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© 1999 American Society for Clinical Oncology Influence of the Interval Between Preoperative Radiation Therapy and Surgery on Downstaging and on the Rate of Sphincter-Sparing Surgery for Rectal Cancer: The Lyon R90-01 Randomized TrialFrom the Departments of Surgery and Radiation Oncology, Centre Hospitalier Lyon-Sud, Pierre-Bénite; Medical Statistic Laboratory, Hospices Civils de Lyon EA643, Site Lacassagne Lyon; Departments of Surgery and Gastroenterology, Hôpital de la Croix-Rousse-Lyon; Department of Surgery, Clinique Ste Marie-Thérèse-Bron; and Department of Surgery, Hôpital Edouard Herriot-Lyon, France. Address reprint requests to Pr J.P. Gérard, Centre Hospitalier et Universitaire Lyon-Sud, Hospices Civils de Lyon, 165 Chemin du Grand Revoyet, 69495 Pierre-Bénite Cedex, France; email gerard@ radiotherapie.univ-lyon1.fr.
PURPOSE: The optimal timing of surgery after preoperative radiotherapy in rectal cancer is unknown. The aim of this trial was to evaluate the role of the interval between preoperative radiotherapy and surgery. PATIENTS AND METHODS: Patients with rectal carcinoma accessible to rectal digital examination, staged T2 to T3, NX, M0, were randomized before radiotherapy (39 Gy in 13 fractions) into two groups: in the short interval (SI) group, surgery had to be performed within 2 weeks after completion of radiation therapy, compared with 6 to 8 weeks in the long interval (LI) group. Between 1991 and 1995, 201 patients were enrolled onto the study. RESULTS: A long interval between preoperative radiotherapy and surgery was associated with a significantly better clinical tumor response (53.1% in the SI group v 71.7% in the LI group, P = .007) and pathologic downstaging (10.3% in the SI group v 26% in the LI group, P = .005). At a median follow-up of 33 months, there were no differences in morbidity, local relapse, and short-term survival between the two groups. Sphincter-preserving surgery was performed in 76% of cases in the LI group versus 68% in the SI group (P = 0.27). CONCLUSION: A long interval between preoperative irradiation and surgery provides increased tumor downstaging with no detrimental effect on toxicity and early clinical results. When sphincter preservation is questionable, a long interval may increase the chance of a successful sphincter-saving surgery.
THE BASIC TREATMENT OF infiltrating T2-T3-T4 rectal cancer is radical surgery (with or without preservation of the sphincter). Despite complete surgical resection of the tumor, 10% to 40% of the patients will have local pelvic relapse.1-5 The value of additional radiotherapy has been assessed in trials using either pre- or postoperative irradiation. In North America, adjuvant postoperative radiochemotherapy6-8 is a standard treatment for pathologic T3/4 or pathologic N1/2/3 tumors, whereas in Europe9,10 and particularly in France,11 preoperative radiotherapy is preferred. The European Organization for Research and Treatment of Cancer4 and Stockholm12 randomized trials have shown a significant reduction in the local recurrence rate with preoperative radiotherapy. More recently, the Swedish Rectal Cancer Group5 has demonstrated an improvement in 5-year survival (58% in the radiotherapy-plus-surgery group v 48% in the surgery-alone group) with accelerated preoperative radiotherapy (25 Gy in five fractions over 1 week) followed by surgery within 1 week of the completion of radiotherapy. In Lyon, France, since publication of the results of Papillon13 and the Uppsala trial,14 which demonstrated that preoperative irradiation is more effective than postoperative radiotherapy, the standard treatment for rectal cancer has been accelerated preoperative irradiation followed by surgery. Between 1980 and 1990, 158 patients were treated with preoperative radiotherapy (30 to 39 Gy in 10 to 13 fractions over 2 to 3 weeks) followed by surgery,15 which resulted in an overall 5-year survival rate of 69%. Among these patients, 27 underwent surgery within the 2 weeks following radiotherapy, whereas 34 others underwent surgery 6 weeks or more after irradiation. The probability of a pathologic complete response at surgery was 6% and 15% for the short and long intervals, whereas the rates of sphincter-preserving surgery were 40% and 60%, respectively. The optimum interval between radiotherapy and surgery is unknown, but these nonrandomized, retrospective data led to the hypothesis that a long interval between radiotherapy and surgery allows sphincteric preservation more often because of improved downstaging. The aim of Lyon R90-01, a randomized, multicenter, prospective trial conducted between 1991 and 1995, was to evaluate the role of this interval on sphincteric preservation and local control.
Eligibility Criteria for Patient Entry Patients entering this study were required to have a histologically proven adenocarcinoma of the rectum accessible to digital rectal examination. Using the tumor-node-metastasis (TNM) staging system, the tumor had to be classified as either a T2/3, N0/1/2/3, or M0 resectable tumor and the surgeon was required to estimate the largest and perpendicular diameters of the tumor. Patients had to be fit for major surgery and could be eligible for either sphincter preservation or abdominoperineal resection at the time of diagnosis. Patients who could be treated with local excision were excluded from this trial. Pretreatment endorectal sonography was recommended and was performed in 179 cases by experienced gastroenterologists. When there was a discrepancy between the endorectal sonogram and the physical examination for tumor or node staging, the sonogram results were recorded as the clinical stage. A metastatic work-up was performed for each patient, using abdominal sonography, chest x-ray, serum carcinoembryonic antigen level, and liver function tests. The trial was conducted in full compliance with the standards of the Institutional Committee for the Protection of Human Subjects, in accordance with the Helsinki Declaration of 1975.
Radiotherapy The dose per fraction was 3 Gy, prescribed and specified at the ICRU point (intersection of the central axes of the three beams). The total dose was 39 Gy in 13 fractions delivered in 17 days.
Randomization
Sample Size and Statistical Method Rates of tumor response and sphincter preservation were compared by using Fisher's exact test. Survival was estimated by the product-limit procedure of Kaplan and Meier, and survival curves were compared with the log-rank test. No corrections were made for multiple significance tests.
Surgery and Histopathologic Examination
Follow-Up
Patient Characteristics Between February 1991 and December 1995, 210 patients were randomized, but nine patients (4.3%) were not eligible for the following reasons: three patients had distant metastases discovered before the start of radiotherapy, one patient had anal canal cancer, two patients had been randomized twice, one patient had an in situ cancer in a polyp, one patient died of intercurrent disease before any treatment, and one patient was lost to follow-up before surgery. Overall, 201 patients were assessable (Table 1). There were 29 participating centers (45 surgeons), five of which randomized more than 10 patients. One hundred two patients were randomized to the SI group and the 99 others were assigned to the LI group. There was no significant difference in age, sex, location of the tumor, and rectal endosonography findings between the two groups. Sigmoidoscopy confirmed the low level of the tumors, which were always accessible to rectal digital examination, with a median distance between the lower part of the tumor and the anal verge of 5.7 cm (range, 1 to 11 cm). Despite a strict preoperative work-up, 20 patients had distant metastasis or unresectable tumor at the time of surgery (nine patients in the SI group and 11 in the LI group).
Radiotherapy was well tolerated and never required hospitalization. All of the patients finished the planned course of radiotherapy. The median interval between radiotherapy and surgery was 13 days (range, 1 to 63 days) in the SI group and 46 days (range, 27 to 66 days) in the LI group. There were 39 protocol violations, 24 in the SI group and 15 in the LI group, with patients operated upon outside of the allocated period. In the SI group, 13 patients underwent surgery during the third week, nine patients during the fourth week, and two patients during the fifth and eighth weeks. In the LI group, six patients underwent surgery during the fourth week and nine during the fifth week. All patients were kept in the analysis, which was conducted by intent to treat.
Clinical Response
Pathologic Results
Type of Surgery Before randomization, surgeons were asked to describe the surgical procedure they intended to perform. In the population who underwent surgery with curative intent, in nearly all patients for whom sphincter-preserving surgery was deemed possible by the surgeon before randomization, the sphincter was preserved during the operation (94 of 99 cases). In the patients for whom the surgeon could not choose between sphincteric preservation and abdominoperineal resection or thought conservative surgery impossible, sphincter-saving surgery was performed in 43% of the patients in the SI group and in 44% of the patients in the LI group.
Postoperative Complications An anastomotic complication (fistula, intra-abdominal abscesses, or general peritonitis) occurred in 18% (12 of 67) of the SI patients versus 17% (13 of 77) in the LI group (no significant difference), requiring reoperation in 13% (nine of 67) and 10% (eight of 77) of the patients, respectively. A covering stoma was established initially in 57 of the 144 patients who had had sphincter preservation without any difference between the two groups (SI group: 27 of 67 v LI group: 30 of 77), but reoperations were more frequent in patients without a protective stoma (20 of 87 v three of 57, P = .01). In almost all cases (17 of 20), reoperation was done in order to perform a secondary intestinal diversion.
Short-Term Follow-Up Survival and Local Recurrence
There was a total of 18 local recurrences (9%). Of these recurrences, 17 occurred in patients treated with sphincter-preserving surgery (17 of 144, 11.8%) and one occurred in a patient treated with abdominoperineal resection (one of 67, 1.5%). In the SI group, there was a 9% rate of local recurrence that was identical to the rate for local recurrence for the 144 patients in the LI group who received sphincter-preserving surgery. A total of 119 patients had the distance from the tumor to the distal resection margin measured on the fixed operative specimen. Of the 119 patients, 43 (23 in the SI group and 20 in the LI group) had a distal resection margin of less than 15 mm. Seven (16.3%) of these 43 patients had a local recurrence. In the patients who had sphincter preservation where conservative surgery did not seem possible initially, local recurrence occurred in 12% (one of 17 in SI group v three of 17 in the LI group.) Among the 112 patients who are alive without colostomy, anal function was evaluated by the surgeon in 82 patients and was considered to be normal in 64 cases (29 of 39 in the SI group v 35 of 43 in the LI group).
The aim of this trial was to evaluate whether delayed surgery after radiotherapy could increase the chances of sphincteric preservation. Unlike investigators of other trials,4,5,14 we excluded patients with high rectal or rectosigmoid cancer because sphincter-saving surgery is nearly always possible in these patients. This study was strictly limited to patients with rectal cancers palpable on digital rectal examination for whom sphincter preservation is questionable. Despite a trend toward more conservative surgery in the LI group, no significant difference was demonstrated between the two groups (68% in the SI group v 76% in the LI group). The difference was larger for the patients with tumors of the lower rectum (23% in the SI group v 38% in the LI group) and for those treated according to protocol allocation (23% in the SI group v 41% in the LI group), but these differences were not significant and are not representative of the original randomized groups. The duration of the interval between preoperative radiation and surgery had no influence on the rate of conservative surgery in comparison to the surgeon's intent before randomization. This trial demonstrated two points. First, a longer interval between the completion of radiotherapy and surgery increases the likelihood of clinical and pathologic downstaging: a complete or partial primary tumor clinical response was more frequent in the LI group (53.1% in the SI group v 71.7% in the LI group). Tumors with no or only a few residual tumoral cells were more frequent in the LI group (10% in the SI group v 26% in the LI group). These results are similar to those reported in the literature: pathologic downstaging to a pathologic CR or with few residual tumoral cells was found in 30% to 35% of patients when surgery was performed 1 to 2 months after the completion of radiotherapy10,17-20 compared with 3% to 7% of patients when the operation was performed just after radiotherapy.9,21,22 Clinical response was also higher with a long interval, but the surgeon's estimation of the size of the tumor on digital rectal examination is subject to large error. Second, a longer interval between radiotherapy and surgery does not increase the incidence of complications. The postoperative mortality rate was 3.5% in our series and similar to the mortality rates reported in the literature when preoperative radiotherapy had been administered (3% to 7%).4,5,9,17,21-23 The morbidity, tolerance, and side effects of treatment seemed acceptable. An anastomotic complication occurred in 17% of the patients with conservative surgery, but we included asymptomatic fistulae discovered during radiologic investigations, intra-abdominal abscesses, and general peritonitis. The incidence of fistula after preoperative radiotherapy is quite variable in the literature (3% to 24%)9,10,12,21,24-26 because some teams calculate its incidence in the overall population (including patients with abdominoperineal resections), include only symptomatic fistulae, or classify separately pelvic sepsis or intra-abdominal abscesses, which are due in almost all cases to anastomotic complications. Preoperative radiotherapy may not be responsible for this high incidence of fistulae, because in different randomized trials (preoperative radiotherapy v surgery alone or with postoperative radiotherapy),9,10,12,21 the incidence of anastomotic complications was not increased when preoperative radiotherapy was administered. Radiotherapy given with curative intent uses standard doses per fraction close to 2 Gy. In this trial, the dose per fraction was 3 Gy. It is possible that this higher dose per fraction may increase radiation toxicity, but this is true mainly for chronic complications. The Swedish Group, which uses a dose of 4 Gy per fraction, did not observe an increased risk of anastomotic complication after conservative surgery and preoperative radiation therapy.5 The optimum dose per fraction remains controversial, but it is unlikely that 3 Gy per fraction significantly increased the rate of anastomotic complications, given the Swedish data. In our series, the high incidence of anastomotic complications could be explained by the low location of the tumors, our conservative approach, and, finally, the inclusion of 45 different surgeons with varying experience.27,28 We believe that low rectal cancers treated by preoperative radiotherapy and conservative surgery should be protected by a diverting stoma, excepted for cases where a modified Babcock procedure (delayed coloanal anastomosis)29 is used. Our median follow-up time was short (33 months), and no differences in survival and local recurrence have been observed between the two groups. In our series, all patients had a positive digital rectal examination (corresponding to a low or middle rectal cancer), and the rate of sphincter preservation was 72%. This rate of conservation is higher than in other series using preoperative radiotherapy (14% to 50%),4,5,9,10,12,14,17 although their inclusion criteria were less restrictive (tumors within 15 cm from the anal verge) than in our series. Our sphincter preservation rate was similar to that reported in some single-institution series (75% to 81%),18,20,24,30 but these series are associated with a local recurrence rate of 12% to 22%.18,24,26 In the Stockholm trial reported by Holm et al,27 sphincter preservation does not seem to increase the risk of local failure (11% in anterior resection v 16% in abdominoperineal resection), but the percentage of sphincter preservation in this series was low (40%). We have not observed an excessive increase of local recurrences in patients with a distal resection margin on the fixed specimen that was less than 15 mm from the tumor. It has generally been recommended that the surgeon leave a distal margin of at least 2 cm from the tumor2,3,11,22,31-34 to yield at least a 1-cm margin, as measured by the pathologist.33 Nevertheless, some teams suggest that transgression of the 2-cm rule in the course of sphincter preservation surgery will not result in excessive local failure.18,30,33,35-37 On the basis of the results of our trial, we suggest the following policy: In patients with tumors located more than 6 cm from the anal verge (sphincter preservation almost certain) or in patients with tumors very close to the anus or involving it (abdominoperineal resection required), the interval between radiotherapy and surgery probably has no influence on the type of surgery. The date of operation could be decided according to the surgeon's or patient's preference, but it is our current practice to delay surgery for 4 weeks after radiation is completed. For other tumors, when sphincteric preservation is questionable, it is possible to delay the operation until the fifth or sixth week following the end of radiotherapy. Such a delay is not detrimental to the patient, and increased downstaging may improve the possibility of sphincter-saving surgery. In conclusion, this multicenter prospective randomized trial including only patients with low or middle rectal cancers demonstrates that there is an increased probability of downstaging of the tumor when there is a long interval between the completion of radiation therapy and surgery. Toxicity and early clinical results are not altered by delayed surgery. There was a nonsignificant trend for increased sphincter preservation with a longer interval.
Supported by the Ligue Nationale de la Lutte Contre le Cancer and the departmental committees of the Ain, Rhône, and Saône et Loire, and by the French Programme Hospitalier de Recherche Clinque Program of the Ministry of Health. We are deeply grateful to Professor Ian Tannock and Dr Suzanne Russo for their advice and support in writing this article.
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O'Connell M Martenson J, Wieand H, et al: Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med331:502-507, 1994 8. Krook JE, Moertel CG, Gunderson LL, et al: Effective adjuvant therapy for high risk rectal carcinoma. N Engl J Med324:709-715, 1991[Abstract] 9. Dahl O, Horn A, Morild I, et al: Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Cancer66:2286-2294, 1990[Medline] 10. Medical Research Council Rectal Cancer Working Party: Randomised trial of surgery alone vs. radiotherapy followed by surgery for potentially operable locally advanced rectal Cancer. Lancet348:1605-1610, 1996[Medline] 11. Anonymous: Conférence de consensus (Paris 1-2 Décembre 1994): Le choix des thérapeutiques du cancer du rectum. Lettre Cancer4:12-17, 1995 12. Stockholm Rectal Cancer Study Group: Preoperative short-term radiation therapy in operable rectal carcinoma: A prospective randomized trial. Cancer66:49-55, 1990[Medline] 13. Papillon J: Present status of radiation therapy in the conservative management of rectal cancer. Radiother Oncol17:275-283, 1990[Medline] 14. Frykholm GC, 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 Rectum36:564-572, 1993[Medline] 15. Fric D, Ayzac L, Coquard R, et al: Radiotherapie pré-operatoire accélérée du cancer du rectum: Analyse d'une série de 158 patients. Lyon Chir92:79-96, 1996 16. Spiessl B, Beahrs OH, Hermanek P, et al: T.N.M. Atlas: Illustrated Guide to the T.N.M. Classification of Malignant Tumors (ed 3, 2nd rev). Berlin, Germany, Springer-Verlag, 1992 17. Hyams DM, Mamounas EP, Petrelli N, et al: A clinical trial to evaluate the worth of preoperative multimodality therapy in patients with operable carcinoma of the rectum. Dis Colon Rectum40:131-139, 1997[Medline] 18. Gouillat C, Berard P, Chavatte PY, et al: Traitement du cancer du bas rectum par résection rectale conservatrice après irradiation pré-opératoire: Résultats à long terme d'une étude prospective. Gastroenterol Clin Biol (in press) 19. Berger C, de Muret A, Garaud P, et al: Preoperative radiotherapy for rectal cancer: Predictive factors of tumor downstaging and residual tumor cell density—Prognosis implications. Int J Radiat Oncol Biol Phys37:619-627, 1997[Medline] 20. Grann A, Minsky BD, Cohen AM, et al: Preliminary results of preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for clinically resectable T3 rectal cancer. Dis Colon Rectum40:512-522, 1997 21. Pahlman L, Glimelius B: Pre or postoperative radiotherapy in rectal and rectosigmoid carcinoma. Ann Surg211:187-195, 1990[Medline] 22. Izar F, Fourtanier G, Pradere B, et al: Pre-operative radiotherapy as adjuvant treatment in rectal cancer. World J Surg16:106-112, 1992[Medline] 23. Holm T, Rutqvist LE, Johansson H, et al: Postoperative mortality in rectal cancer treated with or without radiotherapy: Causes and risk factors. Br J Surg83:964-968, 1996[Medline] 24. Mohiuddin M, Ahmad N, Marks G: A selective approach to adjunctive therapy for cancer of the rectum. Int J Radiat Oncol Biol Phys27:765-772, 1993[Medline] 25. Holm T, Rutqvist LE, Johansson H, et al: Abdominoperineal resection and anterior resection in the treatment of rectal cancer: Results in relation to adjuvant preoperative radiotherapy. Br J Surg82:1213-1216, 1995[Medline] 26. Wagman R, Minsky BD, Cohen AM, et al: Sphincter preservation with pre-operative radiation therapy (R.T.) and coloanal anastomosis: Long term follow-up. Int J Radiat Oncol Biol Phys 39:S167, 1997 (abstr) 27. Holm T, Johansson H, Cedermark B, et al: Influence of hospital- and surgeon-related factors on outcome after treatment of rectal cancer with or without preoperative radiotherapy. Br J Surg84:657-663, 1997[Medline] 28. Simons AJ, Ker R, Groshen S, et al: Variations in treatment of rectal cancer: The influence of hospital type and caseload. Dis Colon Rectum40:641-646, 1997[Medline] 29. Baulieux J, Adham M, Nasser Y, et al: Anastomose colo-anale "différée" sans colostomie temporaire de protection pour cancer du bas rectum après radiothérapie pré-opératoire. Lyon Chir92:87-93, 1996 30. Rouanet P, Fabre JM, Dubois JB, et al: Conservative surgery for low rectal carcinoma after high-dose radiation. Ann Surg221:67-73, 1995[Medline] 31. Abel M, Rosen L, Kodner IJ, et al: Practice parameters for the treatment of rectal carcinoma: Supporting documentation. Dis Colon Rectum36:989-1005, 1993[Medline] 32. Kwok SPY, Lau WY, Leung KL, et al: Prospective analysis of the distal margin of clearance in anterior resection for rectal carcinoma. Br J Surg83:969-972, 1996[Medline] 33. Vernava AM, Moran M, Rothenberger DA, et al: A prospective evaluation of distal margins in carcinoma of the rectum. Surg Gynecol Obstet175:333-336, 1992[Medline] 34. Williams NS: The rationale for preservation of the anal sphincter in patients with low rectal cancer. Br J Surg71:574-581, 1984 35. Marks G, Mohiuddin M, Eitan A, et al: High-dose preoperative radiation and radical sphincter-preserving surgery for rectal cancer. Arch Surg126:1534-1540, 1991[Abstract] 36. Andreola S, Leo E, Belli F, et al: Distal intramural spread in adenocarcinoma of the lower third of the rectum treated with total rectal resection and coloanal anastomosis. Dis Colon Rectum40:25-29, 1997[Medline] 37. Bokey EL, Chapuis PH, Dent OF, et al: Factors affecting survival after excision of the rectum for cancer. Dis Colon Rectum40:3-10, 1997[Medline] Submitted December 11, 1998; accepted April 12, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test with a two-sided significance level of .05 will have 80% power to detect this difference when the sample size in each group is 103. As a result, 206 patients were required in this trial. 
