A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum

PURPOSE: National Surgical Adjuvant Breast and Bowel Project Protocol R-03 was designed to determine the worth of preoperative chemotherapy and radiation therapy in the management of operable rectal cancer. METHODS: Thus far, 116 patients of an eventual 900 with primary operable rectal cancer have been randomized to receive multimodality therapy to begin preoperatively (59 patients) or identical therapy beginning after curative surgery (57). All patients received seven cycles of 5-fluorouracil (FU)/leucovorin (LV) chemotherapy. Cycles 1 and 4 through 7 used a high-dose weekly FU regimen. In Cycles 2 and 3, FU and low-dose LV chemotherapy was given during the first and fifth week of radiation therapy (5,040 cGy). The preoperative arm (Group 1) received the first three cycles of chemotherapy and all radiation therapy before surgery. The postoperative arm (Group 2) received all radiation and chemotherapy after surgery. Primary study end points included disease-free survival and survival. Secondary end points included local recurrence, primary tumor response to combination therapy, tumor downstaging, and sphincter preservation. RESULTS: Overall treatment-related toxicity was similar in both groups. Although seven preoperative patients had events after randomization that precluded surgery, eight events occurred during an equivalent follow-up period in the postoperative group. No patient was deemed inoperable because of progressive local disease. Sphincter-saving surgery was intended in 31 percent of Group 1 patients and 33 percent of Group 2 patients at the time of randomization. Such surgery was actually performed in 50 percent of the preoperatively treated patients and 33 percent of the postoperatively treated patients. The use of protective colostomy in patients undergoing sphincter-sparing surgery and the development of perioperative complications in all surgical patients were similar in both groups. There was evidence of tumor downstaging in evaluable patients under-going preoperative therapy, with 8 percent of Group 1 patients having had a pathologic complete response. CONCLUSION: These data do suggest that the preoperative chemotherapy and radiation therapy regimen used are, at least, as safe and tolerable as standard postoperative treatment. There is presently a trend to tumor downstaging and sphincter preservation in the preoperative arm. Whether this arm will have greater or lesser survival and long-term toxicity awaits the completion of this relevant study.Supported by National Cancer Institute Grants U10-CA-12027 and U10-CA-37377 and American Cancer Society Grant R-13.Read at the meeting of The American Society of Colon and Rectal Surgeons, Seattle, Washington, June 9 to 14, 1996.     

The Effect of Circumferential Tumor Location in Clinical Outcomes of Rectal Cancer Patients Treated With Total Mesorectal Excision

PURPOSE A positive circumferential resection margin is associated with a high risk of local recurrence and distant metastasis after total mesorectal excision for rectal cancer. The mesorectum is thinner anteriorly than posteriorly, and the risk of a positive resection margin may be higher for anterior than for posterior tumors. We sought to determine the effect of the tumor's position in the circumference of the rectum on the treatment and outcomes of rectal cancer patients treated by total mesorectal excision. METHODS We retrospectively analyzed 401 patients with rectal cancer staged by preoperative endorectal ultrasound and treated by sharp mesorectal excision with or without neoadjuvant therapy. Tumors were classified into four groups (anterior, posterior, lateral, and circumferential) according to the location of deepest point of penetration on endorectal ultrasound. Differences in recurrence and survival rates were analyzed with logistic regression analysis. RESULTS Of the 401 tumors, 27 percent were anterior, 26 percent posterior, 32 percent lateral, and 15 percent circumferential. The groups did not differ in age, gender, tumor distance from the anal verge, or tumor grade. The ultrasound and pathology stages were more advanced in the circumferential group, and the proportion of uT4 tumors was higher in the anterior group. Circumferential and anterior tumors were more likely to receive preoperative adjuvant radiation. After an average follow-up of 44 months, 20 percent of patients had developed recurrence (13 percent distant, 6 percent local, and 1 percent distant and local). Recurrence was associated with advanced tumor stage, tumor proximity to the anal verge, and no preoperative adjuvant therapy. Early tumor stage and preoperative chemoradiation were associated with lower recurrence and improved survival. When tumor stage was controlled for, patients with poor or undifferentiated tumors and male patients with anterior tumors were shown to have a higher risk of recurrence or death. The estimated five-year disease-free survival for the entire group was 73 percent. CONCLUSIONS Tumor stage is the main criterion to estimate prognosis in rectal cancer patients. The position of the tumor within the circumference of the rectum may provide valuable clinical information. Anterior tumors tend to be more advanced and, at least in male patients, has a higher risk of recurrence and death than tumors in other locations. Presented at the meeting of the Minnesota Surgical Society, St. Paul, Minnesota, April 27, 2001.     

Indicators for Surgical Resection and Intraoperative Radiation Therapy for Pelvic Recurrence of Colorectal Cancer

PURPOSE: We retrospectively analyzed prognostic factors for surgical resection and intraoperative radiation therapy to identify indicators for this treatment strategy. METHODS: Thirty-nine consecutive patients with locally recurrent colorectal cancer who underwent surgical resection with intraoperative radiation therapy from January 1, 1987, to June 30, 1999, were analyzed. The mean electron energy was 10.5 MeV and the mean intraoperative radiation dose was 22.6 Gy. Kaplan-Meier survival estimates were obtained for the 37 patients who recovered postoperatively. Prognostic factors were analyzed univariately by log-rank test and multivariately by Coxs proportional hazards model. RESULTS: Three-year cumulative survival was 44 percent (standard error = 11) for 26 patients free of unresectable distant metastasis who underwent surgical resection and intraoperative radiation therapy for pelvic recurrence of colorectal cancer, but none of the 11 patients with unresectable distant metastasis survived 3 years. Preoperative prognostic factors which were significant on univariate and multivariate analysis were unresectable distant metastasis (P = 0.001) and elevated preoperative serum CA 19–9 (P = 0.02). Patients with synchronous resection of local recurrence and distant metastasis had a significant survival advantage over those without resection of metastases (P = 0.02). Univariate analysis in a subgroup of 26 patients without unresectable distant metastasis revealed pain (P = 0.0003) to be a useful preoperative prognostic indicator, whereas tumor fixation (P = 0.01) and amount of residual tumor after surgical resection (P = 0.01) were significant intraoperative and postoperative factors, respectively. Fluorouracil-based postoperative systemic chemotherapy produced a significant survival benefit (P = 0.04). CONCLUSIONS: Patients with unresectable distant metastasis are not suitable candidates for surgical resection and intraoperative radiation therapy, whereas those with resectable metastasis are potential candidates. Intraoperative radiation therapy may be less useful for patients with pain, elevated preoperative CA19–9, fixed tumors, or gross residual tumor after surgical resection. Multimodal treatment strategies combining preoperative and/or postoperative external beam radiation therapy and intraoperative radiation therapy with fluorouracil-based systemic chemotherapy are recommended for patients with these indicators.     

Preoperative radiation with or without chemotherapy and full-thickness transanal excision for selected T2 and T3 distal rectal cancers

BACKGROUND AND AIMS: To evaluate the clinical outcome of selected patients with distal rectal cancer treated by preoperative radiation with or without chemotherapy and full-thickness local excision (FTLE). PATIENTS AND METHODS: Ten patients with invasive distal rectal cancer (six T2, four T3) were treated with preoperative radiotherapy (3600-5040 cGy) with or without 5-fluorouracil based chemotherapy. FTLE was performed 4-6 weeks after completion of radiotherapy, primarily because of comorbid diseases or patient refusal of a permanent colostomy. Median follow-up was 28.5 months. RESULTS: There were no prolonged wound complications, and only one positive microscopic margin was detected. Among three cases of complete pathological response, two remain without evidence of disease. All patients retained sphincter function and avoided creation of a stoma. Two patients developed recurrence, one with widespread disease including pelvic recurrence 26 months after surgery and the other with distant disease only at 23 months. There were four deaths: two unrelated to cancer, one of undetermined cause after 7 years, and one after widespread recurrence at 26 months, with death 4 months later. Two-year actuarial survival was 78%. CONCLUSIONS: This pilot study demonstrates that preoperative radiotherapy and FTLE avoids major abdominal surgery yet facilitates sphincter preservation, excision with negative margins, and short-term local control in selected patients with distal rectal cancer.     

Incidence and Clinical Impact of Sterilized Disease and Minimal Residual Disease After Preoperative Radiochemotherapy for Rectal Cancer

PURPOSE In advanced rectal cancer, chemoradiation can induce downstaging until complete disappearance of the tumor or its persistence in minimal form. The complete sterilized and the minimal residual disease often are considered similar. We evaluated the specific incidence of these two conditions and analyzed their impact in terms of local recurrence, distant metastasis, and survival. METHODS We studied 139 uT3/T4 N0/N+ rectal cancers, treated with preoperative chemoradiation and curative surgery after six to eight weeks. We evaluated ypTNM stage and tumoral regression, according to the five degrees proposed by Dworak, with special attention to 4 and 3 (sterilized and minimal residual disease). RESULTS Tumor downstaging occurred in 65 patients (46.7 percent), including 25 sterilized lesions (17.9 percent) and 24 minimal residual disease (17.2 percent). In median follow-up of 30 months, none of the patients with sterilized disease developed local or distant recurrence. Among patients with minimal residual disease, none developed local recurrence, whereas two (8.3 percent) developed distant metastasis, and one died from disease. In patients with gross residual disease (Grade 2, 1, 0) the percentage of local recurrence was 8.8 percent, distant recurrence 26.6 percent, and 13.3 percent died from disease. The difference between three groups is statisti-cally significant as regards local and distant recurrence. CONCLUSIONS After preoperative therapy, the sterilized disease shows an excellent prognosis. The minimal residual disease has an important numeric incidence. Its outcome is different, with a not-negligible risk of distant recurrence. The minimal residual disease has a much better prognosis in comparison with the gross residual disease.     

Endocavitary irradiation

PURPOSE: Endocavitary irradiation delivers high-dose irradiation with limited penetration and is an established modality for the curative treatment of select tumors. The purpose of this study was to review the experience from our institution with endocavitary irradiation. METHODS: All patients with rectal cancer treated with endocavitary irradiation between 1973 and 1992 were studied. Collected data included: tumor size, tumor differentiation, distance from the anal verge, mean follow-up, recurrence, and other treatments used. RESULTS: One hundred ninety-nine patients received endocavitary irradiation, with 126 treated with curative intent. No significant differences were found between groups with recurrence and no recurrence when examining tumor size, differentiation, distance from the anal verge, or follow-up. With a mean time to recurrence of 16.1 (range, 1–56) months, 37/126 patients had a recurrence, and 89/126 had no recurrence. Ten recurrences were distant, and all patients died of the disease. Twentyseven patients had local recurrence. Following additional treatments, 14 additional patients were rendered free of disease. CONCLUSION: Endocavitary irradiation initially rendered 71 percent (89/126) free of disease. With additional treatment 11 percent (14/126) were rendered free of disease. In the subgroup of patients followed more than five years, 68 percent had no evidence of disease at follow-up after endocavitary irradiation, and 91 percent had no evidence of disease with additional treatment. Tumor size, differentiation, morphology, and distance from the anal verge did not influence recurrence. Debulking or surgical excision before endocavitary irradiation did not increase recurrence. Diligent long-term follow-up and a liberal policy to biopsy suspicious areas may increase the salvage rate.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Chicago, Illinois, May 2 to 7, 1993Podium presentation at the Tripartite Colorectal Meeting, Sydney, Australia, October 17 to 20, 1993.     

High preoperative serum carcinoembryonic antigen predicts metastatic recurrence in potentially curative colonic cancer: Results of a five-year study

INTRODUCTION: Serum carcinoembryonic antigen is used mainly for tumor follow-up to detect recurrence of colonic cancer. However, raised preoperative carcinoembryonic antigen levels may be helpful for the identification of understaged cases and of patients meriting more intensive preoperative and postoperative diagnostic workup. METHODS: From a prospectively collected database, the data on 261 patients who had curative colonic carcinoma with a minimal follow-up of five years and who had preoperative carcinoembryonic antigen levels assessed were retrieved and analyzed. Outcome parameters were local and/or distant recurrence and time to recurrence. These parameters were correlated with Dukes staging and preoperative carcinoembryonic antigen levels. RESULTS: The cumulative diseasefree survival of patients with a preoperative carcinoembryonic antigen level within the normal range was significantly better than that of those whose carcinoembryonic antigen was 5 ng/ml or more (P=0.001). No patient with carcinoembryonic antigen levels less than 1 ng/ml developed metastatic recurrence. Twenty-three percent of all patients with a raised carcinoembryonic antigen above 5 ng/ml compared with 2.1 percent of patients with carcinoembryonic antigen below 5 ng/ml developed a metastasis at two years. At five years, these figures were 37.2 percent and 7.5 percent, respectively. Dukes staging and carcinoembryonic antigen levels were found to be directly correlated (P<0.001) when all patients were included. Carcinoembryonic antigen of more of 15 ng/ml was found to be a significant adverse prognostic indicator for disease-free survival irrespective of Dukes staging (P<0.02). Raised carcinoembryonic antigen levels predicted distant metastatic recurrence (P<0.001) but did not predict local recurrence (P=0.72). CONCLUSIONS: High preoperative carcinoembryonic antigen levels above 15 ng/ml predicted an increased risk of metastatic recurrence in potentially curative colonic cancer and may indicate undetectable disseminated disease. Preoperative carcinoembryonic antigen levels predict understaging and the possibility of distant recurrence. Such patients may therefore be selected for adjuvant therapy where indicated. Therefore, carcinoembryonic antigen is complementary to conventional Dukes staging for the prediction of recurrence and survival.     

Selective use of adjuvant radiation therapy in resectable colorectal adenocarcinoma

Colorectal cancer recurs within the operative field in 10–20 per cent of patients undergoing potentially curative surgery. In certain subgroups, the recurrence rate is 20–50 per cent. There are some data to suggest either preoperative or postoperative radiation therapy as an adjuvant to potentially curative surgery can reduce the local operative failure rate. However, since radiation therapy has significant side effects, patient selection to maximize the therapeutic ratio is important. This report defines the criteria at the Massachusetts General Hospital for selection of patients with colorectal cancer for adjuvant radiation therapy, defines radiation therapy-surgery sequencing alternatives used, and deseribes techniques to reduce radiation side effects. Over a period of three and a half years, 196 patients received adjuvant radiation therapy: 51 patients received either moderate or low dose preoperative radiation therapy to rectal or rectosigmoid cancers, and 161 patients received postoperative radiation therapy to the pelvis or extrapelvic colonic tumor-lymph node beds. Some patients who received low-dose preoperative radiation therapy also received moderate-dose postoperative radiation therapy. We prefer moderate-dose postoperative radiation therapy as the approach most likely to decrease the local recurrence rate with minimal interference with surgical procedures and late small-bowel complications. Patients who received postoperative radiation therapy were those without distant metastases, whose primary tumor pathology revealed macroscopic or extensive microscopic transmural tumor penetration into extraperitoneal tissues. Careful case selection, multiple field techniques, the use of reperitonealization, omental flaps, and retroversion of the uterus into the pelvis were combined with postoperative small-bowel x-rays, bladder distention, and lateral portals to minimize radiation damage to normal structures.     

Outcome of patients with rectal adenocarcinoma and localized pelvic non-nodal metastatic foci

PURPOSE: The aim of this study was to evaluate the outcome of patients with primary rectal adenocarcinoma and soft tissue metastatic foci restricted to the pelvis and to determine whether this entity, which is considered N1 disease in the American Joint Committee on Cancer staging system, behaves like completely replaced nodal disease or the first sign of M1 disease. The clinical course for patients with this finding is not well-described in the literature. METHODS: The authors retrospectively reviewed the medical records of 395 patients with rectal adenocarcinoma who received radiation treatment. Eighteen patients had pelvic soft tissue metastatic foci. Exclusions from this study included 1) cases without metastatic pelvic foci; 2) cases of recurrent cancer; 3) cases with known distant metastatic disease as defined by American Joint Committee on Cancer criteria; and 4) cases with extrapelvic metastatic foci. All patients received adjuvant radiotherapy. Thirteen cases received preoperative radiotherapy. Four cases received postoperative radiotherapy. One case received both preoperative and postoperative radiotherapy. Eight cases received chemotherapy. RESULTS: All eighteen patients had T3 or T4 lesions. Thirteen patients had lymph nodes that contained metastatic disease and would therefore have been scored N1 or N2 even without the pelvic tumor implants. Sixteen of 18 (89 percent) patients died of disease after a survival time of 12 to 37 (mean, 25) months. Only 1 of 18 (6 percent) patients was disease free at five years. The other remaining survivor was undergoing palliative therapy for metastatic disease to the lung. This is significantly worse than our institution's experience with T3,4N+ disease after preoperative radiation (5-year survival, 11 vs. 56 percent; P = 0.0002, Generalized Wilcoxon of Breslow). There was a high incidence of local (9/18) and distant (14/18) failure. No other factor, including radiation dose, margin status, chemotherapy, T stage, and number of involved nodes or soft tissue implants, correlated independently with outcome. CONCLUSIONS: Pelvic metastatic foci confer a significantly worse prognosis than other T3,4N+ disease. Such cases should be excluded from prospective trials for localized disease. Although this entity probably represents M1 disease for most patients, survival can be long, and aggressive locoregional and systemic treatment is warranted.     

Extensive surgery after high-dose preoperative chemoradiotherapy for locally advanced recurrent rectal cancer

PURPOSE: This was a pilot study of high-dose preoperative concurrent radiation and chemotherapy before extensive surgery in patients with locally advanced recurrent rectal cancer. Here we report on curative resectability, acute toxicities during chemoradiotherapy, surgical complications, local control, and three-year survival rates achieved with this aggressive multimodal regimen. METHODS: Between 1994 and 1997, 35 previously nonirradiated patients with pelvic recurrence of rectal cancer were entered in the study. All patients presented with tumor contiguous or adherent to adjacent pelvic organs and were not deemed amenable to primary curative surgery. A total radiation dose of 50.4 Gy with a small-volume boost of 5.4 to 9 Gy was delivered in conventional fractionation (single dose, 1.8 Gy). 5-Fluorouracil was scheduled as a continuous infusion of 1,000 mg/m²/day on Days 1 to 5 and 29 to 33. Six weeks after completion of chemoradiotherapy, patients were reassessed for resectability, and radical surgery was attempted whenever feasible. RESULTS: After preoperative chemoradiotherapy 28 of 35 patients (80 percent) underwent resection with curative intent. In 16 of 35 patients (57 percent) extended resection of adjacent organs was performed. Resections with negative margins were achieved in 17 patients (61 percent); 9 patients had microscopic, and 2 patients had gross residual disease. There was no postoperative mortality. Fourteen patients (44 percent) experienced postoperative complications. Toxicity from chemoradiotherapy occurred mainly as diarrhea (National Cancer Institute Common Toxicity Criteria Grade 3; 23 percent), dermatitis (Grade 3; 11 percent), and leucopenia (Grade 3; 11 percent). One patient died of tumortoxic multiple organ failure during chemoradiotherapy. With a median follow-up of 27 months, local re-recurrence after curative resection was observed in only three patients (18 percent); six patients developed distant metastases. Three-year actuarial survival rate was significantly improved after complete resection (82 percent) as compared with noncurative surgery (38 percent;P=0.03). CONCLUSION: A combination of high-dose preoperative chemoradiotherapy followed by extended surgery can achieve clear resection margins in more than 60 percent of patients with recurrent rectal tumor not amenable to primary surgery. An encouraging trend evolved for this multimodal treatment to improve long-term local control and survival rate.Presented at the meeting of the German Society for Radiation Oncology, Radiation Biology and Medical Physics (DEGRO), Nürnberg, Germany, November 7 to 10, 1998.     

DCC protein as a predictor of distant metastases after curative surgery for rectal cancer

PURPOSE: The aim of this study was to determine the value of DCC (deleted in colorectal cancer) protein for predicting metachronous distant metastases after curative surgery for rectal cancer. The DCC protein—for which a gene has been located on chromosome 18q—has recently been reported to have a prognostic value in colorectal cancer. This finding might have implications for treatment of International Union Against Cancer Stage II rectal carcinoma, in which distant metastases will develop in 14 percent of patients despite optimal surgery. METHODS: Paraffin-embedded tissues from 85 patients who developed distant metastases, but no local recurrence, after curative surgery for rectal cancer were matched with 85 samples from patients who remained disease-free. Matching criteria were tumor stage, age, gender, and date of surgery. Expression of DCC protein was assessed using immunohistochemistry. End points of follow-up were recurrence of disease and death. Mean follow-up was 9.6 years. No patient received either local or systemic adjuvant therapy. RESULTS: The DCC protein was found to be expressed in 64.9 percent of tumor samples. Nonexpression of DCC protein had an negative influence on survival (P=0.03). For all tumor stages together, sensitivity of the test for subsequent occurrence of distant metastases was 42 percent and specificity was 71 percent. In Stage II cancers, the positive predictive value was 19 percent, and the negative predictive value was 88 percent. CONCLUSIONS: Our results confirm that DCC protein is a useful prognostic marker in patients with rectal carcinomas, but the positive predictive value of DCC protein for occurrence of metachronous metastases does not appear to be sufficient to justify adjuvant therapeutic measures in Stage II rectal cancer.     

Postoperative concomitant chemoradiotherapy in locally advanced rectal cancer

BACKGROUND/AIMS: To gain maximal effectiveness while decreasing toxicity by giving 5-fluorouracil for 45 minutes starting just within 5 minutes after the completion of radiotherapy thrice weekly. METHODOLOGY: Thirty-eight patients with locally advanced rectal cancer were enrolled in the study. Ranges of total radiation doses were between 50.4 Gy and 61.2 Gy with a median of 59.4 Gy with fraction size of 1.8 Gy five times weekly. 5-fluorouracil was administered thrice weekly with the dose of 250-300mg/m2/day concomitantly with radiation therapy. RESULTS: Median follow-up time was 30 months. Administration of chemotherapy concomitant with radiotherapy (p=0.089), AJCC stage III (p=0.079), Duke's stage C (p=0.079), presence of lymph node involvement (p=0.079) and presence of local recurrence (p=0.066) appeared to be effecting distant metastasis although differences did not reach statistically significance. Mean overall survival was 46 months in patients without any distant metastasis (SD: 3.28; 95% CI: 39.46 and 52.31) while it was 35 months in patients with distant metastasis (SD: 5.71; 95% CI: 23.52 and 45.90, p=0.016). CONCLUSIONS: Our results have provided further evidence of the ability of postoperative chemoradiotherapy to delay and prevent local recurrence and metastasis of rectal cancer.     

Epidermoid carcinoma of the anal canal

Thirty consecutive patients with epidermoid carcinomas of the anal canal larger than 2 cm were treated with the concomitant application of radiation and two cycles of chemotherapy (5FU and mitomycin-C) between January 1982 and January 1988. Twenty-eight patients were treated with curative intention and two for palliation only. All patients were reexamined after a period of one to 2 months, under light general anesthesia, and any residual tumor or scar tissue was biopsied. Control biopsy was positive in eight patients. Three of six patients who had abdominoperineal excision died from locoregional recurrence; the remaining are alive and cancer free after 1 to 4 years. Two patients had local excision; one is alive and the other died of other cancer metastasis four years later. Seventeen patients who had negative biopsies are alive and free of disease after 1 to 5 years; two died of unrelated causes, two died with distant metastasis (present prior to treatment), and one died with locoregional recurrence. Locoregional failures occurred in four patients (13.3 percent) in the entire series. Individualization of each patient, adjustment of doses, and carefully executed radiation and chemotherapy are the most important points for the success of treatment. Read at the meeting of the American Society of Colon and Rectal Surgeons, Anaheim, California, June 12 to 17, 1988.     

Efficacy of Preoperative Radiation Therapy for Resectable Rectal Adenocarcinoma When Combined With Oral Tegafur-Uracil Modulated With Leucovorin

PURPOSE: The aim of this study was to evaluate the efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma (T3-T4) when delivered in combination with chemotherapy (oral tegafur-uracil modulated with leucovorin). METHODS: Thirty-eight patients (23 males; mean age, 62 years.) with histologically proven rectal adenocarcinoma with primary tumor clinical classification T3-T4 (resectable) and N0 or N1-N2, according to TNM staging system, took part in the present clinical trial. After tumor and metastasis resectability confirmation, radiation therapy was administered by delivering a dose of 45 Gy in 25 fractions for 5 weeks. Chemotherapy treatment was initiated on the same day as radiotherapy and consisted of intravenous infusion of 6S-steroisomer of leucovorin 250 mg/m2/day in 2 hours on Day 1, followed by oral 350 or 300 mg/m2/day of tegafur (a 5-fluorouracil prodrug) plus uracil on Days 1 to 14 divided into 2 daily doses, and oral 6S-steroisomer of leucovorin 7.5 mg/12 hours on Days 2 to 14, with a total of 102 courses of neoadjuvant chemotherapy (i.e., mean of 2.7 courses per patient). Six additional courses of tegafur-uracil were given postoperatively to all 38 patients but 1 who refused. RESULTS: As a result of preoperative chemoradiation treatment, 4 (10.5 percent) complete responses, 20 (52.6 percent) partial responses, and 14 (36.8 percent) patients with disease stabilization were observed. No patients had preoperative disease progression. Histologically proven downstaging was observed in 23 (60 percent) patients. On initial evaluation, only 39 percent of patients were considered as being good candidates for sphincter-preserving surgery; however, on preoperative chemoradiation completion this figure increased up to 60 percent. For the 23 patients eventually undergoing sphincter-preserving surgery, postoperative sphincter function assessment showed excellent function in 15 (65 percent) patients, good in 5 (22 percent), fair in 2 (9 percent), and poor in 1(4 percent). With a median follow-up of 37 (range, 10–62) months, local failure was found in 3 (8 percent) patients and distant failure in 2 (5 percent). Three-year actuarial disease-free survival and 3-year overall survival rates were 83 and 90 percent, respectively. Local control rate was 92 percent. Toxicity and postoperative complication rates were reasonable. CONCLUSIONS: Our neoadjuvant radiation therapy protocol is efficient for the preoperative treatment of resectable rectal adenocarcinoma when combined with chemotherapy (oral tegafur-uracil modulated with leucovorin). However, this protocol needs to be tested in a phase-III clinical trial with a larger sample size.     

Palliative operations for colorectal cancer

A review of 96 consecutive patients who underwent palliative surgery for primary colorectal cancer was undertaken to clarify the value of palliation achieved with surgical treatment. The overall rate of postoperative mortality was 8 percent (8 of 96) and the overall rate of postoperative morbidity was 24 percent (23 of 96). The mortality rate was 5 percent (3 of 66) after resective surgery and 17 percent (5 of 30) after nonresective surgery. Three deaths were related to the malignant disease, three were related to the intra-abdominal infection, and two were related to formation of intestinocutaneous fistulas. Of the 8 patients who died, 1 had a tumor with local visceral involvement only and 7 had a tumor with more distant spread. Median survival was 10 months for all patients, 15 months for patients treated with resective surgery, and 7 months for nonresected patients. Five patients (5 percent) have survived for longer than 5 years. The median relief of preoperative cancer symptoms was 4 months (4 months after resective surgery and 1 month after nonresective surgery). Twenty-five patients have undergone second surgery. It is concluded that palliative resective surgery for colorectal cancer can improve patient comfort with an acceptable postoperative mortality rate when cancer growth is localized and in favorable cases with more distant spread, whereas nonresective surgery fails to achieve symptom relief.     

A Pathologic Complete Response to Preoperative Chemoradiation Is Associated With Lower Local Recurrence and Improved Survival in Rectal Cancer Patients Treated by Mesorectal Excision

PURPOSE: Preoperative chemoradiation reduces tumor size and nodal metastasis in patients with rectal cancer. Tumor downstaging has been associated with an increased probability of a sphincter-saving procedure and with improved local control. However, pathologic complete response to chemoradiation has not been correlated with local control and patient survival. We studied the prognostic value of pathologic complete response to preoperative chemoradiation in rectal cancer patients. METHODS: We have prospectively followed up 168 consecutive patients with ultrasound Stages II (46) and III (122) rectal cancer treated by preoperative chemoradiation followed by radical resection with mesorectal excision; 161 had a curative resection. Recurrence and survival were compared with tumor characteristics and pathologic complete response. Average follow-up was 37 months. RESULTS: Tumor downstaging occurred in 97 (58 percent) patients, including 21 (13 percent) patients who had a pathologic complete response. None of the clinical or pathologic variables was associated with pathologic complete response. The estimated 5-year rate of local recurrence was 5 percent; of distant metastasis, 14 percent. None of the patients with pathologic complete response has developed disease recurrence. We found no difference in survival among patients with pathologic Stages I, II, or III tumors. CONCLUSIONS: A pathologic complete response to preoperative chemoradiation is associated with improved local control and patient survival. For patients without pathologic complete response, the pathology stage does not have prognostic significance.     

Phase II clinical trial of preoperative combined chemoradiation for T3 and T4 resectable rectal cancer: preliminary results

PURPOSE: Although preoperative chemoradiation for high-risk rectal cancer may improve survival and local recurrence rate, its adverse effects are not well defined. This prospective study evaluated the use of preoperative chemoradiation for T3 and T4 resectable rectal cancer, with special emphasis on treatment morbidity, pathologic remission rate, quality of life, and anorectal function. METHODS: Forty-two patients (30 men, 12 women) were enrolled in the study. Median distance of the distal tumor margin from the anal verge was 6.5 cm. Preoperative staging was based on digital rectal examination, endorectal ultrasound, and computed tomography. None of the patients had distant metastases. All patients had 45 Gy (1.8 Gy/day in 25 fractions) over five weeks, plus 5-fluorouracil (350 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33. Quality of life was assessed with the European Organization for Research and Treatment of Cancer 30-item quality-of-life questionnaire (QLQ-C30) and its colorectal cancer-specific module (QLQ-CR38) questionnaires. Objective anorectal function was assessed by anorectal manometry and pudendal nerve terminal motor latency. Surgery was performed 46 (range, 24-63) days after completion of adjuvant therapy. RESULTS: Nineteen patients (45 percent) had Grade 3 or 4 chemoradiation-induced toxic reactions. Four patients developed intercurrent distant metastases or intraperitoneal carcinomatosis at completion of chemoradiation. Thirty-eight patients underwent surgical resection: abdominoperineal resection, anterior resection, and Hartmann's procedure were performed in 55 percent, 39 percent (11 of 15 patients had a diverting stoma), and 5 percent, respectively. Major surgical complications occurred in 7 patients (18 percent) and included anastomotic leak (n = 1), pelvic abscess (n = 1), small-bowel obstruction (n = 3), and wound breakdown (n = 2). Final pathology was Stage 0 (no residual disease), I, II, and III in 6 (16 percent), 7 (18 percent), 9 (24 percent), and 16 (42 percent) patients, respectively. There was a deterioration, after chemoradiation and surgery, in the quality of life on all subscales assessed, with physical, role, and social function being most severely affected. The symptoms most adversely affected were micturition, defecation, and gastrointestinal problems. Body image and sexual enjoyment deteriorated in both men and women. Chemoradiation alone led to prolonged pudendal nerve terminal motor latency in 57 percent of 7 patients assessed. CONCLUSION: Preliminary results have identified defined costs with preoperative chemoradiation, which included treatment-induced toxicity, a high stoma rate, and adverse effects on quality of life and anorectal function.     

Influence of simultaneous neoadjuvant radiotherapy and chemotherapy on bronchoscopic findings and lung function in patients with locally advanced proximal esophageal cancer

To assess the bronchoscopic and lung function changes induced by preoperative radiochemotherapy (30 Gy radiation and 5-fluorouracil) in patients with proximal esophageal cancer, we prospectively compared the findings in 77 consecutive patients before and after the therapy. All patients completed the radiochemotherapy protocol; toxicity was minimal. Sixty-four patients underwent surgery, 48 had total gross removal of disease, and six had a complete histologic response. Of the 13 patients who developed apparent direct macroscopic signs of tumor invasion into the airways during therapy, histologic proof of cancer was obtained in only one of the abnormalities. Bronchoscopy was falsely negative in six patients in whom airway invasion of the cancer was found at surgery. Neoadjuvant therapy led to no systematic changes in the appearance of the uninvolved tracheal mucosa; microscopically, an increase in postinflammatory changes, hyperplasia, and metaplasia was found. There was no significant change in the values of lung function parameters after the therapy. No patient developed symptoms suggestive of radiation-induced lung changes, although in one of them, subtle radiologic features consistent with radiation pneumonitis were found. No patient died of postoperative pulmonary complications. The interpretation of bronchoscopy in the assessment of airway invasion of esophageal cancer after radiochemotherapy is more difficult than at baseline staging; the positive predictive value of macroscopic abnormalities without microscopic proof of cancer is low, and even with extensive sampling for histology and cytology, the procedure was falsely negative in 9.4%. Neoadjuvant therapy did not induce radiation pneumonitis or changes in lung function that could be of concern at the following operation.     

Preoperative staging of irradiated rectal cancers using digital rectal examination, computed tomography, endorectal ultrasound, and magnetic resonance imaging does not accurately predict T0,N0 pathology

PURPOSE: The postradiation preoperative staging results of 25 patients with rectal cancer who were found to have Stage T0,N0 lesions after surgery were examined. Our aim was to assess the ability of preoperative staging following radiation therapy to predict the absence of disease. METHODS: From 1983 to 1994, 25 patients treated with preoperative radiation therapy for biopsy-proven rectal cancer were found to have no pathologic evidence of disease in the resected specimen (T0,N0). The preoperative postradiation disease staging results of these patients were compared with the postoperative pathologic findings. Each patient received 4,500 to 5,580 cGy during a five-week to six-week period, and four patients had preoperative chemotherapy. Surgical resection was performed six to eight weeks after completion of radiation therapy. All 25 patients were staged by digital rectal examination before surgery. In addition, 13 patients were assessed using computed tomography, 6 by endorectal ultrasound, and 1 by magnetic resonance imaging. RESULTS: Most irradiated lesions were overstaged by radiologic assessment and physical examination. No technique could reliably distinguish between postradiation fibrosis and residual cancer. The negative predictive value for digital rectal examination was 24 percent. Computed tomography accurately staged 23 percent of lesions, and endorectal ultrasound predicted 17 percent of lesions correctly. The single patient evaluated by magnetic resonance imaging was overstaged and thought to have a T2 lesion. CONCLUSIONS: Our ability to assess local eradication of rectal cancer following radiation therapy remains poor. Conventional imaging and clinical examination techniques are unable to safely predict which patients do not require surgical excision following curative radiation therapy for rectal cancer.     

Oncologic Results Following Abdominoperineal Resection for Adenocarcinoma of the Low Rectum

PURPOSE: The role of abdominoperineal resection for rectal cancer has changed because of advances in sphincter-preserving surgery. Our aim was to evaluate the results of this operation in the five-year period following introduction of the concept of total mesorectal excision METHODS: Data on all patients undergoing abdominoperineal resection for very low rectal cancer between 1992 and 1997 were collected prospectively. All patients had had total mesorectal excision. Curative resection was defined as absence of macroscopic disease after resection and local recurrence as any infiltration or tumor identified in the pelvis, alone or combined with distant disease. Survival and local recurrence rates were calculated using the Kaplan-Meier method and log-rank analysis. RESULTS: Of 165 abdominoperineal resections performed, 106 were for primary adenocarcinoma of the rectum. The male:female ratio was 50:56, with a median age of 65 (range, 33–85) years. There was one postoperative death. Twenty-seven patients received short-course preoperative radiotherapy (25 Gy over 1 week), whereas 22 had a longer course, with concomitant chemotherapy in 2. Postoperative chemotherapy was administered in 29, postoperative radiotherapy in 4, and combined therapy in 8. After curative resection (n = 91), survival at five years was 76 percent and differed significantly by stage. Recurrence at any site was 7 percent (3/34) for Stage I, 27 percent (6/26) for Stage II, and 53 percent (16/31) for Stage III. Nine patients presented with local recurrence, with an overall rate at five years of 10 percent. Isolated locale recurrence was observed in only 5 percent of patients CONCLUSIONS: After abdominoperineal resection and total mesorectal excision, good rates of local control may be achieved provided surgical technique is meticulous.