Adjuvant therapy of rectal cancer.

For patients with clinically resectable stage T3 and/or node-positive rectal cancer, adjuvant radiation therapy decreases the rate of local recurrence. The addition of systemic chemotherapy further enhances local control and improves survival. Compared with postoperative therapy, preoperative treatment may have less toxicity and may increase the chance of sphincter preservation. The acute and long-term toxicity of pelvic radiation is related to the technique of delivery. Therefore, appropriate conventional radiation doses and techniques are recommended. Randomized trials comparing preoperative and postoperative combined modality therapy are in progress.     

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 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.     

Analysis of surgical salvage after failure of primary therapy in rectal cancer: results from Intergroup Study 0114.

PURPOSE: Intergroup Study 0114 was designed to study the effect of various chemotherapy regimens delivered after potentially curative surgical resection of T3, T4, and/or node-positive rectal cancer. A subset analysis was undertaken to investigate the prevalence and influence of salvage therapy among patients with recurrent disease. PATIENTS AND METHODS: Adjuvant therapy consisted of two cycles of fluorouracil (FU)-based chemotherapy followed by pelvic irradiation with chemotherapy and two more cycles of chemotherapy after radiation therapy. A total of 1,792 patients were entered onto the study and 1,696 were assessable. After a median of 8.9 years of follow-up, 715 patients (42%) had disease recurrence, and an additional 10% died without evidence of disease. Five hundred patients with follow-up information available had a single organ or single site of first recurrence (73.5% of all recurrences). RESULTS: A total of 171 patients (34% of those with a single organ or single site of recurrence) had a potentially curative resection of the metastatic or locally recurrent disease. Single-site first recurrences in the liver, lung, or pelvis occurred in 448 patients (90% of the single-site recurrences), with 159 (35%) of these undergoing surgical resection for attempted cure. Overall survival differed significantly between the resected and nonresected groups (P <.0001), with overall 5-year probabilities of.27 and.06, respectively. Controlling for worst performance status at the time of recurrence does not alter this relationship. Patients who underwent salvage surgery had significantly increased survival (P <.001) for each site. CONCLUSION: Attempted surgical salvage of rectal cancer recurrence is performed commonly in the United States. The chance of a long-term cure with such intervention is approximately 27%.     

Adjuvant therapy for high-risk, early stage cervical cancer

The identification of various pathologic risk factors after primary surgical management of early stage cervical cancer portends a higher rate of relapse and decreased survival. Historical attempts to improve outcome focused mainly on the use of adjuvant pelvic radiation, with limited success overall. Analysis of patterns of failure after radical hysterectomy led to better stratification of patients into risk groups and incorporated testing of systemic agents in those considered at high risk of distant failure. Two recently reported randomized, clinical trials have greatly advanced our understanding of the role of postoperative therapy in cervix cancer. In patients with positive nodes, the use of combined adjuvant chemotherapy and radiation significantly improves relapse-free survival and overall survival, compared with radiation alone. For node-negative patients with other primary tumor risk features, pelvic radiation significantly improves relapse-free survival, compared with no further therapy. An observed improvement in survival for irradiated patients awaits statistical confirmation after maturation of the data. Further improvements in adjuvant therapy for high risk, early stage cervical cancer will come from enhanced definition of prognostic variables, better patient selection, and refinements in both local and systemic therapies.     

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 of stage II breast cancer

Summary A prospective, randomized clinical trial of adjuvant treatment of 318 stage II breast cancer patients, using chemotherapy, the antiestrogen tamoxifen, and immunotherapy is reported at 48 months follow-up.Women whose primary tumors have no estrogen receptors fall into a significantly poorer prognostic group than those whose tumors contain estrogen receptors. None of the adjuvant regimens appeared to offer any clear-cut advantage for the estrogen receptor negative patients.Those women whose primary tumor contains estrogen receptors appear to be in a prognostically favorable group, when their treatment regimen included the antiestrogen, tamoxifen. The adjuvant use of BCG immunotherapy does not appear to offer additional benefit, but the follow-up period of these treated patients is too brief to be conclusive.A longer period of observation is needed to determine whether this systemic treatment in estrogen receptor positive patients is preventing recurrence or merely delaying it. Address for reprints: C.A. Hubay, M.D., Dept. of Surgery, 2074 Abington Rd., Cleveland, OH 44106.     

Adjuvant radiochemotherapy in rectal cancer: analysis of acute and late-onset toxicity

Objective

To analyse the factors related to the appearance, incidence and severity of toxicity associated with post-operative radiochemotherapy in rectal cancer.

Material and methods

Between January 1994 and September 1997, we prospectively collected the data on 122 patients treated for rectal adenocarcinoma in the B2-C stage. Surgery was followed by radiotherapy and chemotherapy (5-FU plus leucovorin) administered as an alternating, or as a concomitant, scheme. Pelvic volume was treated with a four-portal, or a two-portal, irradiation technique using megavoltage photon beams (⁶⁰Co or 23 MV photons). Total administered dose was 50 Gy in 1.8–2 Gy fractions. Statistical analysis was performed to identify factors related to the incidence of toxicity, and its severity.

Results

Acute side effects were noted in 98 (80.3%) patients; the most frequent being diarrhea (55%) followed by skin reactions (40.1%). Toxicity occurred following the administration of a mean radiation dose of 26 Gy (range: 8–50 Gy). Grade 3 toxic events were observed in 20.5% of patients. It was necessary to interrupt treatment in 32.8% of patients for a mean period of 8.8 days. There were no grade 4 toxicities or therapy-related deaths. The concomitant scheme of radiochemotherapy (compared to alternating) was the main predictive factor for higher incidence (91.1% versus 74%; p=0.04), higher severity grade 3 (33.3% versus 13%; p=0.014) and early (following 22.7 Gy versus 28.4 Gy, p=0.012) acute toxicity. With a median follow-up of 68.9 months, late grade 3 toxicity appeared in 13 patients (10.8%), and 10 patients (8.3%) required surgical treatment to resolve an intestinal obstruction. None of the parameters analysed influenced the late-onset toxicity, or the development of small-bowel obstruction.

Conclusions

In our study, the concomitant radiochemotherapy combination scheme was the main predictive factor for acute toxicity, but with no influence on late-onset toxicity. Our overall results were similar to others reported in the literature.     

Adjuvant systemic therapy of early stage breast cancer

Opinion statement Adjuvant chemotherapy reduces the risk of recurrence and mortality in patients with early stage breast cancer. Anthracycline-based regimens are the most widely used standard in the United States. The inclusion of the taxanes into adjuvant chemotherapy programs offers an improvement in disease-free survival rates and probably overall survival rates compared to an anthracycline-based regimen alone. Although adjuvant chemotherapy is effective in all age groups, the magnitude of benefit is greatest in younger premenopausal patients. Treatment decisions need to be individualized. Dose-dense chemotherapy approaches are promising and can be considered an option for patients with early stage breast cancer. Adjuvant tamoxifen therapy should be administered for 5 years in patients with hormone receptor-positive breast cancer. Adjuvant tamoxifen should be administered after the completion of adjuvant chemotherapy. Data from the ATAC (Arimidex, tamoxifen, alone, or in combination) trial provide a compelling argument for choosing anastrozole as adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive early stage breast cancer. Long-term follow-up of patients is necessary to determine the effects of chronic aromatase inhibitor treatment on bone density, cognitive function, and other endpoints.     

Acute diarrhea during adjuvant therapy for rectal cancer: a detailed analysis from a randomized intergroup trial

PURPOSE: During adjuvant radiotherapy (RT) for rectal cancer, patients receiving 5-fluorouracil (5-FU) by protracted venous infusion have a higher risk of diarrhea than have patients receiving bolus 5-FU. Toxicity from a previously reported randomized clinical trial was analyzed to quantify the difference in this risk. Additionally, the persistence of diarrhea after RT was analyzed. METHODS AND MATERIALS: A total of 656 patients were eligible. Patients with T3-4 N0-2 M0 or T1-2 N1-2 M0 resected, high-risk rectal cancer were randomly allocated to receive 5-FU by either protracted venous infusion or bolus during RT (50.4-54.0 Gy). Two cycles of bolus 5-FU were given before and after RT. One-half of the first 445 patients were also randomly allocated to receive lomustine in conjunction with the bolus 5-FU. The incidence and severity of diarrhea in relation to patient and treatment characteristics were evaluated. RESULTS: The rate of diarrhea was significantly greater in patients receiving 5-FU by protracted venous infusion than in patients receiving bolus 5-FU; the difference was most pronounced for Grade 3 (severe) diarrhea (21% versus 13%, p = 0.007). The incidence and magnitude of diarrhea before and after RT were similar. Patients treated with an anterior resection had a higher rate of severe or life-threatening diarrhea than did patients treated with an abdominoperineal resection (31% vs. 12%, p < 0.001). CONCLUSIONS: During pelvic RT, patients who receive 5-FU by protracted venous infusion rather than by bolus have a higher risk of severe or life-threatening diarrhea during RT. This risk does not appear to persist during chemotherapy after completion of pelvic RT.     

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 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III.

Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990, we conducted a prospective trial. 1029 patients were randomised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon (n = 730) or rectal cancer (n = 299). 45% were in stage II and 55% in stage III. With a median follow-up of 4 years and 9 months a significant reduction in odds of death (25%, SD 9%, P = 0.007) was observed for those with adjuvant treatment (65% at 5 year) compared to the observation group (55%). Improved relative survival was present in stage III (56% vs 44%), and in stage II patients (78% vs 70%). In rectal cancer a non-significant difference in disease-free or overall survival was observed. Distant metastases developed in 76%, while local recurrence alone occurred in 14%. An early start of adjuvant treatment (< 4 weeks) did not affect results. Compliance to 5FU plus levamisole was 69%. Severe toxicity did not occur. In conclusion, one year 5FU plus levamisole was of benefit in stage II and III colonic cancer; in rectal cancer a significant positive effect could not be demonstrated.     

Adjuvant therapy for stage II colon cancer: prognostic and predictive markers

The treatment of stage II colon cancer is a controversial issue that has persisted for the past decade. Clinicians must understand that accurate assessment of risk factors is the key to identifying patients who will benefit from treatment. Pathologic staging for colon cancer is based on the American Joint Committee on Cancer 6th edition staging system. In addition, distinct pathologic factors characterize a patient at high risk for stage II disease. More recent retrospective data suggest that molecular markers and gene expression microarrays may be valuable as prognostic and predictive tests. Unfortunately, previous research studies were not powered to properly assess efficacy in stage II disease. However, 2 recent clinical trials, National Surgical Adjuvant Breast and Bowel Project C-07 and MOSAIC, have provided more insight into defining the optimal treatment approach. With the development of the newer therapeutic agents, oxaliplatin and bevacizumab, ongoing trials such as Intergroup E5202 should help determine risk versus benefit of chemotherapy in the adjuvant treatment of stage II colon cancer.