorin in patients with locally advanced upper-abdominal gastrointestinal cancer. METHODS AND MATERIALS: Patients with locally advanced or locally recurrent gastric, pancreatic, or extrapelvic colon cancer were eligible for this study. Radiation therapy consisted of 45 Gy in 25 fractions to the tumor and regional lymph nodes, followed by 5.4-9 Gy in three to five fractions to the tumor. Treatment with leucovorin, 10 mg orally daily, and continuous infusion 5-fluorouracil was initiated on the first day of radiation therapy. 5-Fluorouracil was administered at an initial daily dose of 125 mg/m2, with dose escalation planned in 25-mg increments, depending on patient tolerance. RESULTS: Twenty-one evaluable patients participated in this study. Six were treated at the initial daily 5-fluorouracil dose of 125 mg/m2. One patient experienced Grade 4 anorexia and nausea. No other Grade > or = 3 toxicity was observed at this dose. Fifteen evaluable patients were entered at a planned 5-fluorouracil dose of 150 mg/m2 daily; 6 of them experienced Grade 3 toxicity, and none experienced Grade > or = 4 toxicity. Grade 3 toxicities and the number of patients who developed each were: vomiting (three patients); nausea (two patients); diarrhea (two patients); and skin toxicity, hand-foot syndrome, catheter-related infection, and stomatitis in one patient each. Four of the six patients who experienced Grade 3 toxicity developed more than one type of Grade 3 toxicity. CONCLUSIONS: In patients with upper-abdominal gastrointestinal cancer, continuous infusion 5-fluorouracil (150 mg/m2 daily), leucovorin (10 mg orally daily), and radiation therapy (50-54 Gy) resulted in a 40% rate of severe toxicity but no life-threatening toxicity. This clinical trial excludes, with 90% confidence, a 20% risk of Grade 4 toxicity with this combination. The 40% rate of severe toxicity suggests that this combination of agents is near the maximal tolerated dose.

Am Surg 1996 Jul;62(7):546-49; discussion 549-50

Patterns of recurrence for advanced colon cancer modified by whole abdominal radiation and chemotherapy.

Estes NC, Giri S, Fabian C

University of Kansas Medical Center, Kansas City, 66160, USA.

Abdominal failure for colonic carcinoma patients following curative resection has been high in patients with advanced disease stage, particularly when increased numbers of lymph nodes are involved. Surgeons desire curative treatment for their patients, but they interpret local and regional lymph node recurrence as a failure of surgical resection. The effect of current adjuvant treatment protocols on modifying patterns of relapse, particularly in the abdomen, has not been well studied and is of interest to surgeons. We analyzed reported patterns of failure of patients with Stage C2 colon cancer from two colon cancer adjuvant treatment studies; 5-FU plus levamisole (SWOG 8591) and 5-FU, whole-abdominal radiation, and tumor boost. The total number of recurrences in SWOG 8591 at all sites was reduced. The percent of lung relapses was reduced from 34 per cent to 20 per cent in the treatment group, but the percentage of local relapse increased from 20 per cent in the observation group to 27 per cent in the 5-FU plus levamisole group. Similarly, the number of first relapses was fewer at a local site in the 5-FU plus levamisole group, but the percent of relapses at the local site was not reduced (18 vs. 22%). Advanced C2 patients who received regional treatment on 5FU and whole-abdominal radiation produced the lowest percent of local relapse (12%), suggesting a benefit for regional treatment. Further study of patterns of relapse after resection and adjuvant treatment in high risk C2 patients may lead to further progress in control of advanced, curative colon carcinoma.

Dis Colon Rectum 1995 Oct;38(10):1088-92

Whole abdominal radiotherapy and concomitant 5-fluorouracil as adjuvant therapy in advanced colon cancer.

Ben-Josef E, Court WS

Department of Radiation Oncology, Wayne State University, Detroit, Michigan, USA.

This analysis was undertaken to assess whole abdomen radiation therapy and concurrent 5-fluorouracil for toxicity and patterns of failure in high-risk colon cancer patients after curative surgical resection. METHODS: Eighteen patients were treated adjuvantly after curative resection.  Four patients received whole abdominal radiation only, 30 Gy at 1 Gy/day. Fourteen patients had an additional locoregional boost of 9.6 to 16 Gy at 1.6 Gy/day. The liver received 19.8 Gy at 0.67 Gy/day. 5-Fluorouracil was given as a continuous infusion during therapy. RESULTS: With a median follow-up of three years, 6 of 18 (33 percent) patients have relapsed. Failure occurred locally in 3 of 18 (17 percent) and distantly in 4 of 18 patients (22 percent). Four of six (67 percent) failures occurred in the liver. The five-year actuarial survival and disease-free survival were 78 percent and 66 percent, respectively. Median elapsed time on radiotherapy was 73 days, with 5 of 18 patients (28 percent) requiring two or more weeks of unplanned treatment breaks. Acute Grade 3 to 4 toxicity (diarrhea, leukopenia) occurred in 3 of 18 patients (17 percent), with late complications (bowel obstruction) occurring in 2 of 18 patients (11 percent). CONCLUSIONS: Whole abdominal radiotherapy with concomitant 5-fluorouracil appears to improve local control but not to prevent liver metastases. Significant toxicity resulted in frequent interruption of therapy and protracted its course. Whether this adjuvant regimen impacts on survival or offers an advantage over locoregional irradiation remains to be studied.

J Clin Oncol 1993 Jun;11(6):1112-7

Postoperative radiation therapy for high-risk colon carcinoma.

Willett CG, Fung CY, Kaufman DS, Efird J, Shellito PC

Department of Radiation Oncology, Massachusetts General Hospital Cancer Center, Boston 02114.

PURPOSE: This study examines the experience of patients treated with postoperative radiation therapy after resection of high-risk colon carcinoma in an effort to assess the potential role of this modality in combination with current systemic therapies. PATIENTS AND METHODS: From 1976 to 1989, 203 patients received postoperative radiation therapy with and without concurrent fluorouracil (5-FU) chemotherapy following resection of modified Astler-Coller B2, B3, C2, and C3 colon tumors. Of the 203 patients, 30 (15%) were identified as having residual local tumor after subtotal resection, whereas 173 (85%) had no known residual disease. The 173 patients treated with adjuvant radiation therapy were compared with a historical control group of 395 patients undergoing surgery only. RESULTS: Three groups of patients who appeared to benefit from postoperative radiation were identified. Improved local control and recurrence-free survival rates were seen for patients with stage B3 and C3 colon carcinoma treated with postoperative radiation therapy compared with a similarly staged group of patients undergoing surgery only. Irradiated patients whose tumors had an associated abscess or fistula formation had improved local control and recurrence-free survival rates compared with a similar group of patients undergoing surgery only. There appears to be a subset of patients with residual local disease after subtotal resection that may be salvaged by high-dose postoperative radiation therapy. CONCLUSION: Selected groups of patients with colon carcinoma may benefit from postoperative radiation in addition to current systemic therapies. Integration of 5-FU and levamisole with postoperative radiation therapy should be considered for patients with (1) stage B3 and C3 lesions, (2) tumors associated with abscess or fistula formation, and (3) residual local disease after subtotal resection.