Management of patients who present with Synchronous distant metastases

The initial management strategy in patients who present with distant metastases from colorectal cancer is controversial. Commonly, patients are treated initially with surgery followed by systemic therapy, and symptomatic patients should be considered for surgical palliation prior to being offered chemotherapy. However, nonsurgical options for asymptomatic patients have gained popularity as the chemotherapy regimens become more effective. Initial chemoradiation has been used with some success instead of nontherapeutic colostomy in rectal cancer patients when systemic options were more limited. Durable symptomatic palliation was achieved in 80% of patients and colostomy was avoided in 90%. The clinical activity and survival improvements for colorectal cancer patients who have been seen with the new chemotherapeutic regimens introduced in recent years makes the use of front-line chemotherapy very appealing in patients with synchronous metastatic and asymptomatic intact primary disease. However, surgery and radiotherapy should be considered for symptomatic patients.

In contrast to rectal cancer, colon cancer is frequently resected with wide negative margins and local recurrences are less of a problem. In a retrospective analysis, patients with T4 N0 or T4 N1 colon cancer were first shown to have an approximately 30 to 50% local failure rate and a 10% isolated local failure rate. Subsequently, postoperative radiation was used and higher local disease control and disease-free survival rates were seen in these patients. The indications for postoperative chemoradiation (50.4 Gy to the tumor bed) are invasion of surrounding organs and tumor perforation of the visceral peritoneum (T4 disease).

This therapy is typically given with concurrent continuous infusion of 5-FU and integrated with the adjuvant chemotherapy. The results of the only randomized trial evaluating the role of postoperative chemoradiation in patients with colon cancer who had either T3 N1 or T3 N2 or tumor adherence to or invasion of surrounding structures have been published. Patients were randomized to receive bolus 5-FU and levamisole for one year with or without radiotherapy. There was no detectable difference in overall survival between the two arms, but the authors acknowledge that clinically significant differences in survival could not be excluded because the study was terminated early owing to poor accrual.

Local recurrence after surgery alone for operable rectal cancer has been reported to be between 25 and 50% for stage II and III rectal adenocarcinoma. These high recurrence rates are probably the result of incomplete dissection of the mesorectum. However, with total mesorectal excision, the risk of local recurrence is significantly lower. In the Dutch total mesorectal excision trial, a randomized prospective trial, local recurrence was 8.2% after total mesorectal excision (TME) alone for resectable rectal cancer.

The major risk factors for pelvic tumor recurrence include nodal involvement and tumor penetration beyond the bowel wall (T3 and T4 disease). Extension of tumor into the perirectal fat or adjacent viscera increases the rate of local recurrence to approximately 25 to 50% with surgery alone. The extent of tumor penetration beyond the bowel wall is also a significant factor predicting for recurrence risk. Willet and colleagues examined a group of patients with T3 N0 rectal cancer who underwent resection alone. Surgical specimens were assessed for maximum depth of tumor invasion into perirectal fat, lymphatic or venous involvement, and tumor grade. Local tumor control correlated with increasing extent of tumor penetration beyond the rectal wall. Tumor penetration more than 2 mm led to a > 20% local recurrence rate. In 25 patients with tumors with favorable histological features (well-differentiated or moderately well-differentiated carcinomas invading less than 2 mm into perirectal fat, without lymphatic or venous vessel involvement), the 10-year actuarial rates of local control and recurrence-free survival were 95% and 87%, respectively. The anatomic location of the tumor also correlates with the risk of tumor recurrence. Tumors that are lower in the pelvis are more difficult to resect with wide negative margins because of physical anatomic restrictions. Several clinical experiences bear this out, including the Dutch TME Trial. Although the factors are probably interrelated, the width of radial margins of resection has also been correlated with the risk of pelvic tumor recurrence in patients who undergo surgery alone. In the Dutch TME Trial, patients who were randomized to total mesorectal excision alone whose resected tumors had at least a 1 cm negative radial margin had 5-year pelvic tumor recurrence risk of less than 5%. A margin of ≤ 2 mm was associated with a local recurrence risk of 16% (p

< .0001). The radial margin of excision can also serve as an indicator of the quality of the surgery. In the Dutch trial, in a sample of 656 patients who underwent total mesorectal excision alone, 18.3% (n = 120) had a positive circumferential margin after curative resection. Patients undergoing abdominoperineal resection (APR) had a higher incidence (28.8%) than those undergoing low anterior resection (LAR) (13.5%). Distant metastases occurred in 37.6% of patients with positive circumferential margins, whereas it was 12.7% in patients with > 1 cm margin. Systematic macroscopic evaluation of the mesorectum was performed in 180 specimens of patients undergoing TME. Almost 24% of the patients had an incomplete mesorectal excision as defined by the pathologist. Even though the follow-up was short, there was a statistically significant difference in survival in patients with a macroscopically incomplete TME. However, there was no statistically significant difference in local recurrence.

In the INT-0114, lower body mass index and female sex correlated with sphincter preservation. Obese men, but not obese women, had significantly worse sphincter preservation and pelvic control. These outcomes are possibly related to the mechanical difficulties associated with adiposity and with operating in the comparatively narrow male pelvis. In summary, the major risk factors for tumor recurrence in patients with resected rectal cancer treated with resection alone include tumor penetration of the muscularis propria (and the extent of penetration), nodal involvement, the number of negative nodes in node-negative patients, and the width of the radial margin. The ability to achieve negative margins and optimize pelvic tumor control is also related to adiposity in male patients. Other favorable factors for local control that are probably not independent include tumor grade and lymphovascular space invasion. Thus a highly selected subgroup of patients with T3 N0 tumors and T1-2 N1 tumors, may have a low risk of tumor recurrence with no further therapy. This concept would be an interesting one to study on a prospective trial.

Miguel A. Rodriguez-Bigas, MD, Paulo Hoff, MD, Christopher H. Crane, MD

  • Wolmark N, Wieand HS, Kuebler JP, et al. A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: results of Protocol C-06 [abstract 3500]. Proc Am Soc Clin Oncol 2005;23.
  • Van Cutsem E, Hoff PM, Harper P, et al. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 2004;90:1190-7.
  • Twelves C, Wong A, Nowacki M, et al. Updated efficacy findings from the X-ACT phase III trial of capecitabine (X) vs bolus 5-FU/LV as adjuvant therapy for patients (pts) with Dukes’ C colon cancer. Proc Am Soc Clin Oncol 2005;23:251.
  • Minsky BD, Conti JA, Huang Y, Knopf K. Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer. J Clin Oncol 1995;13:1409-16.
  • Valentini V, Coco C, Cellini N, et al. Preoperative chemoradiation for extraperitoneal T3 rectal cancer: acute toxicity, tumor response, and sphincter preservation. Int J Radiat Oncol Biol Phys 1998;40:1067-75.
  • Hyams DM, Mamounas EP, Petrelli N, et al. A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum: a progress report of National Surgical Breast and Bowel Project Protocol R-03. Dis Colon Rectum 1997;40:131-9.
  • Crane CH, Skibber JM, Feig BW, et al. Response to preoperative chemoradiation increases the use of sphincter-preserving surgery in patients with locally advanced low rectal carcinoma. Cancer 2003;97:517-24.
  • Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer.[comment]. N Engl J Med 2004;351:1731-40.
  • Pahlman L, Glimelius B. Pre- or postoperative radiotherapy in rectal and rectosigmoid carcinoma. Report from a randomized multicenter trial. Ann Surg 1990;211:187-95.
  • Janjan NA, Khoo VS, Rich TA, et al. Locally advanced rectal cancer: surgical complications after infusional chemotherapy and radiation therapy. Radiology 1998;206:131-6.
  • Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980-7.
  • Cedermark B, Johansson H, Rutqvist LE, Wilking N. The Stockholm I trial of preoperative short term radiotherapy in operable rectal carcinoma. A prospective randomized trial. Stockholm Colorectal Cancer Study Group. Cancer 1995;75:2269-75.
  • Holm T, Rutqvist LE, Johansson H, Cedermark B. Postoperative mortality in rectal cancer treated with or without preoperative radiotherapy: causes and risk factors. Br J Surg 1996;83:964-8.
  • Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000;284:1008-15.
  • Suwinski R, Taylor JM, Withers HR. Rapid growth of microscopic rectal cancer as a determinant of response to preoperative radiation therapy. Int J Radiat Oncol Biol Phys 1998;42:943-51.
  • Frykholm GJ, Isacsson U, Nygard K, et al. Preoperative radiotherapy in rectal carcinomaтАФaspects of acute adverse effects and radiation technique. Int J Radiat Oncol Biol Phys 1996;35:1039-48.
  • Kapiteijn E, Kranenbarg EK, Steup WH, et al. Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Dutch ColoRectal Cancer Group. Eur J Surg 1999;165:410-20.
  • Bosset J, Calais G, Mineur L, et al. Preoperative radiation (Preop RT) in rectal cancer: effect and timing of additional chemotherapy (CT) 5-year results of the EORTC 22921 trial [abstract 3505]. J Clin Oncol 2005;23(Suppl 16):247S.
  • Gerard J, Bonnetain F, Conroy T, et al. Preoperative (preop) radiotherapy (RT) + 5 FU/folinic acid (FA) in T3-4 rectal cancers: results of the FFCD 9203 randomized trial [abstract 3504]. J Clin Oncol 2005;23(Suppl 16):S1.
  • Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709-15.
  • Douglass HO Jr, Moertel CG, Mayer RJ, et al. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986;315:1294-5.
  • Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 1985;312:1465-72.
  • NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990;264:1444-50.
  • Wolmark N, Wieand HS, Hyams DM, et al. Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-02. J Natl Cancer Inst 2000;92:388-96.
  • O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502-7.
  • Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301-8.
  • Tepper JE, O’Connell MJ, Petroni GR, et al. Adjuvant postoperative fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup 0114. J Clin Oncol 1997;15:2030-9.
  • Smalley S, Benedetti J, Williamson S, et al. Intergroup 0144тАФa phase III trial rectal surgical adjuvant trial of pelvc radiation plus 5-FU based chemotherapy (bolus 5-FU before and after PVI +XRT vs PVI before, during, and after XRT + PVI vs biochemically modulated bolus 5-FU and XRT): Mature outcome results andpelvic failure analysis [abstract 114]. Int J Radiat Oncol Biol Phys 2004;60(Suppl 1):S137.
  • Lee JH, Ahn JH, Bahng H, et al. Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: a preliminary report. J Clin Oncol 2002;20:1751-8.
  • Janjan NA, Crane C, Feig BW, et al. Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer. Am J Clin Oncol 2001;24:107-12.
  • Mohiuddin M, Regine WF, John WJ, et al. Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response. Int J Radiat Oncol Biol Phys 2000;46:883-8.
  • Sauer R, Roedel C, Martus P, et al. Prognostic factors after neoadjuvant radiochemotherapy for rectal cancer: update of the CAO/ARO/AIO-94 phase III study [abstract 3503]. J Clin Oncol 2005;16:246s
  • Gunderson LL, Nelson H, Martenson JA, et al. Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer. Dis Colon Rectum 1996;39:1379-95.
  • Wong CS, Cummings BJ, Brierley JD, et al. Treatment of locally recurrent rectal carcinomaтАФresults and prognostic factors. Int J Radiat Oncol Biol Phys 1998;40:427-35.
  • Mohiuddin M, Marks G, Marks J. Long-term results of reirradiation for patients with recurrent rectal carcinoma. Cancer 2002;95:1144-50.
  • Scheithauer W, Rosen H, Kornek GV, et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993;306:752-5.
  • Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol 2001;19:2282-92.
  • Douillard JY, Hoff PM, Skillings JR, et al. Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2002;20:3605-16.

Provided by ArmMed Media