ANTICANCER RESEARCH 26: 2419-2424 (2006) Pre-operative Radiochemotherapy with Raltitrexed for Resectable Locally-advanced Rectal Cancer: A Phase II Study* MARIA CRISTINA LEONARDI1, MARIA GIULIA ZAMPINO2, FABRIZIO LUCA3, BARBARA ALICJA JERECZEK-FOSSA1, ELENA PETAZZI1, BRUNILDA TATANI3, ROBERTA LAZZARI1, ROBERTO BIFFI3, KATIA LORIZZO2, ELENA MAGNI2, DIEGO SCANNIFFIO2, FRANCO ORSI4, GUIDO BONOMO4, GIUSEPPE PETRALIA4, CRISTINA TROVATO5, CRISTIANO CROSTA5, BRUNO ANDREONI3,6 and ROBERTO ORECCHIA1,6 Divisions of 1Radiation Oncology, 2Medical Oncology, 3General Surgery, 4Radiology and 5Endoscopy, European Institute of Oncology, Milan; 6University of Milan, Milan, Italy Abstract. Background: The aim of the study was to evaluate 30% of patients and resulting in therapeutic failure and death the response to and toxicity of pre-operative radiochemotherapy (3). Randomized trials have shown better results in terms of containing raltitrexed (Tomudex) for resectable rectal local control and survival in patients treated with adenocarcinoma. Patients and Methods: From November postoperative radiochemotherapy when compared to surgery 2000 to June 2002, 18 consecutive patients staged T3 N0/N+ alone. However, such an approach is correlated to significant were treated with pre-operative chemotherapy (3 mg/m2 of acute and chronic morbidity and may reduce the overall raltitrexed on days 1, 19, 38) and concurrent radiotherapy compliance to treatment (4-7). In randomized studies of pre- (RT) (50.4 Gy) in 6 weeks, followed by radical surgery within operative radiotherapy (RT) alone, promising results with 8 weeks. Results: The treatment compliance was high. No manageable toxicity were reported (8, 9). The addition of major acute toxicity was reported. Concerning late toxicity, chemotherapy in a neo-adjuvant setting should bring some genitourinary adverse effects were prevalent. A complete further advantages, based on the ability to act as an enhancer response was observed in one patient (6%), partial response in of the RT response. Currently, new chemotherapeutic agents eight (47%), stable disease in seven (41%) and progression in are under investigation. In the present study, raltitrexed, a one case. Three-year actuarial disease-free and overall survival quinazoline folate analog that acts as a specific thymidylate rates were 37% and 87.5%, respectively. Conclusion: synthase inhibitor and as a radiation sensitizer, was Raltitrexed did not increase the pathological response rate administered for three cycles concomitantly with pre- compared with the rates obtained with use of preoperative RT operative RT. This drug does not require the positioning of a alone and reported in the literature. Acute morbidity was low central catheter and has a long terminal half-life (260 hours) and acceptable, while late toxicity was considerable, prevalently (10). The aim of this phase II trial was to evaluate the toxicity concerning sexual dysfunction and urinary complications. and response to treatment in patients with clinically resectable locally-advanced rectal cancer. Rectal carcinoma is one of the most common cancers in the United States and in Western Europe (1, 2). Local recurrence Patients and Methods after radical surgery is the major threat, occurring in 15% to Patients with resectable histologically-proven locally advanced rectal adenocarcinoma were eligible for this study. The clinical staging work-up consisted of computed tomography (CT) of * The authors are members of the Digestive Tumors Task Force abdomen and pelvis, chest X-ray or CT, routine blood tests, of the European Institute of Oncology and participated in the complete colonoscopy, endoscopic ultrasonography (EUS) and design, execution and data analysis of this trial. rectal examination. Hematological, renal and liver toxicities were graded by the National Cancer Institute Common Toxicity Criteria Correspondence to: Maria Cristina Leonardi, Division of Radiation (NCI-CTC) (11). Toxicity of the gastrointestinal tract, Oncology, European Institute of Oncology, Via Ripamonti 435, genitourinary tract and skin were graded on the base of the 20141, Milan, Italy. Tel: 0039 02 57489037, Fax: 0039 02 57489036, Radiation Therapy Oncology Group (RTOG) scale (12). Late e-mail: [email protected] toxicity, registered 6 months after the completion of the neo- adjuvant radiotherapy and on every follow-up visit, was evaluated Key Words: Raltitrexed, neoadjuvant chemoradiotherapy, rectal based on the Subjective Objective Management Analytic Late carcinoma. Effect of Normal Tissue (SOMA/LENT) criteria (13). Tumor 0250-7005/2006 $2.00+.40 2419 ANTICANCER RESEARCH 26: 2419-2424 (2006) response was assessed according to the World Health Organization Table I. Patient characteristics. (WHO) criteria (14). Down-staging was defined as any reduction of stage between the clinical and pathological stage. Characteristic No. of patients Pre-operative treatment protocol. Pre-operative radiotherapy was Median age, years (range) 62.5 (40-72) delivered using a high-energy linear accelerator (15 MV). All patients Gender received 45 Gy in 25 fractions over 5 weeks to the whole pelvis Male 13 followed by a boost dose of 5.4 Gy in three fractions to the tumor mass Female 5 Performance status (ECOG) with a 2-3 cm margin, at 1.8 Gy per fraction (up to the total dose of 05 50.4 Gy). The whole pelvis was treated with four-field technique, while 113 the boost area was irradiated in the majority of patients with posterior- TNM staging at diagnosis anterior and two lateral fields (three-field technique). Customized cT3N0 11 blocking, an immobilization system and hypogastric compressor were cT3N+ 7 used in all cases. Concurrent chemotherapy using raltitrexed at 3 Grading 2 mg/m was administered as a short i.v. infusion for about 15 min on 28 days 1, 19 and 38 (3 cycles). Six weeks after the end of RT, clinical and 31 radiological assessments (chest X-ray/CT, abdomen and pelvis CT and unknown 9 EUS) were performed. Surgical resection was undertaken within 8 weeks from completion of the pre-operative RT to allow patient recovery and maximum tumor shrinkage. perineal rectum resection (Miles’procedure). Distal and Statistical analysis. This phase II trial was planned as two-stage trial taking into account treatment response. The initial sample size radial margins were negative in all patients. In two cases, comprised 35 patients and an interim analysis was fixed for the first one liver localization was detected intra-operatively and 18 cases. The aim was to achieve at least a 10% pathological was radically resected. Total mesorectal excision was complete response rate. routinely performed. The median number of the examined Disease-free and overall survival were calculated from the date lymph nodes was eleven (range 3-23), while the number of of surgery and assessed with the Kaplan-Meier methodology. The metastatic lymph nodes varied from zero to five (median response rate and toxicity were calculated as a simple ratio. of 0.75). The median length of the surgery and of the hospital stay was 215 min (range 95-360) and 13 days Results (range 11-30), respectively. Out of the 17 operated patients, six (35%) developed complications related to the From November 2000 to June 2002, 18 consecutive patients surgery but were treated conservatively: two anasthomotic entered the present clinical trial. The sociodemographic and leakages, four wound infections managed with drainage clinical patient characteristics are shown in Table I. and antibiotics. No post-operative deaths occurred. Treatment compliance. All but three out of the 18 patients Toxicity. Acute toxicity was monitored weekly during completed the planned three cycles of chemotherapy: one treatment. There was no severe toxicity and no patient patient refused the third cycle, two patients received only required hospital admission because of acute reactions. The two cycles due to transaminitis. The raltitrexed dose was incidence of acute and chronic toxicities is shown in Tables reduced by 25% in four patients and in one patient in the II and III, respectively. second and third cycles, respectively. A 50% reduction was made in one patient in the second and third cycles and in Response evaluation. Upon pathological examination, one one patient in the third cycle, due mainly to transaminitis. patient (6%) showed a complete pathological response None of the patients experienced grade 4 toxicity. There (ypT0). A partial pathological response was achieved in eight was no delay of cycles. All patients received the prescribed patients (47%) (two ypT1 and six ypT2). Seven additional radiation dose and in four cases a short interruption of less patients (41%) had stable disease. One patient (6%) than a week was necessary. Post-operatively, all patients but developed disease progression (ypT4). Overall, tumor down- three (one refusal, one anasthomotic leakage, one complete staging occurred in 53% of the patients (9/17). With regard to pathological response) received chemotherapy with adjuvant lymph node down-staging, out of the seven patients with intent of fluorouracil modulated by folinic acid. ultrasound-staged nodal positive disease, three had no pathological evidence of nodal involvement after Surgery. After a median of 58 days from radiotherapy, 17 radiochemotherapy. patients underwent surgery, while one patient refused. Twelve patients underwent anterior resection of the Local control and survival. The median follow-up was 37 rectum (RAR) and the remaining five had abdomino- months (range