Adjuvant therapy of resectable rectal cancer

The two conventional treatments for clinically resectable rectal cancer are surgery followed by postoperative combined modality therapy and preoperative combined modality therapy followed by surgery and postoperative chemotherapy. Preoperative therapy (most commonly combined modality therapy) has gained acceptance as a standard adjuvant therapy. The potential advantages of the preoperative approach include decreased tumor seeding, less acute toxicity, increased radiosensitivity due to more oxygenated cells, and enhanced sphincter preservation. There are a number of new chemotherapeutic agents that have been developed for the treatment of patients with colorectal cancer. Phase I/II trials examining the use of new chemotherapeutic agents in combination with pelvic radiation therapy are in progress.     

Adjuvant radiation therapy for rectal cancer

Since 1976, 104 patients with rectal cancer have been treated with a new approach of combined pre- and postoperative radiation. All patients were given 500 rad preoperative irradiation on the day of or the day before surgery. Surgery in the majority of patients was an abdominal perineal resection. The disease was then staged pathologically according to Astler-Coller's modification of Duke's staging. Patients with early stage cancer (Stages A and B1) were followed with no further therapy. Patients with poor prognostic characteristics (Stages B2, C1, C2) were given postoperative pelvic irradiation (4500 rad in 5 weeks). Twenty-nine patients were found to have Stage A or B1 cancer and were followed with no further therapy. Of these 29 patients, 1 patient developed recurrence and one has died of metastatic disease. The excellent survival of patients with early tumors indicates that minimizing the role of adjuvant therapy in this group has not been detrimental to their survival. Fifteen were found to have liver metastases at laparotomy and had just a colostomy and palliative therapy. Sixty patients had Stage B2 and C disease. Thirty-one received postoperative irradiation as per protocol. Twenty-nine patients did not receive postoperative irradiation for a variety of reasons. Follow-up ranges from 1 to 7 years in these patients. Of the 29 patients with Stage B2 and C disease who should have but did not receive postoperative radiation, 10 patients (34%) have developed a recurrence in the pelvis, and 5 other patients (17%) have developed metastatic disease. Of 31 patients who received postoperative irradiation, only 2 patients (6%) developed a local recurrence and 4 patients (13%) have developed distant metastases. Survival at 3 years was 80% for patients receiving the combined treatment, as compared to 42% for those not receiving the postoperative part of the treatment protocol.     

Adjuvant radiation therapy of patients with rectal cancer

The standard in rectal cancer has been to add adjuvant radiation therapy to surgery in patients with stage II and III disease. Total mesorectal excision has led to lower local recurrence rates, and, if properly performed, may make adjuvant radiation unnecessary for certain stage II and III patients, such as T3 N0 patients with proximal lesions. There is also debate about the best method of delivering adjuvant radiotherapy. Preoperative radiotherapy at low dose per fraction with concurrent chemotherapy offers the advantages of maximizing sphincter preservation and greater tolerability. However, this will occasionally result in treating patients who are overstaged by ultrasound and may lead to greater postoperative morbidity and mortality than postoperative radiation. Preoperative radiotherapy has stronger data to support a survival advantage when added to surgery than postoperative radiation. Two randomized, phase III European studies may answer the question of which radiation technique is best for the near future. Protracted venous infusion of 5-fluorouracil (5-FU) is the standard method of radiosensitization. However, studies are ongoing using concurrent oxaliplatin, irinotecan, and oral 5-FU prodrugs. For now, we recommend that stage II and III rectal cancer patients receive protracted venous infusion 5-FU concurrent with preoperative radiation.     

Adjuvant therapy for rectal cancer: results and controversies

During the past decade, advances have been made in the adjuvant treatment of resectable rectal cancer. Postoperative combined-modality therapy significantly improves local control and survival. Recent Inter-group postoperative trials have focused on the identification of optimal chemotherapeutic agents and their method of administration. Preoperative therapy has the potential advantages of producing less acute toxicity and increasing the likelihood of sphincter preservation. New chemotherapeutic agents and radiation techniques are active areas of investigation.     

Adjuvant postoperative radiation therapy for rectal adenocarcinoma.

From October 1975 to August 1988, 261 patients at high risk for local recurrence after curative resection of rectal carcinoma underwent high-dose postoperative irradiation. Patients received 45 Gy by a 4-field box usually followed by a boost to 50.4 Gy or higher when small bowel could be excluded from the reduced field. Since January 1986, patients also received 5-fluorouracil (5-FU) for 3 consecutive days during the first and last week of radiotherapy. Five-year actuarial local control and disease-free survival decreased with increasing stage of disease; patients with Stage B2 and B3 disease had local control rates of 83% and 87% and disease-free survivals of 55% and 74%, respectively. In patients with Stage C1 through C3 tumors, local control rates ranged from 76% to 23%, and disease-free survivals ranged from 62% to 10%, respectively. For patients with Stage C disease, disease-free survival decreased progressively with increasing lymph node involvement, but local control was independent of the extent of lymph node involvement. For each stage of disease, local control and disease-free survival did not correlate with the dose of pelvic irradiation. Preliminary data from this study suggest a trend toward improved local control for patients with Stage B2, C1, and C2 tumors who receive 5-FU for 3 consecutive days during the first and last weeks of irradiation compared with patients who do not receive 5-FU. Current prospective randomized studies are addressing questions regarding the optimum administration of chemotherapy with pelvic irradiation for patients following resection of rectal carcinoma.     

Adjuvant therapy for resectable rectal adenocarcinoma

The mainstay of treatment for rectal cancer over the past 100 years has been surgical resection. However, for the majority of rectal cancers treated conventionally by resection alone, locoregional recurrence is the major mode of failure. Over the past several decades, significant progress has been made in developing effective adjuvant regimens. In the United States, postoperative chemoradiation is standard treatment for T3 or node-positive patients. However, preoperative radiation with or without chemotherapy decreases local recurrence, increases sphincter preservation, and may improve survival. The purpose of this article is to review the role of adjuvant therapy in resectable rectal cancers and to update the status of ongoing randomized trials.     

Adjuvant VHF therapy in locally recurrent and primary unresectable rectal cancer

In a prospective randomized study, 434 mHz microwave therapy combined with external beam radiotherapy (VHF+RT) was compared with standard external beam radiotherapy (RT) in controlling locally recurrent or unresectable primary adenocarcinoma of the rectum. Independent assessors documented quality of life scores, performance status, toxicities, local response to treatment, and systemic disease progression before treatment and after treatment and every 8 weeks thereafter. Of 75 patients randomized, 73 were eligible for inclusion in the study. Forty-three of these patients had local pelvic tumour recurrence only and 21 also had distant metastases. In addition, nine patients had primary inoperable carcinomas, two of whom also had metastases. Thirty-seven patients were randomized to RT and 36 to VHF+RT. The median dose of radiation in the VHF+RT arm was 4275 cGy with a median fraction size of 150 cGy and median duration of therapy of 48.5 days versus 4500 cGy in the RT-only arm with a median fraction size of 180 cGy and median duration of therapy of 38 days. These doses are unlikely to be significantly different in biological effect. No significant difference between the two groups was observed in extent and duration of local control, measures of toxicity or quality of life scores. Additionally, survival and cumulative incidence of pelvic site of first progression did not differ significantly between the groups. We conclude that VHF microwave therapy in conjunction with radiotherapy produces no therapeutic advantage over conventional radiation therapy alone in the treatment of locally recurrent rectal carcinoma.     

Adjuvant therapy of colon cancer.

Colon cancer is an important cause of cancer-related mortality. A series of clinical trials of adjuvant systemic therapy have been performed in attempt to establish means to improve outcome in this disease. By the early 1990s, a role for 5-fluorouracil (5-FU)-based chemotherapy in stage III colon cancer had been firmly established. The precise role for chemotherapy in stage II disease remains under investigation. Progress continues toward optimizing the schedule and duration of systemic therapy, allowing for maximal efficacy with a minimum of toxicity. It appears that approximately 6 months of 5-FU and leucovorin are as effective as more prolonged regimens. Levamisole does not appear to add to the benefit of 5-FU and leucovorin. Several newer agents such as the oral fluorinated pyrimidines, irinotecan (CPT-11) and oxaliplatin have demonstrated activity in metastatic colon cancer and hold promise as potentially effective drugs to be tested in the adjuvant setting.     

Adjuvant therapy for breast cancer.

Different aspects of adjuvant therapy in breast cancer have been noteworthy in the past year. Evaluation of long-term results with nonspecific immunostimulatory agents in conjunction with adjuvant chemotherapy or tamoxifen have failed to show therapeutic benefit. Studies have also focused on whether tamoxifen represents an alternative to chemotherapy alone, or is more effective in combination with chemotherapy or radiation therapy.     

Adjuvant therapy in gastric cancer.

Gastric cancer has a poor prognosis. The majority of patients will relapse after definitive surgery, and 5-year survival after surgery remains poor. The role of adjuvant therapy in gastric cancer has been controversial given the lack of significant survival benefit in many randomized studies so far. The results of a large North American study (Gastrointestinal Cancer Intergroup Trial INT 0116) reported that postoperative chemoradiotherapy conferred a survival advantage compared with surgery alone, which has led to the regimen being adopted as a new standard of care. However, controversies still remain regarding surgical technique, the place of more effective and less toxic chemotherapy regimens, and the use of more modern radiation planning techniques to improve treatment delivery and outcome in the adjuvant and neoadjuvant setting. This article reviews the current status of the adjuvant treatment for gastric cancer including discussion on the research directions aimed at optimizing treatment efficacy. Issues such as the identification of patients who are more likely to benefit from adjuvant therapy are also addressed. Further clinical trials are needed to move towards better consensus and standardization of care.