Distal Margin Requirements After Preoperative Chemoradiotherapy for Distal Rectal Carcinomas: Are 1cm Distal Margins Sufficient?

Annals of Surgical Oncology, 8(2):163 169 Published by Lippincott Williams & Wilkins 2001 The Society of Surgical Oncology, Inc. Distal Margin Requirements After Preoperative Chemoradiotherapy for Distal Rectal Carcinomas: Are 1cm Distal Margins Sufficient? Boris Kuvshinoff, MD, Irfan Maghfoor, MD, Brent Miedema, MD, Mark Bryer, MD Steven Westgate, MD, John Wilkes, MD, and David Ota, MD Background: Sphincter-sparing alternatives to abdominoperineal resection (APR) in the treatment of rectal cancer often are underused out of concern for inadequate distal margins and local failure. The present study addresses whether sphincter-sparing techniques with distal margins 1 cm adversely influence oncological outcome in patients given preoperative chemoradiotherapy. Methods: Thirty-seven patients with rectal cancer 8 cm from the anal verge were enrolled in the study. Preoperative external beam radiotherapy (5400 Gy) was administered together with continuous infusion of 5-fluorouracil (300 mg/m 2 /day). Surgical resection was performed in 36 patients with pathological assessment of tumor response and margins. Patients with sphinctersparing resection and distal margins 1cmor 1 cm and those who underwent APR were compared. Results: Thirty-six patients completed preoperative chemoradiotherapy, with successful sphincter-preservation in 28 patients. At a median follow-up of 33 months, there were 12 recurrences overall, which included 11 distant failures and four pelvic failures. Disease-free survival (DFS) was not different between those who had an APR compared with sphincter-sparing resection with distal margins 1 cm. DFS was worse (P.02) when radial margins were 3 mm compared with 3 mm. Conclusions: Sphincter preservation is feasible in more than 75% of patients with tumors 8cm from the anal verge after preoperative chemoradiotherapy. Sphincter-sparing surgery with distal margins 1 cm can be used without adversely influencing local recurrence or DFS. Limited radial margins ( 3 mm), however, are associated with increased disease recurrence. Key Words: Rectal cancer Distal margins Radiation therapy Chemotherapy Sphincter preservation. Received April 14, 2000; accepted September 25, 2000. From the Departments of Surgery, Medical Oncology and Radiology, University of Missouri Ellis Fischel Cancer Center and Harry S. Truman VAMC, Columbia, Missouri. Presented at the 1998 Annual Meeting of the Society for Surgery of the Alimentary Tract, New Orleans, Louisiana, May 18, 1998. Address correspondence and reprint requests to: Boris W. Kuvshinoff, MD, FACS, Ellis Fischel Cancer Center, 115 Business Loop 70 W, Columbia, MO 65203; Fax: 573-884-6054; E-mail: Kuvshinoffb@health.missouri.edu The standard operative procedure for carcinoma of the lower rectum is an abdominoperineal resection (APR) with a permanent sigmoid colostomy. If sphincter preservation is a desirable goal, then a new treatment paradigm is needed. Recent studies have shown that there is considerable regression of rectal carcinomas with preoperative chemoradiotherapy, and this may offer an important adjunct for sphincter preservation. 1 5 Advances in surgical technique that include total mesorectal excision (TME) with transanal transection and anastomosis also have improved local control and preservation of sphincter function. 6,7 It would seem reasonable that if preoperative therapy can downstage rectal carcinomas significantly, then the use of TME with distal margin 2cm should not compromise local control and would permit sphincter preservation for many distal rectal cancers. The purpose of this study was to determine if local recurrences and survival are affected adversely with a distal margin 1 cm after preoperative chemoradiotherapy. The regimen of 5-fluorouracil (5-FU) and concurrent external beam radiotherapy has been used success- 163

164 B. KUVSHINOFF ET AL. fully for both preoperative and postoperative adjuvant therapy in stage II and III rectal adenocarcinomas. 5,8 15 Our aim was to use an aggressive preoperative chemoradiotherapy regimen to permit a sphincter-preserving operation in patients with rectal carcinoma who otherwise would require an APR, without compromising local disease control or disease-free survival. METHODS Patient Eligibility Requirements All eligible patients treated at the University of Missouri Ellis Fischel Cancer Center, Harry S. Truman VAMC, and Mid-Missouri Medical Foundation between 1993 and 1997 who had biopsy-proven primary (n 34) or recurrent (n 3) rectal adenocarcinoma within 8 cm from the anal verge were enrolled in the study. These patients were judged by the attending surgeon to likely require an APR for adequate treatment. Initial evaluation included a complete history and physical, digital rectal exam, complete colonoscopy, rigid proctoscopy, chest x-ray, and computed tomography of the abdomen and pelvis. Transrectal ultrasound data were available in only five patients late in the study period. Patients with distant metastases, severe comorbid disease, poor performance status (Zubrod 2), concurrent malignancy other than skin cancer, or active alcohol abuse were ineligible for this trial. This protocol was approved by the University of Missouri Institutional Review Board and included informed patient consent. Preoperative Chemoradiotherapy External beam radiotherapy consisted of 6- or 15-MV photons generated by a linear accelerator with a targetto-axis distance of 100 cm. Patients were treated primarily with a three- or four-field plan on an open tabletop in the prone position, to exclude the small bowel from the radiation portal. The top of the field was placed at the sacral promontory, with lateral borders 1.5 cm outside the bony pelvis and the inferior margin 3 cm below gross tumor. A dose of 45 Gy was delivered, given at 1.8 Gy/day for 5 days a week in 25 fractions followed by a 9-Gy boost to the tumor in 5 fractions. Patients were seen weekly to assess tolerance, weight, and complete blood counts. 5-FU was administered concomitantly during the 6 weeks of radiation therapy. A central venous access device was used and flushed with 100 U heparin on weekends. The dose of 5-FU was 300 mg/m 2 /day, delivered as a continuous infusion from Monday morning to Friday afternoon. Acute toxicity from the 5-FU was monitored closely, and appropriate dose modifications were made when NCI grade 3 toxicity or higher was identified. Nonhematologic toxicity was monitored by close clinical observation. Hematologic toxicity, mainly anemia and leukopenia, was assessed weekly by following the hemoglobin and white blood cell count, respectively. Patients with hemoglobin 8.0 gm/dl were considered for transfusion. A white blood cell count 2.0 thou/cu mm was defined as grade 3 leukopenia, and at that level chemotherapy was withheld. Operative Therapy Surgery was performed 5 to 8 weeks after completion of the chemoradiotherapy. Operative strategies included low anterior resection, transsacral resection, or APR. Total mesorectal excision was performed as described by MacFarlane et al. 6 and Enker et al. 7 A proximal diverting loop ileostomy or colostomy was performed routinely if the surgeon performed a coloanal anastomosis. Both perioperative and long-term morbidity were recorded. After surgery, four cycles of bolus 5-FU (425 mg/m 2 / day, days 1 5) and leucovorin (20 mg/m 2 /day, days 1 5) were administered every 4 weeks. Pathological Assessment of the Resected Specimen The distal margin was determined by measuring the distance of the fixed tissue from the lowest edge of the tumor or ulcer to the distal cut edge. Tumor involvement of the distal edge also was assessed by intraoperative frozen section. In four patients the distal margin was histologically involved, necessitating further distal resection until microscopically free of tumor. If a tumor-free distal margin could not be obtained, then an APR was performed. The primary site was identified for the pathologist at the time of resection, and serial sections were taken to assess the extent of residual disease. A complete response was noted when no viable tumor or residual mucin could be identified. Radial margins also were assessed to the nearest millimeter from any viable tumor to the closest radial inked surface. Radial margins in the cases of complete responses were assessed from the residual fibrosis. Standard hematoxylin and eosin staining was used to assess lymph nodes. Statistical Analysis Disease-free survival curves were generated for the 36 patients who completed therapy by using the LIFETEST procedure from the statistical package SAS (SAS/STAT Release 6.12, SAS Institute, Cary, NC). Predictors of survival were analyzed independently, because the study size was insufficient to fit multivariable models. Survival curves were compared by using the log-rank test, with significance reported at the P.05 level.

DISTAL MARGINS FOR RECTAL CANCER 165 RESULTS There were 37 patients with biopsy-proven distal rectal adenocarcinomas ( 8 cm from the anal verge) enrolled in the protocol with a median follow-up of 33 months. The median age of the group was 60 years (range, 23 89 years), and there were 26 men and 11 women. All but one patient completed the entire course of preoperative radiotherapy. External-beam radiation was stopped in this patient at 5040 cgy due to small bowel in the radiation field. 5-FU was discontinued in two patients because of grade 3 GI toxicity, one patient with both grade 3 skin and GI toxicity, and another patient with grade 4 cardiac toxicity (Table 1). Sphincter preservation was successful in 28 patients (76%), and APR was required in 8 patients (24%). Two patients who initially underwent sphincter preservation subsequently required permanent colostomy, one due to fecal incontinence and the other as a result of a persistent rectovaginal fistula. The three patients who presented with recurrent rectal cancer all were able to undergo sphincter-sparing surgery. Significant perioperative morbidity occurred in 4 of 36 patients (11%). These complications included an anastomotic leak with subsequent rectovaginal fistula, a small bowel obstruction treated nonoperatively, a prolonged ileus, and one episode of urosepsis. There was no perioperative mortality in this series. Long-term morbidity included three patients with anastomotic strictures that required rectal dilation. Four patients did not receive the four planned cycles of postoperative adjuvant chemotherapy based on their 5-FU intolerance during radiation therapy. Five patients had a complete response (14%) whereas 13 patients (35%) had only microscopic residual disease on final pathological assessment. The median distance of the lowest edge of the tumor to the anal verge for patients who underwent sphincter preservation was 5 cm (range, 3.5 8 cm) and for APR 3.8 cm (range, 2.0 7.0 cm). The median distal margin for patients who underwent sphincter preservation was 1.0 cm (range, 0.1 5.5 cm) compared with 2.5 cm (range, 0.5 5.6 cm) for APR (Table 2). TABLE 1. Preoperative chemoradiotherapy and maximal treatment toxicity Grade 1 Grade 2 Grade 3 Grade 4 Patients Gastrointestinal 22 6 3 0 31 Skin 12 0 1 0 13 Genitourinary 3 0 0 0 3 Mucosal 1 1 0 0 1 Cardiac 0 0 0 1 1 Hematological 1 0 0 0 1 Total occurrences 39 7 4 1 The influence of distal margins after sphincter preservation or APR on disease-free survival is shown in Figure 1. There were 16 patients whose distal margins were 1 cm, 12 patients with distal margins 1 cm, and 8 who underwent APR. There were 12 recurrences overall, 5 (62%) in the group that underwent APR, six (38%) in those with distal margins 1 cm, and one (8%) when distal margins exceeded 1 cm. Disease-free survival was significantly different between the three groups (P.03), although there was no difference between APR and the sphincter-sparing group with margins 1 cm. Significant improvement in disease-free survival was observed in the sphincter-sparing group with 1 cm distal margins compared with APR (P.01) but not when compared with sphincter-sparing with subcentimeter margins (P.06). Pelvic or local recurrences were documented in four patients, three who underwent APR (37.5%) and one who had sphincter preservation (3.6%). Among nine patients with distal margins 5 mm, there was only one local recurrence. This patient had 21 positive lymph nodes on pathological assessment and failed throughout her pelvis. Consequently, there were no isolated intraluminal recurrences in the sphincter-preservation group. Two of the patients with pelvic failures in the APR group presented initially as a local recurrence. Only one pelvic recurrence was seen in the absence of metastatic disease, in a patient who had an APR but with a positive radial margin. Radial margins were reported in 32 patients who had evidence of residual disease or ulcerated scar after chemoradiotherapy. Radial margins were considered positive in four patients, all of whom underwent APR. Pathological assessment of radial margins demonstrated a median distance of 0.5 cm for both the sphincter preservation group (range, 0.1 1.0 cm) and the APR group (range, 0 0.7 cm; Table 2). Disease-free survival was significantly worse (P.02) when radial margins were 3 mm (Fig. 2). All four patients with positive radial margins have recurred in the pelvis but only one in the absence of prior or concurrent metastatic disease. Among the patients with 1-mm radial margins, two of five have recurred with distant disease only. Lymph nodes that contained adenocarcinoma were demonstrated in the pathological specimen in five patients from the APR group with four recurrences and in seven patients from the sphincter preservation group with two recurrences. There were six recurrences among the 25 patients without pathological evidence of lymph node metastases. Three of the four pelvic recurrences occurred among patients with positive nodes. There was no difference (P.17) in disease-free survival based on the pathological finding of lymph node metastases (Fig. 3).

166 B. KUVSHINOFF ET AL. TABLE 2. Patients Assessment of surgical margins according to surgical treatment Median distance from anal verge (cm) Median distal margin (cm) Median radial margin (cm) Abdominoperineal resection 8 3.8 (2.0 7.0) 2.5 (0.5 5.6) 0.5 (0 0.7) Sphincter-sparing 28 5 (3.5 8) 1.0 (0.1 5.5) 0.5 (0.1 1.0) a a n 24. DISCUSSION Despite the increasing use of sphincter preservation for rectal cancers, nearly 50% of patients still undergo APR. 16 In many circumstances, APR is performed out of concern for adequate distal margins despite mounting evidence that more limited distal margins may be appropriate. Although distal margins as great as 5 cm were advocated in the past, 17 more recent data suggest that 2 cm distal margins are adequate. 18 23 Paty et al. 23 found no increase in pelvic recurrence when the distal margin was 2 cm compared with 2 cm. A number of authors also have shown that distal margins 2cmdo not increase local recurrence or compromise 5-year survival compared with distal margins 2 cm. 19,20 A number of clinical pathological studies that examined distal intramural spread suggest that smaller distal margins, even 1 cm, may be adequate in the majority of cases. This is supported by pathological evidence that distal intramural spread rarely exceeds 1 2 cm. 24,25 When significant distal spread does occur, long-term survival is affected adversely, despite treatment with APR. 19 In a recent study of 505 patients who underwent curative rectal resection, only 3.8% showed evidence of microscopic distal spread. 22 Moreover, most of these had distal spread 1 cm. The presence of distal spread was associated with decreased survival primarily due to distant disease recurrence. Although mounting evidence supports the use of 2-cm distal margins in rectal cancer resections, the use of centimeter and subcentimeter margins remains quite controversial. Karanjia et al. 26 compared patients who underwent anterior resections with TME who had 1 cm and 1 cm distal margins. The authors found no difference in either local recurrence or survival between the two groups. In contrast, Vernava et al. 21 found a decreased 5-year survival and increased anastomotic recurrence rate when distal margins were 8 mm. In the present study, we accepted even smaller distal margins, often 5 mm. Patients with margins 1 cm had an equivalent local recurrence rate and disease-free survival when compared with those with 1 cm margins. Our study does differ from many earlier reports that examined distal margins, because we used preoperative chemoradiotherapy. The effective downstaging of these lowlying tumors might well include the pathological clearance of distal microscopic spread. FIG. 1. Disease-free survival based on procedure (sphinctersparing [SS] or abdominoperineal resection [APR]) and distal margins (dm) (SS, 1cmor 1 cm). Although there was a difference when all three groups were considered together (P.03), there was no significant difference between APR and SS with distal margin 1cm(P.27) or between the two SS groups (P.06) by log-rank analysis.

DISTAL MARGINS FOR RECTAL CANCER 167 FIG. 2. Disease-free survival for pathological radial margins (RM) 3 mm (dashed line) and 3 mm (solid line). Log-rank comparison is significant (P.02). Pelvic recurrences were seen in 4 of 36 (11%) patients, which is in keeping with previous reports that used preoperative radiotherapy. 5,8 10 When only patients with primary disease were considered, pelvic recurrences were seen in 3 of 33 (6%) patients. We noted no isolated pelvic recurrences in our series, but rather pelvic recurrences occurred in conjunction with distant metastatic disease. A number of factors may have contributed to the low incidence of pelvic recurrences in this high-risk group. We used a dose of external beam radiation therapy (5400 cgy) that is higher than generally reported (4500 5040 cgy). Concurrent infusional 5-FU also was used, which has been shown to enhance the effects of external beam radiotherapy. 27 The efficacy of preoperative chemoradiotherapy is demonstrated in the current study by the 14% complete response rate and the observation that an additional 35% of the patients had only microscopic foci of residual disease on final pathological assessment. This clinical response likely contributed to successful sphincter preservation in the majority of patients who otherwise would have required an APR. Attention to the pathological assessment of distal margins FIG. 3. Influence of pathological (routine hematoxylin and eosin staining) lymph node status on disease-free survival. Note that pathological assessment was performed after chemoradiation and surgery.

168 B. KUVSHINOFF ET AL. at the time of surgery also may be a factor. If microscopically free distal margins were not documented by frozen section, then sphincter preservation was abandoned and an APR performed. The use of TME also must be considered as a contributing factor in reducing pelvic recurrences. TME, a technique of sharp dissection that incorporates the entire mesorectum in the resected specimen, has been championed by MacFarlane et al. 6 and Enker, 7 with reported local recurrence rates as low as 5% to 8% in high-risk patients. Quirke et al. 28 demonstrated that radial spread into the mesorectum is a common occurrence. Sharp dissection along the parietal pelvic fascia ensures resection of these small ( 5 mm) occult nodal metastases that otherwise might be left behind. In the present study we took special care to assess radial margins. In patients with radial margins 3 mm, there was an increase in overall recurrence rate (53%, 8 of 15) compared with radial margins 3 mm (12%, 2 of 17). This suggests that radial margins are a more important predictor of disease recurrence and survival than distal margins. On the contrary, the presence or absence of positive lymph nodes and tumor response to preoperative chemoradiotherapy did not have prognostic significance. This may be attributed to both the relatively small number of cases analyzed and the high incidence of clinical downstaging that occurred before pathological assessment. In the current study there was an increased recurrence rate with APR (62.5%) compared with sphincter preservation (25%). The increased risk of recurrence for patients who undergo APR has been described previously and likely reflects the worse prognosis attributed to tumors of the low rectum compared with midrectal tumors. 7 All eight cases that involved APR in the present series involved lower-third rectal tumors, as did most of the group with distal margins 1 cm. When patients who underwent sphincter-sparing surgery with distal margins 1 cm were compared with those who had an APR, no difference in disease-free survival was found. This suggests that the location of the tumor may be a more important prognostic factor than the type of operation performed. The treatment schema in the present study of preoperative chemoradiotherapy followed by surgery was well tolerated. Despite the use of slightly higher doses of external beam radiotherapy together with infusional 5-FU, we did not see toxicity beyond that reported in other studies. 4,29,30 Most of the toxicity in the present study was grade 1 and easily manageable. Although a formal functional assessment of bowel function was not performed, the majority of patients were content with their postoperative fecal continence. The present study demonstrates that sphincter preservation is feasible in approximately 75% of patients after preoperative chemoradiotherapy for low-lying rectal cancers that otherwise would require APR. Distal margin clearance 1 cm was used often in the present series without adversely affecting pelvic recurrence or diseasefree survival. Despite margins as small as 1 mm, there was only one pelvic recurrence out of 28 patients (3.6%) who underwent sphincter preservation. Radial margins seem to be a more important prognostic indicator of disease recurrence. 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