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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer Ellen Kapiteijn, M.D., Corrie A.M. Marijnen, M.D., Iris D.
Nagtegaal, M.D., Hein Putter, Ph.D., Willem H. Steup, M.D., Ph.D., Theo Wiggers, M.D., Ph.D., Harm J.T. Rutten, M.D., Ph.D., Lars Pahlman, M.D., Ph.D., Bengt Glimelius, M.D., Ph.D., J. Van Krieken, M.D., Ph.D., Jan W.H.
Leer, M.D., Ph.D., and Cornelis J.H. Van de Velde, M.D., Ph.D., for the Dutch Colorectal Cancer Group N Engl J Med 2001; 345:638-646 DOI: 10.1056/NEJMoa010580. Results Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate.
The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent.
The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P. Local recurrence is a serious problem in the treatment of rectal cancer, since it causes disabling symptoms and is difficult to treat. There is a high incidence of local recurrence (15 to 45 percent) after conventional surgery, in which blunt dissection of the rectal fascia often fails to remove all the tissue that may bear tumor. In an attempt to improve local control and survival after conventional surgery, radiotherapy has been given. The only randomized trial that compared preoperative and postoperative radiotherapy showed the superiority of preoperative radiotherapy for local control.
The Swedish Rectal Cancer Trial found that preoperative radiotherapy also improved the rate of survival at five years. A recent meta-analysis concluded that the combination of preoperative radiotherapy and surgery, as compared with surgery alone, significantly improved overall survival and cancer-specific survival. The recognition that involvement of the circumferential margin by tumor cells is important in local recurrences has led to the general use of total mesorectal excision, in which the entire mesorectum is enveloped and resected by precise, sharp dissection. Improvements in local control with this technique have been shown, mainly in retrospective series.
In previous studies of radiotherapy for rectal cancer, surgery was not standardized. Since surgical technique is a key factor in the success of tumor control, standardization and quality control with respect to surgery are indispensable for evaluating the effects of adjuvant therapy. Optimal quality must also include the use of standardized methods of pathological examination.
Background Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable.
A prospective, randomized trial was organized by the Dutch Colorectal Cancer Group to investigate the efficacy of preoperative radiotherapy in combination with standardized total mesorectal excision in patients with rectal cancer. In this article, we present the results of the trial after a median follow-up of two years. Eligibility, Randomization, and Sample Size Patients were enrolled between January 1996 and December 1999. To be eligible, patients had to have histologically confirmed adenocarcinoma of the rectum, without evidence of distant metastases, and the inferior margin of the tumor had to be located not farther than 15 cm from the anal verge and below the level of S1–2. Patients with fixed tumors or tumors that were treated by local (transanal) resection were excluded. Patients with previous or coexisting cancer and those who had previously undergone large-bowel surgery, chemotherapy, or radiotherapy of the pelvis were also excluded.
After informed consent had been obtained, we randomly assigned the patients to treatment with preoperative radiation (5 Gy on each of five days) followed by total mesorectal excision or to total mesorectal excision alone. Randomization was performed at the central trial office and was based on permuted blocks of six, with stratification according to center and the expected type of operation (low anterior resection or abdominoperineal resection). The trial was approved by the medical ethics committees of all the participating hospitals.
The trial design and the calculation of the sample size have been described in detail elsewhere. Quality Control In the Netherlands, participating surgeons attended workshops and symposiums, saw instructional videotapes, and were monitored by specially trained instructor surgeons. At each hospital, the first five total mesorectal excisions were supervised by an instructor surgeon. Pathologists were trained to identify lateral spread of tumor according to the protocol of Quirke et al. The results of histopathological examination of the specimens were reviewed by a panel of supervising pathologists and a quality manager. Patients' eligibility and treatment and the details of follow-up were checked by study coordinators. Local and distant recurrences were confirmed radiologically or histologically and checked by a radiation oncologist.
In Sweden, the technique of total mesorectal excision was introduced on a national basis several years ago, as was the protocol of Quirke et al. The European Organization for Research and Treatment of Cancer participated in this trial under protocol 40971. Visits to other participating hospitals and specialists were made before the start of the trial to ensure the quality of treatment at those sites. For logistic reasons, no quality control with respect to radiotherapy, surgery, or pathological examination was performed outside the Netherlands during the trial. Statistical Analysis Case-report forms were sent to the central trial office, where information on the forms was entered into a data base and analyzed with SPSS statistical software (version 9.0 for Windows, SPSS, Chicago).
Chi-square tests were used to compare proportions. Mann–Whitney tests were used to compare quantitative and ordinal variables. Univariate analyses of survival were carried out by the Kaplan–Meier method, and the evaluation of differences between the two groups was performed with the log-rank test. The Cox proportional-hazards model was used to calculate hazard ratios and 95 percent confidence intervals in the univariate and multivariate analyses. A two-sided P value of 0.05 or less was considered to indicate statistical significance. The starting point for the analyses of survival and recurrence was the day of surgery.
Data on patients who were alive or free of recurrence were censored at the time of the last follow-up. The analysis of overall survival was performed on an intention-to-treat basis and thus included all the eligible patients. The rate of local recurrence was calculated on the basis of the number of eligible patients who underwent a macroscopically complete local resection. The rate of distant recurrence was calculated on the basis of the number of eligible patients who did not have distant metastasis at the time of surgery.
The overall rate of recurrence was calculated on the basis of the number of eligible patients who had macroscopically complete local resection without distant metastasis. Analyses of postoperative morbidity and mortality were based on the total number of eligible patients who underwent resection.
Patients A total of 1861 patients were randomly assigned to one of the two treatment groups. There were 1530 patients from 84 Dutch hospitals, 228 from 13 Swedish hospitals, and 103 from 11 other European and Canadian centers. Of these 1861 patients, a total of 56 were found to be ineligible before randomization, including 4 patients for whom there was no information on eligibility. Our analysis therefore included 1805 eligible patients. Of these, 1653 patients had a curative resection. Of the remaining 152 patients, 57 did not undergo a macroscopically complete local resection, and 95 were found to have distant metastasis at surgery ( Table 1 Characteristics of the Eligible and Ineligible Patients and Rates of Macroscopically Complete Local Resection, According to Treatment Group.
The characteristics of the 1805 patients who were eligible for the study and the features of their tumors were similar in the two treatment groups ( Table 2 Characteristics of the 1805 Eligible Patients. In 28 patients (2 percent), no tumor was found in the resected specimen, despite a preoperative biopsy that showed an adenocarcinoma. Major Violations Of the 897 eligible patients assigned to undergo radiotherapy before total mesorectal excision, 29 did not receive preoperative radiotherapy for the following reasons: known metastases (8 patients), carcinoma in situ (1), sigmoid carcinoma (3), a second cancer (1), withdrawal of informed consent (11), and physical limitations that made radiotherapy impossible (5).
Long-term preoperative radiotherapy was given to seven patients for locally advanced tumors. One patient was unable to tolerate surgery and was treated with long-term radiotherapy alone. Preoperative radiotherapy was discontinued in 14 patients, mainly because of neurotoxicity. Of the 908 eligible patients assigned to total mesorectal excision alone, 3 patients withdrew their informed consent and requested radiotherapy (5 Gy on each of five days), and 8 patients had advanced local tumors for which long-term preoperative radiotherapy was given. Postoperative adjuvant therapy was not allowed in patients who had microscopically tumor-free margins without spillage of tumor cells during the operation. Of 1759 eligible patients with available information on margins and tumor spillage, 1351 (77 percent) had tumor-free margins without tumor spillage.
Eighty-five of these patients (38 in the group assigned to radiotherapy and surgery and 47 in the group assigned to surgery alone) received adjuvant therapy (chemotherapy, radiotherapy, or chemoradiotherapy), which was a major protocol violation. Minor Violations Of the 846 eligible patients randomly assigned to preoperative radiotherapy who received the total dose of 25 Gy, the interval between the first day of radiotherapy and the day of surgery exceeded 10 days in 110 patients (13 percent).
In 127 of the patients (15 percent), the upper border of the treatment field was at the level of S1–2 instead of at the promontory, and in 161 of the patients undergoing an abdominoperineal resection (19 percent), the perineum was not included in the treated volume. Postoperative Morbidity and Mortality The median interval between randomization and surgery was 21 days in the group assigned to radiotherapy and surgery and 14 days in the group assigned to surgery alone. The patients assigned to radiotherapy and surgery lost slightly more blood during the operation than those assigned to surgery alone (median loss, 1000 vs. Follow-up As of February 2001, surviving eligible patients without local recurrence had been followed for a median of 24.9 months (range, 1.1 to 56.0). Gta 5 update ps3. Of these patients, 87 percent were followed for at least one year, 54 percent for at least two years, 24 percent for at least three years, and 5 percent for at least four years.
Rates of survival and recurrence are presented here at a follow-up of two years. A reanalysis as of June 1, 2001, produced essentially the same results for all the major end points of the study.
Free Download Nike Ardila Rar. Events As of February 2001, 365 (20 percent) of the 1805 eligible patients had died. Of the 365 deaths, 61 occurred postoperatively, 231 were related to rectal cancer (growth of the primary tumor [in cases of macroscopically incomplete resection] or recurrence), and 70 were not related to rectal cancer. In three patients, the cause of death was unknown. Local recurrence occurred in 87 patients. Of these 87 patients, 45 (52 percent) had local recurrence alone, 28 (32 percent) had both local and distant recurrences, and 14 (16 percent) had local recurrence after distant metastasis was found at surgery (in 9 patients) or during follow-up (in 5). A total of 227 patients were found to have only distant recurrence.
Overall Survival The rate of overall survival at two years was 82.0 percent in the group assigned to radiotherapy before surgery and 81.8 percent in the group assigned to surgery alone (P=0.84) ( Figure 1 Rates of Overall Survival in the Population of 1805 Eligible Patients, According to Treatment Group. At two years, the rate of overall survival was 82.0 percent in the group assigned to radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). The hazard ratio for death in the group assigned to surgery alone as compared with the group assigned to preoperative radiotherapy was 1.02 (95 percent confidence interval, 0.83 to 1.25). Local Recurrence The rate of local recurrence at two years was 5.3 percent in the population of 1748 patients who underwent a macroscopically complete local resection. The rates of local recurrence at two years were 2.4 percent in the group assigned to radiotherapy before surgery and 8.2 percent in the group assigned to surgery alone (P. Discussion In this trial, we evaluated the efficacy of short-term preoperative radiotherapy combined with standardized total mesorectal excision in patients with resectable rectal cancer.
We found that radiotherapy before total mesorectal excision can improve local control of disease. Reported rates of local control after surgery for rectal cancer vary widely. In studies of conventional, nonstandardized surgery, usually with a minimal follow-up of five years, rates of local recurrence have been 15 to 45 percent. By contrast, surgeons who specialize in total mesorectal excision report local-recurrence rates of 7 percent or less. The low rate of local recurrence in the group assigned to total mesorectal excision only in our study (8.2 percent at two years) demonstrates that similar excellent results can be achieved by other surgeons at multiple centers after they are trained in the procedure. We found that preoperative radiotherapy further reduced the two-year rate of local recurrence from 8.2 percent to 2.4 percent, an indication of the value of preoperative radiotherapy when used in conjunction with standardized surgery. In the Swedish Rectal Cancer Trial, the reduction in the rate of local recurrence at five years from 27 percent in the surgery-only group to 11 percent in the radiotherapy-plus-surgery group improved the rate of overall survival at this time point from 48 percent in the surgery-only group to 58 percent in the combined-treatment group.
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Exhibition Marketing. Trade fairs make possible for business to undertake market research and to promote themselves. Promoting the formation and growth of markets and market sectors. Aug 08, 2020.
- > Integrated Circuits (ICs)
- > M3329-C1
- Buy Quantity:
- (1-10000 PCS)
Shipping & Payment
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M3329C H1 with PDF manufactured by ALI. The M3329C H1 is available in QFP Package, is part of the IC Chips. Ati radeon hd 3850 driver windows 10.
Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Preoperative Radiotherapy Combined with Total Mesorectal Excision for Resectable Rectal Cancer Ellen Kapiteijn, M.D., Corrie A.M. Marijnen, M.D., Iris D.
Nagtegaal, M.D., Hein Putter, Ph.D., Willem H. Steup, M.D., Ph.D., Theo Wiggers, M.D., Ph.D., Harm J.T. Rutten, M.D., Ph.D., Lars Pahlman, M.D., Ph.D., Bengt Glimelius, M.D., Ph.D., J. Van Krieken, M.D., Ph.D., Jan W.H.
Leer, M.D., Ph.D., and Cornelis J.H. Van de Velde, M.D., Ph.D., for the Dutch Colorectal Cancer Group N Engl J Med 2001; 345:638-646 DOI: 10.1056/NEJMoa010580. Results Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate.
The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent.
The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P. Local recurrence is a serious problem in the treatment of rectal cancer, since it causes disabling symptoms and is difficult to treat. There is a high incidence of local recurrence (15 to 45 percent) after conventional surgery, in which blunt dissection of the rectal fascia often fails to remove all the tissue that may bear tumor. In an attempt to improve local control and survival after conventional surgery, radiotherapy has been given. The only randomized trial that compared preoperative and postoperative radiotherapy showed the superiority of preoperative radiotherapy for local control.
The Swedish Rectal Cancer Trial found that preoperative radiotherapy also improved the rate of survival at five years. A recent meta-analysis concluded that the combination of preoperative radiotherapy and surgery, as compared with surgery alone, significantly improved overall survival and cancer-specific survival. The recognition that involvement of the circumferential margin by tumor cells is important in local recurrences has led to the general use of total mesorectal excision, in which the entire mesorectum is enveloped and resected by precise, sharp dissection. Improvements in local control with this technique have been shown, mainly in retrospective series.
In previous studies of radiotherapy for rectal cancer, surgery was not standardized. Since surgical technique is a key factor in the success of tumor control, standardization and quality control with respect to surgery are indispensable for evaluating the effects of adjuvant therapy. Optimal quality must also include the use of standardized methods of pathological examination.
Background Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable.
A prospective, randomized trial was organized by the Dutch Colorectal Cancer Group to investigate the efficacy of preoperative radiotherapy in combination with standardized total mesorectal excision in patients with rectal cancer. In this article, we present the results of the trial after a median follow-up of two years. Eligibility, Randomization, and Sample Size Patients were enrolled between January 1996 and December 1999. To be eligible, patients had to have histologically confirmed adenocarcinoma of the rectum, without evidence of distant metastases, and the inferior margin of the tumor had to be located not farther than 15 cm from the anal verge and below the level of S1–2. Patients with fixed tumors or tumors that were treated by local (transanal) resection were excluded. Patients with previous or coexisting cancer and those who had previously undergone large-bowel surgery, chemotherapy, or radiotherapy of the pelvis were also excluded.
After informed consent had been obtained, we randomly assigned the patients to treatment with preoperative radiation (5 Gy on each of five days) followed by total mesorectal excision or to total mesorectal excision alone. Randomization was performed at the central trial office and was based on permuted blocks of six, with stratification according to center and the expected type of operation (low anterior resection or abdominoperineal resection). The trial was approved by the medical ethics committees of all the participating hospitals.
The trial design and the calculation of the sample size have been described in detail elsewhere. Quality Control In the Netherlands, participating surgeons attended workshops and symposiums, saw instructional videotapes, and were monitored by specially trained instructor surgeons. At each hospital, the first five total mesorectal excisions were supervised by an instructor surgeon. Pathologists were trained to identify lateral spread of tumor according to the protocol of Quirke et al. The results of histopathological examination of the specimens were reviewed by a panel of supervising pathologists and a quality manager. Patients' eligibility and treatment and the details of follow-up were checked by study coordinators. Local and distant recurrences were confirmed radiologically or histologically and checked by a radiation oncologist.
In Sweden, the technique of total mesorectal excision was introduced on a national basis several years ago, as was the protocol of Quirke et al. The European Organization for Research and Treatment of Cancer participated in this trial under protocol 40971. Visits to other participating hospitals and specialists were made before the start of the trial to ensure the quality of treatment at those sites. For logistic reasons, no quality control with respect to radiotherapy, surgery, or pathological examination was performed outside the Netherlands during the trial. Statistical Analysis Case-report forms were sent to the central trial office, where information on the forms was entered into a data base and analyzed with SPSS statistical software (version 9.0 for Windows, SPSS, Chicago).
Chi-square tests were used to compare proportions. Mann–Whitney tests were used to compare quantitative and ordinal variables. Univariate analyses of survival were carried out by the Kaplan–Meier method, and the evaluation of differences between the two groups was performed with the log-rank test. The Cox proportional-hazards model was used to calculate hazard ratios and 95 percent confidence intervals in the univariate and multivariate analyses. A two-sided P value of 0.05 or less was considered to indicate statistical significance. The starting point for the analyses of survival and recurrence was the day of surgery.
Data on patients who were alive or free of recurrence were censored at the time of the last follow-up. The analysis of overall survival was performed on an intention-to-treat basis and thus included all the eligible patients. The rate of local recurrence was calculated on the basis of the number of eligible patients who underwent a macroscopically complete local resection. The rate of distant recurrence was calculated on the basis of the number of eligible patients who did not have distant metastasis at the time of surgery.
The overall rate of recurrence was calculated on the basis of the number of eligible patients who had macroscopically complete local resection without distant metastasis. Analyses of postoperative morbidity and mortality were based on the total number of eligible patients who underwent resection.
Patients A total of 1861 patients were randomly assigned to one of the two treatment groups. There were 1530 patients from 84 Dutch hospitals, 228 from 13 Swedish hospitals, and 103 from 11 other European and Canadian centers. Of these 1861 patients, a total of 56 were found to be ineligible before randomization, including 4 patients for whom there was no information on eligibility. Our analysis therefore included 1805 eligible patients. Of these, 1653 patients had a curative resection. Of the remaining 152 patients, 57 did not undergo a macroscopically complete local resection, and 95 were found to have distant metastasis at surgery ( Table 1 Characteristics of the Eligible and Ineligible Patients and Rates of Macroscopically Complete Local Resection, According to Treatment Group.
The characteristics of the 1805 patients who were eligible for the study and the features of their tumors were similar in the two treatment groups ( Table 2 Characteristics of the 1805 Eligible Patients. In 28 patients (2 percent), no tumor was found in the resected specimen, despite a preoperative biopsy that showed an adenocarcinoma. Major Violations Of the 897 eligible patients assigned to undergo radiotherapy before total mesorectal excision, 29 did not receive preoperative radiotherapy for the following reasons: known metastases (8 patients), carcinoma in situ (1), sigmoid carcinoma (3), a second cancer (1), withdrawal of informed consent (11), and physical limitations that made radiotherapy impossible (5).
Long-term preoperative radiotherapy was given to seven patients for locally advanced tumors. One patient was unable to tolerate surgery and was treated with long-term radiotherapy alone. Preoperative radiotherapy was discontinued in 14 patients, mainly because of neurotoxicity. Of the 908 eligible patients assigned to total mesorectal excision alone, 3 patients withdrew their informed consent and requested radiotherapy (5 Gy on each of five days), and 8 patients had advanced local tumors for which long-term preoperative radiotherapy was given. Postoperative adjuvant therapy was not allowed in patients who had microscopically tumor-free margins without spillage of tumor cells during the operation. Of 1759 eligible patients with available information on margins and tumor spillage, 1351 (77 percent) had tumor-free margins without tumor spillage.
Eighty-five of these patients (38 in the group assigned to radiotherapy and surgery and 47 in the group assigned to surgery alone) received adjuvant therapy (chemotherapy, radiotherapy, or chemoradiotherapy), which was a major protocol violation. Minor Violations Of the 846 eligible patients randomly assigned to preoperative radiotherapy who received the total dose of 25 Gy, the interval between the first day of radiotherapy and the day of surgery exceeded 10 days in 110 patients (13 percent).
In 127 of the patients (15 percent), the upper border of the treatment field was at the level of S1–2 instead of at the promontory, and in 161 of the patients undergoing an abdominoperineal resection (19 percent), the perineum was not included in the treated volume. Postoperative Morbidity and Mortality The median interval between randomization and surgery was 21 days in the group assigned to radiotherapy and surgery and 14 days in the group assigned to surgery alone. The patients assigned to radiotherapy and surgery lost slightly more blood during the operation than those assigned to surgery alone (median loss, 1000 vs. Follow-up As of February 2001, surviving eligible patients without local recurrence had been followed for a median of 24.9 months (range, 1.1 to 56.0). Gta 5 update ps3. Of these patients, 87 percent were followed for at least one year, 54 percent for at least two years, 24 percent for at least three years, and 5 percent for at least four years.
Rates of survival and recurrence are presented here at a follow-up of two years. A reanalysis as of June 1, 2001, produced essentially the same results for all the major end points of the study.
Free Download Nike Ardila Rar. Events As of February 2001, 365 (20 percent) of the 1805 eligible patients had died. Of the 365 deaths, 61 occurred postoperatively, 231 were related to rectal cancer (growth of the primary tumor [in cases of macroscopically incomplete resection] or recurrence), and 70 were not related to rectal cancer. In three patients, the cause of death was unknown. Local recurrence occurred in 87 patients. Of these 87 patients, 45 (52 percent) had local recurrence alone, 28 (32 percent) had both local and distant recurrences, and 14 (16 percent) had local recurrence after distant metastasis was found at surgery (in 9 patients) or during follow-up (in 5). A total of 227 patients were found to have only distant recurrence.
Overall Survival The rate of overall survival at two years was 82.0 percent in the group assigned to radiotherapy before surgery and 81.8 percent in the group assigned to surgery alone (P=0.84) ( Figure 1 Rates of Overall Survival in the Population of 1805 Eligible Patients, According to Treatment Group. At two years, the rate of overall survival was 82.0 percent in the group assigned to radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). The hazard ratio for death in the group assigned to surgery alone as compared with the group assigned to preoperative radiotherapy was 1.02 (95 percent confidence interval, 0.83 to 1.25). Local Recurrence The rate of local recurrence at two years was 5.3 percent in the population of 1748 patients who underwent a macroscopically complete local resection. The rates of local recurrence at two years were 2.4 percent in the group assigned to radiotherapy before surgery and 8.2 percent in the group assigned to surgery alone (P. Discussion In this trial, we evaluated the efficacy of short-term preoperative radiotherapy combined with standardized total mesorectal excision in patients with resectable rectal cancer.
We found that radiotherapy before total mesorectal excision can improve local control of disease. Reported rates of local control after surgery for rectal cancer vary widely. In studies of conventional, nonstandardized surgery, usually with a minimal follow-up of five years, rates of local recurrence have been 15 to 45 percent. By contrast, surgeons who specialize in total mesorectal excision report local-recurrence rates of 7 percent or less. The low rate of local recurrence in the group assigned to total mesorectal excision only in our study (8.2 percent at two years) demonstrates that similar excellent results can be achieved by other surgeons at multiple centers after they are trained in the procedure. We found that preoperative radiotherapy further reduced the two-year rate of local recurrence from 8.2 percent to 2.4 percent, an indication of the value of preoperative radiotherapy when used in conjunction with standardized surgery. In the Swedish Rectal Cancer Trial, the reduction in the rate of local recurrence at five years from 27 percent in the surgery-only group to 11 percent in the radiotherapy-plus-surgery group improved the rate of overall survival at this time point from 48 percent in the surgery-only group to 58 percent in the combined-treatment group.
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An effect of preoperative radiotherapy on overall survival has not yet been detected in our trial, probably because of the small number of local recurrences and the short follow-up. However, we believe that a median follow-up time of 24.9 months is sufficient to detect the effect of preoperative radiotherapy on local recurrences, 55 to 80 percent of which occur during the first 2 years after surgery, with the peak rate at 6 to 12 months. The beneficial effect of preoperative radiotherapy in our trial was observed for all tumor locations 15 cm or less from the anal verge and for all TNM stages. However, in a univariate subgroup analysis, the effect was not significant in patients who had tumors with an inferior margin more than 10 cm from the anal verge and in patients who had TNM stage I or IV tumors. Nevertheless, multivariate tests indicated that the treatment effect probably did not differ among subgroups defined according to tumor location, TNM stage, and treatment assignment.
Therefore, considering the difficulties involved in predicting the location of tumors high above the anal verge and in determining the TNM stage preoperatively, the decision not to irradiate before surgery should be carefully considered. Preoperative radiotherapy does not result in 'down-staging' and is therefore not suitable for locally advanced tumors. To avoid short-term irradiation of such tumors, we advocate accurate preoperative imaging (for example, computed tomography or magnetic resonance imaging). This lack of down-staging explains why short-term preoperative radiotherapy has no effect on sphincter preservation, which is often an end point in conventional trials of long-term radiotherapy. Concern has been expressed about the side effects of hypofractionated radiation. In the Stockholm I trial and Imperial Cancer Research Fund trial, postoperative mortality was higher among patients who received radiotherapy than among those who did not. In both trials, a suboptimal irradiation technique increased the treated volume considerably.
In the Swedish Rectal Cancer Trial, postoperative mortality did not increase with radiation, provided that radiotherapy was optimal. In our trial, there was no difference in in-hospital mortality between the two groups. In the Swedish Rectal Cancer Trial, however, there was more incontinence among patients who underwent preoperative irradiation and subsequently underwent a sphincter-preserving surgery. In conclusion, total mesorectal excision can significantly decrease the risk of local recurrence of resectable rectal cancer. This result was achieved in a large, multicenter trial that included extensive instruction and quality control of the surgical technique. In this large group of patients who underwent standardized surgery, short-term preoperative radiotherapy further reduced the risk of local recurrence.
Source Information From the Departments of Surgery (E.K., C.J.H.V.), Clinical Oncology (C.A.M.M.), and Medical Statistics (H.P.), Leiden University Medical Center, Leiden; the Departments of Pathology (I.D.N., J.H.J.M.K.) and Radiotherapy (J.W.H.L.), University Medical Center St. Radboud, Nijmegen; the Department of Surgery, Leyenburg Hospital, The Hague (W.H.S.); the Department of Surgery, University Hospital Groningen, Groningen (T.W.); and the Department of Surgery, Catharina Hospital, Eindhoven (H.J.T.R.) — all in the Netherlands; and the Departments of Surgery (L.P.) and Oncology (B.G.), Akademiska Sjukhuset, Uppsala, Sweden. Address reprint requests to Dr. Van de Velde at the Department of Surgery K6-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands,. References • 1 Wiggers T, de Vries MR, Veeze-Kuypers B. Surgery for local recurrence of rectal carcinoma.
Dis Colon Rectum 1996;39:323-328 • 2 Holm T, Cedermark B, Rutqvist LE. Local recurrence of rectal adenocarcinoma after `curative' surgery with and without preoperative radiotherapy.
Br J Surg 1994;81:452-455 • 3 Harnsberger JR, Vernava VM III, Longo WE. Radical abdominopelvic lymphadenectomy: historic perspective and current role in the surgical management of rectal cancer. Dis Colon Rectum 1994;37:73-87 • 4 Phillips RK, Hittinger R, Blesovsky L, Fry US, Fielding LP.
Local recurrence following `curative' surgery for large bowel cancer. The overall picture. Br J Surg 1984;71:12-16 • 5 Kapiteijn E, Marijnen C, Colenbrander AC, et al. Local recurrence in patients with rectal cancer, diagnosed between 1988 and 1992: a population-based study in the west Netherlands.
Eur J Surg Oncol 1998;24:528-535 • 6 Frykholm GJ, Glimelius B, Pahlman L. Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects. Dis Colon Rectum 1993;36:564-572 • 7 Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med 1997;336:980-987[Erratum, N Engl J Med 1997;336:1539.] • 8 Camma C, Giunta M, Fiorica F, Pagliaro L, Craxi A, Cottone M.
Preoperative radiotherapy for resectable rectal cancer: a meta-analysis. JAMA 2000;284:1008-1015 • 9 MacFarlane JK, Ryall RD, Heald RJ. Mesorectal excision for rectal cancer. Lancet 1993;341:457-460 • 10 Enker WE, Thaler HT, Cranor ML, Polyak T. Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 1995;181:335-346 • 11 Aitken RJ.
Soundcraft Vi3000 Review there. Mesorectal excision for rectal cancer. Br J Surg 1996;83:214-216 • 12 Martling AL, Holm T, Rutqvist LE, Moran BJ, Heald RJ, Cedermark B. Effect of a surgical training programme on outcome of rectal cancer in the County of Stockholm. Lancet 2000;356:93-96.
