Preoperative Radiotherapy in Resectable Rectal Cancer: A Prospective Randomized Study of Two Different Approaches

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1 Journal of the Egyptian Nat. Cancer Inst., Vol. 22, No. 3, September: , 21 Preoperative Radiotherapy in Resectable Rectal Cancer: A Prospective Randomized Study of Two Different Approaches MAHFOUZ A. EITTA, M.D.*; GAMAL F. EL- WAHIDI, M.D.*; MONA A. FOUDA, M.D.*; NABEL GAD EL-HAK, M.D.** and ENGY M. ABO EL-NAGA, M.Sc.* The Departments of Clinical Oncology & Nuclear Medicine* and Gastro-Entrology Surgery**, Faculty of Medicine, Mansoura University ABSTRACT Background: Preoperative radiotherapy in resectable rectal cancer has a number of potential advantages, most importantly reducing local recurrence, increasing survival and down-staging effect. Purpose: This prospective study was designed to compare between two different approaches of preoperative radiotherapy, either short course or long course radiotherapy. The primary endpoint is to evaluate the local recurrence rate, overall survival (OS) and disease free survival (DFS). The secondary endpoint is to evaluate downstaging, treatment toxicity and ability to do sphincter sparing procedure (SSP), aiming at helping in the choice of the optimal treatment modality. Patients and Methods: This is a prospective randomized study of patients with resectable rectal cancer who presented to the department of Clinical Oncology and Nuclear Medicine, Mansoura University during the time period between June 27 and September 29. These patients received preoperative radiotherapy and were randomized into two arms: Arm 1, short course (SCRT) 25Gy/week/5 fractions followed by surgery within one week, and arm 2, long course preoperative radiotherapy (LCRT) 45Gy/5 weeks/25 fractions followed by surgery after 4-6 weeks. Adjuvant chemotherapy was given 4-6 weeks after surgery according to the postoperative pathology. Results: After a median follow-up of 18 months (range 6 to 28 months), we studied the patterns of recurrence. Three patients experienced local recurrence (LR), two out of 14 (14.2%) in arm 1 & one out of 15 patients (6.7%) in arm 2, (p=.598). Three patients developed distant metastases [two in arm 1 (14.2%) & one in arm 2 (6.7%), p=.598]. Two-year OS rate was 64±3% & 66±2%, (p=.389), and the 2-year DFS rate was 61±2% & 83±2% for arms 1 & 2, respectively (p=.83). Tumor (T) downstaging was more achieved in LCRT arm with a statistically Correspondence: Dr Engy M. Abo El-Naga, The Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, engyms27@yahoo.com significant difference, but did not reach statistical significance in node (N) down-staging. SSP was more available in LCRT but with no statistically significant difference (p=.82). Conclusion: This work showed that there was no statistically significant difference between SCRT & LCRT as regard local control, distant metastasis, and rate of SSP, OS and DFS, while there was a statistically significant difference as regard down-staging in favor of LCRT. Further follow up is needed to determine late toxicity and difference in survival. Key Words: Resectable rectal cancer Preoperative radiotherapy Short course radiotherapy Long course radiotherapy. INTRODUCTION Over the past 25 years, advances have been made in the multimodality management of patients with resectable rectal cancer, indicating that a multimodality treatment approach results in a significantly better outcome [1]. The goal of the treatment of rectal carcinoma is to cure or to locally control the disease with maintenance of an acceptable quality of life. Until recently, surgery had remained the primary treatment modality, but in spite of curative resection, a significant proportion of patients developed local recurrence (2-5%) [2]. The surgical approach to resection in rectal cancer varies with the location of the tumor. Adequate surgical removal of the tumor is the major treatment factor affecting local control and cure [3]. There is a number of potential advantages of preoperative radiation therapy for resectable rectal cancer, including decreasing tumor seeding at the time of surgery, increasing radiosen- 155

2 156 sitivity due to more oxygenated cells, no post surgical fixation of small bowel in the pelvis and down-staging effect [4]. The major theoretical disadvantage is possibly overtreating 1 to 15% of patients with stages T1-2 NM disease, who do not require adjuvant therapy [5]. Postponing surgery for a six-week course of neoadjuvant treatment plus a six-week interval to allow tumor shrinkage and recovery from side effects did not result in an increased rate of surgical complications or an increased incidence of tumor progression [6]. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. After a dose of 44-5Gy in 2Gy fractions, there is a little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation-surgery interval [7]. An increase in tumor response and more sphincter preservation was demonstrated with long interval versus a short radiation-surgery interval in low rectal cancer [8]. Early studies of preoperative radiotherapy that used doses less than 2Gy biologically effective doses (BED) had no significant benefit on local recurrence [9]. Two large meta-analyses concluded that preoperative radiotherapy (at BED 3Gy) was associated with a significant improvement in 5-year survival and drastically reduced local recurrence. However, the occurrence of distant metastases was not reduced. A lower incidence of side effects with preoperative versus postoperative radiotherapy was reported [1], with no evidence that postoperative radiotherapy improved survival [11]. In Europe, there is still much debate about the two different approaches to preoperative radiotherapy, SCRT and LCRT. Even in U.S.A., there is now increasing demand in considering the use of SCRT in order to better stratify for adjuvant therapy, because of the low probability of downsizing and therefore unchanged initial TN-staging [12]. The major advantage of the preoperative irradiation with 5x5Gy is the fast completion of perioperative modalities, followed by resection a week later [13]. However, this short period does not cause significant tumor shrinkage in patients with advanced tumor stages, so that an increase in curative (R) resection or SSP cannot be achieved in this patient subgroup [8]. Preoperative Radiotherapy in Resectable Rectal Cancer Preoperative SCRT decreases the LR rate relative to postoperative radiotherapy, with no indications of increased late morbidity [14], and significantly improves DFS [15]. Even with total mesorectum exision (TME), local recurrence was reduced in the preoperative SCRT arm vs surgery alone, with the same overall survival and sphincter preservation in both study arms [16]. Adding chemotherapy to preoperative radiotherapy slightly increased the incidence of acute toxic effects but did not affect adherence to radiotherapy, the feasibility of surgery, the rate of postoperative complications, or the rates of adherence to postoperative chemotherapy [17]. However chemoradiotherapy (CRT) increased tumor down-staging, with no difference in resectability [18], and achieved more patological complete response [19,2]. Neoadjuvant chemoradiation did not increase survival, local control or late toxicity compared with SCRT alone [21,22]. The development of distant metastases is now the predominant mode of failure in rectal cancer. The challenge is to integrate more effective systemic therapy into combined modality programs: Capecitabine, oxaliplatin, irinotecan, as well as targeted therapies. Phase III trials are ongoing to determine whether these novel combination regimens offer an advantage compared with standard 5-FU-based chemoradiotherapy [23]. Radiotherapy may cause both acute and late effects related to the total radiation dose and the normal tissue volumes irradiated. The reported toxicities do not fundamentally differ between SCRT or LCRT with exception of acute neurogenic pain, which is observed in patients treated with 5 Gy/fraction [11]. Acute morbidity with SCRT schedule administrated in small volumes (upper border at promontary) with multiple beams, was usually limited to delayed wound healing after APR [16]. PATIENTS AND METHODS This study included 32 patients with resectable rectal cancer who presented to the Department of Clinical Oncology & Nuclear Medicine, Mansoura University Hospital during the period between June 27 and September 29. These patients were randomized into two arms: Short

3 Mahfouz A. Eitta, et al. 157 course (SCRT) and long course (LCRT) radiotherapy arms; each arm included 16 patients. These patients were followed-up to the end of the study for a minimal period of 6 months. Inclusion criteria: Inclusion criteria were histologically confirmed adenocarcinoma of the rectum with the inferior margin within 15cm from the anal verge, resectable tumor (Stage T2-4 N-2) as determined by preoperative abdomino-pelvic computed tomography (CT) or MRI, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score -1, no evidence of distant metastases and no previous history of chemotherapy or radiotherapy to the pelvis. Pretreatment assessment: Detailed clinical history. Complete physical examination. Laboratory tests [complete blood count, liver function tests, serum creatinine, tumor markers (CEA & CA 19-9)]. Radiological investigations (chest X-ray, abdominal ultrasound, barium enema & abdomino-pelvic CT or MRI). Endoscopy & pathological examination of the biopsy. Patients were staged according to AJCC staging (22) [24]. After informed consent, patients were randomly (using closed envelope method) allocated in arm 1 and 2. Treatment protocols: Arm 1 (16 patients): Received short course preoperative radiotherapy 25cGy/week/5 fractions followed by surgery within one week. Arm 2 (16 patients): Received long course preoperative radiotherapy 45cGy/5 weeks/ 25 fractions followed by surgery after 4-6 weeks. Radiotherapy: Preoperative radiotherapy, either short course or long course, was given by high energy photon radiation, using Co 6 or linear accelerator (6 MV photons). Patients were treated with 2D three or four field techniques for the whole pelvis. They were simulated in prone position with full bladder to reduce the volume of the small intestine in the irradiated fields. The target volume included the primary rectal tumor, the perirectal nodes, the mesorectum up to the level of the upper border of the first sacral vertebra, and the lymph nodes along the internal iliac vessels. Abdomino-pelvic CT or MRI was done 3-4 weeks after the end of radiotherapy in the LCRT arm, and was compared with the previous pre-radiotherapy one. Surgery: Two major types of surgery were defined: Abdomino-perineal resection (APR) with a permanent colostomy and low anterior resection (LAR) with colorectal or usually coloanal anastomosis. Diverting stoma was left to the surgeon's decision. Chemotherapy: Adjuvant chemotherapy was given 4-6 weeks after surgery. According to postoperative pathology, the chemotherapy protocol was either Mayo Clinic (given in case of low risk patients) or FOLFOX bolus (given in high risk patients). Mayo Clinic: Leucovorin 2mg/m 2 bolus followed by 5 FU 425mg/m 2 bolus form Day 1-5, to be repeated every 4 weeks for 6 cycles. FOLFOX bolus: Oxaliplatin 85mg/m 2 days 1 & 15 in glucose 5% over 2 hours infusion, leucoverin 2mg/m 2 days 1, 8, 15 bolus and 5- FU 5mg/m 2 days 1, 8, 15 bolus, to be repeated every 4 weeks for 6 cycles. Down-staging was defined as a reduction in T or N stage based on pretreatment clinical staging by CT or MRI versus final pathological staging. Patient evaluation: During treatment: Patients were followedup weekly during radiotherapy for acute radiation toxicity using the RTOG acute radiation morbidity scoring schema [25] that sometimes necessitated medical treatment or stoppage of radiation for a short period. Early effects were recorded weekly during treatment and after 4 weeks. Late effects were recorded at 6 months and then annually. Also, patients were followed-up after operation to record early postoperative mortality and morbidity such as delayed wound healing, anastomotic leakage, bleeding, ileus, fistula, which occurred during hospitalization, or within 3 days of the operative procedure.

4 158 Patients were followed-up during chemotherapy for signs or symptoms of toxicity, either haematological (anaemia, leucopenia, thrombocytopenia) or non-haematological (vomiting, diarrhea, mucositis) using the WHO cancer toxicity criteria for grades of toxicity [26]. After end of treatment: Patients were followed-up for detection of local recurrence or late effect every 1-2 months by clinical examination, every 3 months by tumor markers (CEA & CA 19-9) and abdomino-pelvic CT or MRI, or endoscopy every 6 months, for the first two years. In some cases MRI, endoscopy and biopsy were done if local recurrence was suspected. Statistical analysis: Data were analyzed using SPSS (Statistical Package for Social Sciences) version 15. Unpaired t-test was used for comparison between different groups. Qualitative data were presented as number & percentage. The Chi-square test was used for comparison between groups, when appropriate. Survival was compared using the Kaplan-Meier method with the log-rank test of significance. p.5 was considered to be statistically significant. DFS was calculated from the date of surgical resection until the date of recurrence (either local or distant) and OS was calculated from the date of diagnosis until the date of death. RESULTS Table (1) shows patient characteristics. Out of 32 patients, there were 29 patients followedup to end of the study while three patients did not complete the treatment protocol [2 patients in arm 1 (SCRT) and one patients in arm 2 (LCRT)] because they died: Two patients developed liver cell failure early postoperatively (6.2%) and one patient died 3 months after operation due to renal failure related to ureteric injury during surgery. There was no statistically significant difference between the both arms as regard age, gender, PS score, presenting symptoms, site of tumor and tumor markers, pathological types, clinical staging and pathological staging. Pathological complete response (PCR) occurred in 2 patients (in arm 2 of LCRT). No PCR was reported in arm 1 of SCRT with no statistically significant difference (p=.15). T Preoperative Radiotherapy in Resectable Rectal Cancer down-staging occurred in 3 out of 14 (21.4%) & 9 out of 15 (6%) patients with statistically significant difference (p=.8). N down-staging occurred in 3 out of 14 (21.4%) & 5 out of 15 (33.3%) patients in arm 1 & 2, respectively, with no statistically significant difference (p=.163) (Figs. 1,2). Table (1): Patients characteristics. Variables Age (years): Range Median Gender: Male Female Male : Female PS: 1 Symptoms: Bleeding/rectum Constipation Abdominal pain Weight loss Others Site: Upper Middle Lower Pathological cell types: Adeno-carcinoma Mucinous Signet-ring Clinical stages: II: T3N T4N III : T3N+ T4N+ Pathological stage: Stage : TN Stage I : T2N Stage II : T3N Stage III: T3N1 T3N2 Tumor marker*: Normal markers CEA level (>5ng/ml) CA19-9 (>35ug/ml) Both elevated Surgical technique: APR LAR Palliative colostomy Exploration Arm 1 (SCRT) N=14 (%) (64.3) 5 (35.7) 1.8:1 7 (5) 7 (5) 12 (85.6) 7 (5) 9 (64.2) 5 (35.7) 4 (28.5) 3 (21.4) 11 (78.6) 7 (5) 5 (35.7) 2 (14.3) 6 (42.9) 2 (14.2) 6 (42.9) 2 (14.3) 6 (42.9) 4 (28.5) 2 (14.3) 7 (5) 2 (14.2) 1 (14.2) 3 (21.4) 1 (34.4) 3 (1.4) Arm 2 (LCRT) N=15 (%) (66.7) 5 (33.3) 2:1 11 (73.3) 4 (26.7) 13 (86.6) 7 (46.7) 7 (46.7) 6 (4) 3 (2) 2 (13.3) 13 (86.7) 7 (46.7) 5 (33.3) 3 (2) 8 (53.3) 1 (6.7) 5 (33.3) 1 (6.7) 2 (13.4) 3 (2) 5 (33.3) 4 (26.7) 13 (32.6) 11 (73.3) 1 (6.7) 2 (13.3) 1 (6.7) 8 (27.7) 6 (2.7) * Tumor markers were not done in1 patient in arm 1. # p-values.5 are considered significant. p value

5 Mahfouz A. Eitta, et al. 159 APR was done for 18 patients (62.1%) [ten patients (34.4%) in the first arm & 8 patients (27.7%) in the second arm]. The difference was statistically insignificant (p=.166). LAR (SSP) was done for 9 (31%) patients [3 (1.3%) patients & 6 (2.7%) patients in arm 1 & 2, respectively; the difference was statistically insignificant (p=.82)]. One patient in each arm was inoperable. Diverting colostomy was done in 5 patients who underwent LAR, closure of colostomy was done after the end of chemotherapy, while resection anastmosis without colostomy was done in 4 patients. The Mayo Clinic protocol was given to 16 (55.2%) patients, while the FOLFOX bolus protocol was given to 11 (37.9%) patients. Two patients (6.9%) refused receiving post operative chemotherapy (in arm 1). Cycles ranged from 3-6 with a median of 6 cycles. Postoperative surgical complications are illustrated in Table (2). Early postoperative mortality occurred in 6.2% of patients. Delayed wound healing was the most common morbidity which occurred in 5 (15.6%) patients [3 patients in arm of SCRT (arm 1) and 2 patients in arm of LCRT (arm 2), with no statistically significant difference (p=.163)]. Two patients developed adhesive intestinal obstruction which occurred 4 & 6 months after surgery, one patient had leakage at the site of anastomsis and another had renal complications. Table (2): Surgical complications. Event Post operative mortality Delayed wound healing Intestinal obstruction Renal complications Anastomotic leakage No. (32) % Acute radiation toxicity occurred in 11 patients (37.9%) in arm 2 (LCRT), while there was no reported acute toxicity in arm 1 patients (SCRT), with a statistically significant difference (p=.2). The most common one was radiation enteritis (mainly of grade II), followed by dermatitis (grade II), and lastly cystitis (grade I). Late complications (urgency & frequency and anastomotic stricture) occurred in 2 patients (6.9%) after LAR (Table 3). Regarding chemotherapy toxicity, haematological toxicity was the most common toxicity in both arms. It was reported in 12 patients (44.4%), followed by diarrhea, abdominal pain and stomatitis. The least frequent non-haematological toxicity was neuropathy. The difference was statistically insignificant (p=.724) (Table 3). The follow-up period ranged from 6 to 28 months with a median of 18 months. The pattern of recurrence was studied. Three patients experienced local recurrence [two out of 14 (14.2%) in the SCRT arm & one out of 15 (6.7%) in LCRT arm], at 13, 15 and 18 months. Distant metastasis developed in 3 patients [two in arm 1 (14.2%) & one in arm 2 (6.7%)], the difference between both arms was statistically insignificant (p=.598). The sites of metastasis were liver, lung (one case for each and were in arm 1) and bone (one case in arm 2) at 8, 11 and 22 months. Table (3): Treatment complications. Toxicity Radiation toxicity (29): Acute Enteritis Dermatitis Cystitis Late Urgency & frequency Anastomotic stricture Chemotherapy toxicity (27): Hematological Anemia Leucopenia Thrombocytopenia Non hematological Diarrhea Abdominal pain Stomatitis Neuropathy Arm 1 No. (%) 7 (25.7) 6 (22.2) 1 (3.7) 3 (11.1) 2 (7.4) 2 (7.4) 1 (3.7) Arm 2 No. (%) 6 (2.7) 3 (1.3) 5 (18.5) 4 (14.8) 1 (3.7) 1 (3.7) 2 (7.4) 3 (11.1) 1 (3.7) Total No. (%) 6 (2.7) 3 (1.3) 12 (44.4) 1 (37) 2 (7.4) 4 (14.8) 4 (14.8) 5 (18.5) 2 (7.4) The relation between recurrence and different prognostic parameters is presented in Table (4). There was no statistically significant relation between recurrence and age, gender, site of tumor, type of pathology, pathological stages, type of surgery, type of chemotherapy protocol and both types of preoperative radiotherapy. A statistically significant relation was only found between elevated both tumor markers at initial presentation and recurrence (p=.37).

6 16 Preoperative Radiotherapy in Resectable Rectal Cancer Table (4): Relation between recurrence and different prognostic factors. Variables Treated patients (29) No recurrence No. (%) Recurrence No. (%) p value Age (years): Age <4y Age >4y Gender: Male Female 9 (31.1) 17 (58.6) 17 (58.6) 9 (31.1) 3 (1.3) Fig. (1): Abdomino-pelvic CT before preoperative LCRT. Black arrow points to thickened rectal wall and white arrow points to enlarged internal iliac lymph nodes. Site of tumor: Upper Middle Lower 4 (13.8) 22 (75.9).454 Pathological cell types: Adeno-carcinoma Mucinous Signet-ring 12 (41.3) 9 (31.1) 5 (17.2).823 Pathological stage: Stage : TN Stage I : T2N Stage II : T3N Stage III: T3N1 T3N2 Tumor marker#: Normal markers CEA level (>5ng/ml) CA19-9 (>5ug/ml) Both elevated Surgical technique##: APR LAR Chemotherapy: No Mayo Clinic Folfox Radiotherapy: SCRT (14) LCRT (15) 5 (17.2) 1 (34.4) 7 (24.1) 17 (58.6) 3 (1.3) 3 (1.3) 15 (51.7) 9 (31.1) 14 (48.4) 1 (34.4) 12 (41.4) 14 (48.3) 3 (1.2) # Tumor markers were not done in1 patient in arm 1. ## 2 patients were inoperable. * p-values.5 are considered significant * The 2-year OS rate was 64±3% for arm 1 & 66±2% for arm 2, (p=.389) (Fig. 3), while the 2-year DFS was 61±2% & 83±2%, respectively (p=.83) (Fig. 4). Fig. (2): Abdomino-pelvic CT after preoperative LCRT. Cum Survival Cum Survival Arm 1 Arm Time (months) Fig. (3): 2-year overall survival for arms 1 & Arm 1 Arm Time (months) Fig. (4): 2-year disease free survival for arms 1 & 2.

7 Mahfouz A. Eitta, et al. 161 DISCUSSION Local tumor control remains an important aim in the treatment of rectal cancer because of the devastating morbidity and unsatisfactory treatment options for local recurrence [27]. Preoperative radiotherapy at adequate doses can be given with low acute toxicity. The longterm consequences of radiotherapy appear to be limited with adequate radiation techniques [2]. In a systematic overview of the effect of radiotherapy in rectal carcinoma, statistically significant lower LR rates have been seen in most trials comparing preoperative radiotherapy (followed by surgery) versus surgery alone [16]. In the preoperative radiotherapy trials, the schedules used ranged from 5Gy x 1-5 fractions to 2Gy x 2 fractions. In the postoperative radiotherapy trials, only conventional fractionation (1.8-2.Gy) was used. Preoperative radiotherapy proved to be more dose efficient than postoperative [16]. The possibility that preoperative irradiation can downstage tumors and render fixed tumors resectable was supported by Kodner et al. [28], where all their patients with fixed tumors were rendered resectable after 45Gy in 5 weeks of preoperative irradiation. In this study, PCR occurred in 2 out of 15 (13%) in the arm 2 patients who received LCRT. This percentage was comparable to those obtained by others series (8-13%), where their patients received neoadjuvant CRT (45Gy/1.8 Gy per fraction ± 5.4Gy as boost with leucovorin & 5-FU either bolus or infusional regimen during the 1 st and 5 th week of radiotherapy) [6,2,29]. Other studies reported a result of 9-13% with treatment by neoadjuvant CPT with capacitabine [3-32], their reports were similar to our results. On the other hand, Read et al. [2] reported 4% in the arm of LCRT (45Gy/ 1.8Gy per fraction) and Gerard et al. [19] reported results of 3.6% vs 11.4% (p<.5) after treatment with preoperative radiotherapy (45Gy/ 1.8Gy per fraction) vs CRT (by using bolus regimen of leucovorin & 5-FU during 1 st and 5 th week of radiotherapy) respectively. No PCR occurred in arm 1 (SCRT). These results were similar to those recorded by some investigators [16-33], however, they differ from those recorded by others (6% in the arm of SCRT) [25]. T down-staging occurred in 21% & 6% of patients in SCRT & LCRT arm, respectively (p=.8). Read et al. [2] reported in their study figures of 42% & 45% for T down-staging in SCRT & LCRT arm (insignificant difference). Mawdesly et al. [29] reported T down-staging in 28% of their patients who received neoadjuvant CRT. N down-staging occurred in 21% & 33% of patients in SCRT & LCRT arm, respectively (p=.163). This is comparable with the results reported by Read et al. [2] for SCRT arm (27%), but it is less than those reported for LCRT (57%) (p=.3) in the same study. In the Swedish Rectal Cancer Trial [34] more patients had tumors in Dukes' stage A or B on postoperative pathological assessment in the SCRT-plus surgery group than in surgery alone group (p=.8), this is more likely due to the down-staging effect of preoperative radiotherapy. On the other hand, Kapiteijn et al. [16] did not record down-staging after SCRT in comparison with the surgery alone group in their studied patients. In the present work, APR was the most common surgical procedure and was done in 62% of patients, while LAR was done in 31%. This differed from Gerard et al. [19] where LAR was the most common procedure (55%). The difference may be due to the surgical decision that prefers APR for more oncologic safety. Also, the age factor affects the surgical decision, as it is preferred to do SSP in younger patients (age group less than 4 years was present in only 31% of our patients). SSP was done in 3 (21%) and 6 (4%) patients in the SCRT & LCRT arms, respectively (p=.82). These results are similar to those reported by Bujko et al. [35], as there was no difference in the rate of SSP between the SCRT and neoadjuvant CRT groups (p=.57). Despite significant downsizing obtained with CRT, the investigators concluded that neoadjuvant chemoradiation did not result in increased SSP in comparison with SCRT. The surgeons' decisions to perform radical surgery (APR) did not change even when down-staging occurred. In this work, postoperative mortality was recorded in 6% of patients, which is comparable to that recorded by the Swedish Trial (4%) [34]. There was no significant increase in postoperative mortality in the immediate postoperative period after preoperative radiotherapy in comparison to surgery alone arm [14,15,34]. Postoperative mortality was high in Stokholm1 Trial

8 162 due to the use of the 2 beams technique and bigger radiation treatment volume with the upper border of pelvic radiation field at L2 [36]. In our study and other studies [14,34], the 3 or 4 fields technique was used and the upper border was at the promontory. On the other hand, our result were higher than those reported by others, (.4%) [6,2], (2%) [19], mainly due to the comorbidity of our patients undergoing surgery. The most common postoperative morbidity was delayed wound healing (15.6%) which is similar to some extent to that reported by others series (18%) [1], and (19%) [29]. Other less frequent postoperative morbidities were anastomotic leakage (3.1%) & intestinal obstruction (6.3%) which are comparable to others results [1,2]. During radiotherapy, enteritis was the most common toxicity experienced in the LCRT arm patients. No toxicity occurred in the SCRT arm which is similar to other reports [2,34]. Dermatitis occurred in 1.3% of patients, which is comparable to Abd Elwanis et al. (9.3%) [32]. Haematological toxicity was the most common toxicity that occurred with chemotherapy (in 44.4% of patients). Anemia was the most common haematological toxicity (in 34% of patients). Also, it was the most frequent toxicity in another study (9.4%) [32]. Leucopenia occurred in 7.2%, which is comparable to other series (6%) [37]. Diarrhea occurred in 14.8% and stomatitis was seen in 18.5% of patients, while neuropathy was observed in 7.2% of patients. Other studies reported 3%, 4% incidence of diarrhea and stomatitis, respectively [19], and 6% incidence of neuropathy [37]. LR was experienced in 3 patients, two (14.2%) in the SCRT arm & one (6.9%) in the LCRT arm, (p=.598). Three patients developed distant metastases (two in SCRT arm (14.2%) & one in LCRT arm (6.9%), p=.598). Bujko et al. [21] found an incidence of 4-year local recurrence rate to be 9% & 14.2% in SCRT vs neoadjuvant CRT (5Gy in 5 weeks with bolus 5-FU and leucovorin during 1 st and 5 th week of radiotherapy). This difference may be due to the small number of patients in our study and short follow-up period. Others studies revealed a pelvic recurrence of 6% & 9%, respectively, after treatment with preoperative CRT with leucovorin & 5-FU and adjuvant 4 cycles of Preoperative Radiotherapy in Resectable Rectal Cancer chemotherapy [6,17]. LR was 13% in preoperative SCRT (25.5Gy in one week) [14]. The reduction of local recurrence with SCRT was observed in many studies. A reduction in LR from 27% to 11% in the surgery alone arm vs SCRT plus surgery was reported [34]. In our study, 14% of patients in the SCRT arm experienced LR, although they received adjuvant chemotherapy, but those patients presented with more advanced stages. Also in a Dutch trial, a reduction in 2-year LR from 8.2% to 2.4% in the surgery alone arm vs SCRT plus surgery (TME) was reported. This means that even with optimum surgery, preoperative radiotherapy reduces the incidence of LR [16]. These figures are less than ours; this difference may be due to different surgical procedures conducted in our study (as the surgery applied was not TME). In the present study, age & sex were not detected as prognostic factors. This disagrees with the finding of several investigators who reported more aggressive tumor behavior and worse survival rates in patients with colorectal cancer whose disease was diagnosed before the age of 4 [38]. Merkel et al. [39] failed to demonstrate a significant difference in prognosis based on gender alone. Chen et al. [4] considered signet-ring carcinoma as an independent poor prognostic factor for survival. However, we did not find a significant relation between pathological types and recurrence. Kapiteijn et al. [16] reported that LR significantly related to distance from the anal verge. This may be due to that 82.8% of patients had a tumor in the lower third. The prognostic impact of some tumor markers (CEA, CA19-9) in CRC is of value to evaluate the prognostic significance and to predict the risk of recurrence as well as the choice of the best type of adjuvant chemotherapy in operable cases with CRC [38,41]. In our study, there is significant relationship between elevated both tumor markers and recurrence (p=.37). In this work, we could not elicit a significant relation between stage of the disease and recurrence (p=.66). On the contrary, Kapiteijn et al. [21] reported that LR significantly related to stage. This difference may be explained by the small sample size of our cases and shorter follow

9 Mahfouz A. Eitta, et al. 163 up period. However, they agreed with our results as there was no significant relation between the type of surgical resection and recurrence. No significant relation was found between recurrence and type of chemotherapy protocol. However Oxaliplatin plus 5-FU/Leucovorin (FL) increased DFS in adjuvant treatment in stage III CRC patients [42]. Also, there was no significant relation between recurrence and type of preoperative radiotherapy [either SCRT or LCRT (p=.529)]. Similarly, other investigators concluded that neoadjuvant CRT did not increase local control compared with SCRT alone [21,22]. Two-year OS & DFS were higher in arm 2 than in arm 1, however this difference was statistically insignificant (66% vs 64% & 83% vs 61%, p=.389 & p=.83 respectively). The Polish Rectal Cancer Group reported a 4-year overall survival of 67.2% in the short-course group and 66.2% in the chemoradiation group (p=.96) [21]. Gerard et al. [19] reported a 5- year OS & DFS of 67.9% & 55.5%, respectively, after preoperative LCRT. The difference between OS & DFS in our study and other studies is primarily attributed to the smaller number of our patients and different surgical procedure. Conclusion: There was no statistically significant difference between both concepts of preoperative radiotherapy as regard local control, distant metastasis and rate of SSP. LCRT achieved higher DFS and OS but did not reach statistical significance. There was a statistically significant difference as regard down-staging in favor of LCRT. No difference was found between SCRT & LCRT in post-operative morbidity or chemotherapy toxicity, but difference was found in acute radiation toxicity in favor of SCRT. Further follow-up is needed to determine late toxicity and difference in survival. REFERENCES 1- Willett CG, Czito BG, Bendell JC. Radiation Therapy in Stage II and III Rectal Cancer. Clin Cancer Res. 27, 13: 693s-8s. 2- Wolpin BM, Meyerhardt JA, Mamon HJ, Mayer RJ. Adjuvant Treatment of Colorectal Cancer. CA Cancer J Clin. 27, 57: Porter GA, Skibber JM. Clinical Aspects and Management of Rectal Adenocarcinoma Management Options: Resectable Rectal Carcinoma. In Abbruzzese JL, Evans DB, Willett CG, Fenoglio-Preiser C, editors. Gastrointestinal Oncology. New York, Oxford University Press. 24, pp De Vita VT, Samuel H, Steven A, editors. Cancer Principles and Practice of Oncology. Philadelphia, Lippincott Williams. 25, pp Minsky B. Adjuvant therapy for rectal cancer-the transatlantic view. Colorectal Dis. 23, 5: Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 24, 351: Withers HR, Haustermans K. Where next with preoperative radiation therapy for rectal cancer?. Int. J Radiot Oncol Biol Phys. 24, 58 (2): Francois Y, Nemoz CJ, Baulieux J, Vignal J, Grandjean J, Partensky C, et al. Infuence of the interval between preoperative radiation therapy and surgery on downstaging and on the rate of sphincter-sparing surgery for rectal cancer: The LyonR9-1 randomized trial. J Clin Oncol. 1999, 17: MRC Working Party-Second Report. The evaluation of low dose preoperative X-ray therapy in the management of operable rectal cancer. Br J Surg. 1984, 71: Camma C, Giunta M, Fiorica F, Pagliaro L, Craxì A, Cottone M. Preoperative radiotherapy for resectable rectal cancer: A meta-analysis. JAMA. 2, 284: Glimelius B, Grönberg H, Järhult J, Wallgren A, Cavallin-Stahl E. A systematic overview of radiation therapy effects in rectal cancer. Acta Oncol. 23, 42 (5-6): Kachnic LA, Hong TS, Ryan DP. Rectal cancer at the crossroads: The dilemma of clinically staged T3, N, M disease. J Clin Oncol. 28, 26: Arnold D, Schmoll HJ. (Neo-) adjuvant treatments in colorectal cancer. Ann Oncol. 25, 16 suppl 2: 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: Sebag-Montefiore D, Steele R, Quirke P, Grieve R, Khanna S, Monson J, et al. Routine short course preop radiotherapy or selective post-op chemoradiotherapy for resectable rectal cancer? Preliminary results of the MRC CR7 randomized trial. J Clin Oncol, 26 ASCO Annual Meeting Proceedings (Post- Meeting Edition). 26, 24: Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 21, 345: Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 26, 355:

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