Long-Term Results of Reirradiation for Patients with Recurrent Rectal Carcinoma

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1 1144 Long-Term Results of Reirradiation for Patients with Recurrent Rectal Carcinoma Mohammed Mohiuddin, M.D. 1,2 Gerald Marks, M.D. 3 John Marks, M.D. 3 1 Department of Radiation Medicine, University of Kentucky Medical Center, Lexington, Kentucky. 2 Department of Surgery, University of Kentucky Medical Center,Lexington, Kentucky. 3 Lankenau Hospital, Section of Colorectal Surgery, Wynnewood, Pennsylvania. Presented at the 43rd Scientific Assembly and Annual Meeting of the American Society of Therapeutic Radiology and Oncology, San Francisco, CA, November 4 8, Address for reprints: Mohammed Mohiuddin, M.D., Department of Radiation Medicine, University of Kentucky Medical Center, 800 Rose Street, Room N-14, Lexington, KY ; Fax: (859) ; mohmohi@pop.uky.edu Received January 28, 2002; revision received March 29, 2002; accepted April 2, BACKGROUND. The current study was conducted to assess the long-term results of reirradiation in patients with recurrent rectal carcinoma. METHODS. One hundred and three patients with recurrent adenocarcinoma of the rectum underwent reirradiation with concurrent 5-fluorouracil based chemotherapy. The initial radiation dose to the pelvis ranged from 3000 to 7400 centigrays (cgy) with a median dose of 5040 cgy. The median time from initial treatment to recurrence was 19 months. Irradiation techniques consisted of two lateral fields with/without a posterior pelvic field to include recurrent tumor with a margin of 2 4 cm only. The reirradiation doses ranged from 1500 to 4920 cgy with a median dose of 3480 cgy. Total cumulative doses ranged from 7060 to 1080 cgy with a median total dose of 8580 cgy. After the reirradiation, 34 patients also underwent surgical resection for residual disease. Fourteen patients underwent pelvic exenteration, 11 patients underwent abdominoperineal resection, 4 patients underwent transanal transabdominal proctosigmoidectomy, 2 patients underwent full thickness local excision, and 3 patients underwent a Hartmann resection. RESULTS. Follow-up ranged from 3 84 months with a median follow-up of 2 years. The median survival for the whole group was 26 months and the 5-year actuarial survival rate was 19%. The median interval and 5-year survival rate of patients undergoing surgical resection after reirradiation was 44 months and 22% compared with 14 months and 15% for patients treated with reirradiation only (P 0.001). Treatment was generally well tolerated. Fifteen patients required a treatment break and early termination of treatment for Grade 3 and higher diarrhea, moist desquamation, or mucositis. Late complications were seen in 22 patients, including persistent severe diarrhea in 18 patients with 10 patients requiring long-term parental support, small bowel obstruction was seen in 15 patients, fistula formation in 4 patients, and coloanal stricture in 2 patients. There was no difference in incidence of acute or long-term complications by the total radiation dose delivered. CONCLUSIO. In patients with recurrent rectal carcinoma, high doses of reirradiation can be delivered with acceptable risks without prohibitive long-term side effects. Surgical salvage and long-term survival of patients are possible. Cancer 2002;95: American Cancer Society. DOI /cncr KEYWORDS: rectal carcinoma, reirradiation, local recurrence, salvage surgery. Local recurrence of rectal carcinoma after radical surgery occurs in 20 25% of patients. 1 3 Although the use of adjunctive preoperative or postoperative chemotherapy/radiation therapy has reduced considerably the incidence of local recurrence, approximately 10 15% of patients still develop recurrence of the disease in the pelvis. 4,5 Salvage surgery for the recurrent carcinoma is rarely successful. 6 8 Single modality chemotherapy 9,10 and radiation have been ineffective in 2002 American Cancer Society

2 Reirradiation for Recurrent Rectal Carcinoma/Mohiuddin et al TABLE 1 Patient Characteristics (n 103 Patients) Median age 65 yrs (37 79) Gender Male 60 (59%) Female 43 (41%) Previous radiation dose Gy Median dose 50.4 Gy Time to local recurrence 2 86 mos Median 19 mos palliating symptoms or prolonging survival. In general, reirradiation of the pelvis has not been undertaken for fear of prohibitive normal tissue complications. We undertook a program of reirradiation for patients with recurrent rectal carcinoma who had previously received adjunctive pelvic radiation to control symptoms of local tumor progression and to improve the survival of these patients. MATERIALS AND METHODS From 1987 to 2000, 103 patients with adenocarcinoma of the rectum who developed locoregional recurrence of disease after surgery and had received either preoperative or postoperative pelvic radiation underwent reirradiation for recurrent carcinomas. Patients ranged in age from 31 to 79 years with a median age of 65 years. Of the 103 patients, 43 were women (41%) and 60 (59%) were men. The interval from initial treatment to local recurrence of disease ranged from 2 to 86 months with a median time of 19 months. Previous radiation doses to the pelvis ranged from 30 to 74 grays (Gy) with a median of 50.4 Gy (Table 1). Reirradiation was undertaken with concurrent 5-fluorouracil (5-FU) continuous intravenous infusion (Fig. 1). High-energy photons (10 25 megaelectron volts [MeV]) were utilized for treatment and patients were treated with opposed lateral fields or with a posterior and two lateral fields. The treatment volume encompassed the presacral region and macroscopic tumor, as identified on computed tomographic scans with a margin of 2 4 cm. Field sizes ranged from 7 7to14 12 cm and were shaped to avoid as much of the bladder and small bowel as possible. A dose of 30 Gy was delivered at 1.2 Gy twice daily with a time interval of 6 hours between fractions. Forty-three patients received the treatment. Sixty patients who, for logistical reasons, could not be irradiated twice a day were treated with 1.8 Gy daily until a dose of 30.6 Gy was reached. A boost dose of 6 20 Gy was delivered to limited tumor volumes (2-cm margins), with an effort made to limit the radiation boost fields to less than 8 8 cm and exclude the bladder and bowel from the FIGURE 1. Treatment schema for combined chemotherapy and reirradiation for recurrent rectal carcinoma. field of treatment. Patients with longer intervals ( l year) from initial treatment to recurrence received higher boost doses of radiation. Total reirradiation doses ranged from Gy with a median dose of 34.8 Gy. Reirradiation doses below 30 Gy, were in patients whose treatments were curtailed due to acute toxicity (15 patients). Cumulative radiation doses (initial doses plus reirradiation) ranged from Gy with a median dose of 85.8 Gy. All patients received concurrent continuous infusion 5-FU, mg/m 2, intravenously through an outpatient portable infusion pump. Surgical exploration was undertaken in 41 patients, 8 12 weeks after reirradiation. Six patients had persistent unresectable disease due to pelvic sidewall involvement (n 3) or diffuse pelvic disease (n 3). One patient who had liver metastasis did not undergo resection. Thirty-four patients underwent resection for residual carcinomas. Fourteen patients underwent a pelvic exenteration and 11 patients underwent an abdominal perineal resection (APR). Six patients underwent a sphincterpreserving surgical procedure with four patients undergoing radical resection with a coloanal anastomosis and two patients undergoing full-thickness local excision. Three remaining patients underwent a Hartman procedure. All patients were followed carefully. The follow-up period ranged from 3 to 84 months with a median follow-up of 24 months. Patients with short follow-up were included for assessment of acute toxicities. Eighty-six patients had died and were followed until death. Follow-up in patients who were alive at the time of last follow-up ranged from 9 to 84 months with a median of 37 months. Survival and local recurrence rates were calculated from the start of reirradiation by the Kaplan Meier method. 14 A univariate analysis for significance for survival and occurrence of late complications was performed.

3 1146 CANCER September 1, 2002 / Volume 95 / Number 5 TABLE 2 Acute Toxicity RTOG Grade 3 toxicity Treatment break/termination for one or more of the following 23/103 (22%) Severe diarrhea 15/103 (15%) Moist desquamation 8/103 (8%) Mucositis 4/103 (4%) RTOG Grade 4 toxicity 6/103 (6%) RTOG: Radiation Therapy Oncology Group. TABLE 3 Late Complications Chronic severe diarrhea (Grade 3) 18/103 (17%) a Small bowel 15/103 (15%) Fistula 4/103 (4%) Skin ulceration 2/103 (2%) a Of these patients, 10 required parenteral nutrition. RESULTS All patients were evaluated for morbidity and survival. There were no operative mortalities. Complications Acute complications were classified as those occurring during reirradiation or before surgery (Table 2). Perineal skin changes during irradiation were often common when the perineum was included in the field. Moderate diarrhea (Grade 1 2) during treatment was also observed in the majority of patients. Twentythree patients (22%) required a significant treatment interruption and 15 patients had to have their treatment terminated for severe diarrhea and/or Grade 3 perineal skin breakdown. Grade 4 diarrhea was observed in six patients (6%). Late complications are shown in Table 3. Ten patients with severe diarrhea during treatment continued to have persistent diarrhea. Eighteen patients required long-term medication for control of bowel movements. Of the 103 patients, 15 (15%) developed small bowel obstruction. They were hospitalized and generally responded to long tube decompression. However, two patients required another operation. Four of these patients also developed small bowel fistulae as a result of progressive abdominal disease and two patients also developed perineal skin ulceration. No patient developed persistent radiation cystitis or bleeding. None of the patients who underwent surgerydeveloped anastomotic or delayed wound dehiscence, soft tissue necrosis, or overt bone fractures. Using magnetic resonance imaging (MRI) scans, insufficiency fractures in the sacrum were observed for two TABLE 4 Univariate Analysis of Factors Influencing Late Toxicity Factor Late toxicity (%) P value Radiation technique Single daily fraction Twice per day 43 Interval to reirradiation (mos) Reirradiation dose (Gy) Total cumulative dose (Gy) patients. No other late radiation effects were observed. There was no correlation between the incidence of long-term complications and reirradiation dose, total cumulative dose, and surgery (Table 4). Long-term complications were reduced significantly in patients receiving hyperfractionated radiation and in patients whose interval to reirradiation was longer than 24 months. Reirradiation resulted in very effective palliation of symptoms (Table 5). Bleeding was palliated in 100% of patients and remained controlled in 80% of patients until death with a median of 10 months. Pain and tumor mass were also palliated, although a complete response was noted in only 55% and 25% of patients with a median of 9 months and 8 months, respectively. Only 39% of patients were completely free of pain at the time of death. Local control was not assessed specifically as an endpoint of the study as most patients were treated palliatively and were not expected to have long-term local tumor control. Therefore, most patients had persistent local disease. However, long-term survivors who were treated with chemotherapy and reirradiation alone appeared to have their local disease controlled. Patients who underwent surgical resection after chemotherapy and reirradiation fared better. However, even in this subgroup, 19 of 34 patients (56%) developed local recurrence. At the time of last follow-up, 86 patients had died, seven without evidence of disease. Nineteen patients remained alive, 10 of whom had no evidence of disease. The actuarial Kaplan Meier and 5-year survival rate for all patients was 19% with a median survival of 26 months (Fig. 2). The 5-year survival rate for patients who underwent surgical resection after reirradiation was 22% with a median of 44 months compared with 15% and 14 months for patients treated with reirradiation alone (P 0.001). Factors affecting survival are

4 Reirradiation for Recurrent Rectal Carcinoma/Mohiuddin et al TABLE 5 Efficacy of Reirradiation for Relief of Symptoms Symptoms No. of patients Complete responses (%) Partial responses (%) Median duration (mos) Palliated until death (%) Bleeding (100) (80) Pain (55) 13 (28) 9 18 (33) Mass effect 36 9 (24) 23 (64) 8 8 (20) TABLE 6 Univariate Analysis of Factors Influencing Survival Factor P value FIGURE 2. Survival of patients after combined chemotherapy and reirradiation for recurrent rectal carcinoma. RT: radiation; SURG: surgery. shown in Table 6. Karnofsky performance status, reirradiation dose, and surgical resection improved survival. Radiation fractionation, disease-free interval, and cumulative dose did not appear to influence survival, although patients with longer disease-free intervals received higher doses of radiation. DISCUSSION Recurrent rectal carcinoma poses a difficult management problem, especially in patients who have previously received pelvic radiation therapy. 15 The symptom complex or rectal bleeding, mucus discharge, and pain significantly impacts the quality of life of patients. This is especially true for patients who live for long periods with an unsatisfactory outcome for symptom control. 16 Adjunctive radiation therapy programs currently utilize high-dose radiation that is often defined by the upper limits of radiation tolerance of the pelvic organs. Historically, radiation tolerance doses have been defined on the basis of a single continuous course of radiation treatment. The small bowel, which is often the major dose-limited structure, has a tolerance dose (TD) of 5/5 with a dose of 45 Gy and a TD of 50/5 with a dose of 50 Gy. 17 The risk of injury to the bowel is increased if there has been previous pelvic surgery. There is an 11% incidence of Gender Males Females KPS Age Initial stage II 0.06 II RT technique Single daily fraction Twice per day Disease-free interval (mos) Reirradiation dose (Gy) Total cumulative dose (Gy) Surgery KPS: Karnofsky performance score. rectal ulceration and hemorrhagic cystitis in patients receiving more than 6500 Gy after treatment for prostate and cervical carcinomas Evidence suggests that significant recovery of radiation effects occurs with time, even in sensitive nongenerating normal tissue such as the spinal cord, after the completion of a course of radiation Reirradiation for recurrent carcinoma is not a new concept. Kramer 24 described results of retreatment in carcinoma patients as early as He concluded that radical retreatment was possible as long as the treatment volume was limited and patients carefully planned for reirradiation. Since then, several authors have reported success with reirradiation for a variety of recurrent carcinomas, including those in the head and neck, brain, breast, 32, and lung,

5 1148 CANCER September 1, 2002 / Volume 95 / Number 5 without producing prohibitive normal tissue damage. Reirradiation has also been used successfully in the management of recurrent gynecologic malignancies, although interstitial implantation of iridium-192 or 125 I was used Hyperfractionated radiation has also led to safe radiation dose escalation while avoiding critical late injuries by limiting the toxicity to slowly proliferating normal tissues. 40 The addition of chemotherapy as a radiation sensitizer has improved the efficacy of radiation treatments, 41 allowing better local tumor control without increasing dose-limiting late effects. This is especially true in patients with rectal carcinoma, in whom the combined radiation and chemotherapy approach has been more efficacious than radiation or chemotherapy alone in the management of primary tumors. 42,43 Several authors have reported significant down staging of advanced disease with the use of radiation combined with chemotherapy Rich et al. 47 reported that prolonged intravenous infusion of 5-FU together with radiation yielded a higher complete response rate and local control than an intravenous bolus of 5-FU. The spatial distribution of toxicities has led to some enhancement of acute toxicities but no significant increase in late toxicities. Therefore, for recurrent carcinomas, combined treatment allows effective local control and palliation even with doses of radiation that traditionally have been considered to be subtherapeutic. This study indicates that reirradiation with chemotherapy does have the potential for enhanced acute reaction as seen by the high incidence of diarrhea and skin toxicities that can be a limiting factor for some patients. The acute toxicities necessitated treatment interruptions or termination in 22% of patients. The incidence of late toxicity, however, was low with only two patients developing skin breakdown. There were no soft tissue or bone necrosis or clinically significant fractures at the doses utilized. Two patients had insufficiency fractures in the sacrum, which were identified onan MRI scan, but were of no clinical significance. These were self-limited with time. The incidence of small bowel obstructions appeared to be the most significant late normal tissue effect. However, small bowel obstructions were often multifactorial, with recurrent carcinoma being a major precipitating factor. Small bowel obstructions without recurrence were seen in four patients only. Several patients developed fistulae, the major cause of which appeared to be the recurrence of the disease in the pelvis or in the extrapelvic region. Although fistulae formation is of some concern, fistulae in the lower pelvis are often associated with recurrent disease and may be exacerbated with tumor destruction. Fistulae did not appear to be correlated with radiation fields and were often both inside and outside the treatment area. Salvage surgery for recurrent rectal carcinoma has always been a difficult procedure and can be hazardous even in carefully selected patients. There is a high rate of postoperative mortality (12 14%) and morbidity (60%). 48,49 Surgery is often incomplete with persistent and second local recurrence rates of 50 62%. 50 However, 25% of carefully selected patients who undergo complete resection of tumor can be salvaged and are long-term survivors. Preoperative reirradiation in these patients has been discouraged because of intraoperative technical problems or poor healing of surgical wounds. Thirty-four of our patients underwent surgical exploration and resection after reirradiation to the pelvis. Although wound healing was slower, surgical morbidity was not dissimilar to patients treated without preoperative reirradiation and there was no mortality. Proper attention to both radiation and surgical technique is essential. The use of small radiation fields, carefully fractionated radiation doses, exclusion of bowel and bladder, and dose titration with a time interval between initial treatment and recurrence of disease (patients with longer intervals to recurrence 12 months were given higher doses of radiation), minimize potential morbidity. Maximal homeostasis during surgery is also essential. Postoperative antibiotics were used for periods much longer than is customary after surgery to reduce the risk of opportunistic infection and tissue breakdown. Ileal anastomosis is avoided in patients with a grossly affected irradiated bowel with preference given to ileohepatic flexor-colic anastomosis. Our results indicate that when special care and adherence to guidelines are followed, radical surgical resection of recurrent carcinoma can be performed safely after cumulative high doses of reirradiation with reasonable healing. For these reasons, there is renewed hope for salvaging patients with recurrent carcinoma who fail initial adjuvant therapy but who need to be treated aggressively and early. The 19% overall survival and 22% survival rates among patients undergoing surgical resection are encouraging and indicate potential salvage for a small but significant number of selected patients. The 15% long-term survival rate among patients treated with chemotherapy and reirradiation, although surprising, may represent a subset of patients with limited disease who received the higher radiation doses to limited volumes. Complete pathlogic response in patients receiving preoperative radiation and chemotherapy for rectal carcinoma ranges from 24 to 30% in other studies Therefore, it is not unrealistic to expect long-term control in these patients. Patients treated purely for palliation achieve long-term symp-

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