FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell Italia Meridionale (GOIM)

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1 Annals of Oncology 16 (Supplement 4): iv56 iv60, 2005 doi: /annonc/mdi909 FOLFIRI regimen in advanced colorectal cancer: the experience of the Gruppo Oncologico dell Italia Meridionale (GOIM) E. Maiello 1,2 *, V. Gebbia 3, F. Giuliani 1, G. Paoletti 4, N. Gebbia 5, N. Borsellino 6, G. Cartenì 7, G. Pezzella 8, L. Manzione 9, S. Romito 10, M. Lopez 4 & G. Colucci 1,11 1 Oncology Institute, Bari; 2 Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo; 3 La Maddalena Hospital, Palermo; 4 Regina Elena Institute, Rome; 5 University of Palermo; 6 University of Napoli; 7 Buccheri La Ferla Hospital, Palermo; 8 Cardarelli Hospital, Naples; 9 Ospedale Nord, Taranto; 10 S. Carlo Hospital, Potenza; 11 Cardarelli Hospital, Campobasso, Italy Purpose: To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy. Patients and methods: Patients entered in three consecutive trials of the GOIM (protocols no. 9706, 9901, and 2301) were reported in this analysis. A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen: Irinotecan 180 mg/m 2 on day 1 with LV5FU2 regimen (LV at 100 mg/m 2 administered as a 2-hour infusion before FU at 400 mg/m 2 as an intravenous bolus injection, and FU at 600 mg/m 2 as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2); the treatment was repeated every 2 weeks. Results: 287 patients entered in these three trials, and 264 (92%) were evaluable for response. The overall response rate was 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was 37% (95% CI: 31% to 43%). Median time to progression, median duration of response and survival were 7 months, 10.5 months and 14 months, respectively. All but three patients were evaluable for toxicity which was globally mild; grade 3 4 toxicity was uncommon, and gastrointestinal disturbances were the most common. Conclusions: FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer. Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy. Key words: colorectal cancer, combination therapy, folinic acid, fluorouracil, irinotecan Introduction For the last decades, fluorouracil-based chemotherapy remained the mainstay of treatment of colorectal patients, and its biomodulation with leucovorin obtained better response rate than FU alone, but meta-analysis data failed to demonstrate a survival benefit compared to FU alone [1]. Prolonged infusion of FU showed better results in terms of response rate and survival time than FU alone [2] and a hybrid regimen of FU (LV5FU2) with a bolus and an infusional administration of FU) obtained significant improvements in response rate and time to progression compared to the standard low-dose LV- FU bolus schedule of the North Central Cancer Treatment Group regimen [3]. Furthermore, the addition to LV5FU2 of irinotecan (FOLFIRI) and oxaliplatin (FOLFOX4) showed *Correspondence to: Dr Evaristo Maiello, Medical Oncology Unit, Casa Sollievo della Sofferenza Hospital, Viale dei Cappuccini, San Giovanni Rotondo, Italy. Tel: ; Fax: ; e.maiello@operapadrepio.it better results than LV5FU2 alone in two large studies [4, 5] and these regimens were therefore commonly used in European countries as first-line therapy in advanced colorectal cancer patients. In this report we analyze the experience of the GOIM with FOLFIRI regimen according to Douillard et al. [4] schedule in the treatment of advanced colorectal cancer patients. In particular, in the first phase II randomized trial (GOIM protocol 9706) we verified the effectiveness and feasibility of the addition of CPT-11 to LV5FU2 combination therapy [6]. In the second trial, in order to verify and compare the activity of FOLFIRI regimen to FOLFOX4 combination therapy, the GOIM started a phase III study (GOIM protocol no. 9901); 360 consecutive, non-selected patients entered into this trial and were randomized to receive FOLFIRI regimen or FOL- FOX4 regimen. Primary endpoint of this study was response rate [7]. In the last ongoing phase II randomized trial (GOIM protocol 2301) we evaluated the addition of Celecoxib to the FOLFIRI regimen. q 2005 European Society for Medical Oncology

2 iv57 Patients and methods Patient Selection In these three consecutive trials the eligibility criteria included the following: histologically-confirmed locally-advanced and/or metastatic colorectal carcinoma with bidimensionally measurable disease, age >_ 18 and <_ 75 years, life expectancy of at least 3 months, performance status 0 2 according to the ECOG scale, adequate bone marrow (platelets count >_ 100,000/L, WBC count >_ 4,000/L, granulocyte count of >_ 1,500/mm 3,a hemoglobin level of >_ 10.0 gm/dl), renal (serum creatinine concentration <_ 2.0 mg/dl), and hepatic functions (serum bilirubin level <_ 2.0 mg/dl and AST <_3 times the institutional normal level in the absence of liver involvement with cancer or up to 5 times the institutional normal level when cancer was present in the liver). No concurrent uncontrolled medical illness was allowed. Patients had to be previously untreated for advanced disease, but prior adjuvant chemotherapy was allowed if 1 year (GOIM 9706) or 6 months (GOIM 9901 and 2301) had elapsed since discontinuation of treatment Patients were excluded if any of these criteria was not met and also in the presence of active infections, cerebral metastases, evidence of congestive heart failure, serious cardiac arrhythmias, symptoms of coronary artery disease, history of thrombo-embolic disease or other malignancy (apart from adequately treated nonmelanotic skin cancer and carcinomain-situ of the uterine cervix), or any psychological condition that precluded treatment or adequate follow-up. Radiotherapy was allowed only in sites other than those measurable for response evaluation. Pretreatment evaluation included a complete medical and clinicalphysical examination, baseline measurement of tumor size based on scans, X-ray examination or other radiographic means (comprising full assessment of all known metastatic disease), chest X-ray, electrocardiogram (ECG), tumor markers. Patients have to agree to, and sign, a statement of Informed Consent prior to entering this study. Informed Consent was previously approved by the Scientific Committee of the G.O.I.M. and Ethic Committees of each individual participating Institutions. Treatment Plan According to our previous experience [8], the size and site of disease were considered as prognostic variables for the stratification of cases and therefore patients were stratified according to presence or absence of hepatic disease, and by total tumor burden defined as limited or extensive disease using 10 cm 2 as the cut-off. The value of this cut-off was arbitrarily chosen. The estimation of tumor size (more or less than 10 cm 2 ) was determined according to the sum of the products of the largest perpendicular diameters of all measurable disease. It was found that this stratification method could be easily reproduced in the various centers participating in the study and did not appear to be subject to investigator bias. Thus, the stratification factors were as follows: (A) size of disease: limited or extensive disease (less or more than 10 cm 2, respectively), and (B) patients with or without liver involvement (H+ and H, respectively). Four patient categories were obtained: Group 1: H+/>10 cm 2 ; Group 2: H+/<10 cm 2 ; Group 3: H />10 cm 2 ; and Group 4: H /<10 cm 2. Patients: received FOLFIRI regimen as follows: CPT-11 at 180 mg/m 2 (150 mg/m 2 for patients of age >_ 70 and <75 years) only on day 1, together with LV at 100 mg/m 2 (l-isomer-form) administered as a 2-hour infusion before 5FU at 400 mg/m 2 as an intravenous bolus injection, and FU at 600 mg/m 2 given as a 22-hour infusion immediately after 5FU bolus injection; LV and FU were repeated on day 1 and 2. This regimen was administered at 2-week intervals. Prophylactic anti-emetics were routinely given before each administration of CPT-11. Diarrhea or abdominal cramping or important symptoms of a cholinergic syndrome which occurred during or within 1 h after receiving CPT-11 were treated with atropine (0.25 mg sc). Routine use of a colony-stimulating factor was not utilized in this trial. For symptoms of diarrhea and/or abdominal cramping that occurred more than 12 h after receiving treatment, patients were instructed to begin taking loperamide as soon as the first liquid stool occurred (2 mg, p.o. every 2 h for at least 12 h and up 12 h after the last liquid stool without exceeding a total treatment duration of 48 h). Oral rehydration with large volumes of water and electrolytes was prescribed during the whole diarrhoeal episode. If diarrhoea persisted for more than 24 h despite the recommended loperamide treatment, a 7-day prophylactic oral, broad spectrum antibiotic therapy with fluoroquinolone was initiated. Evaluation of Response and Toxicity Response was first evaluated after four cycles and then every two months, according to a slight modification of WHO criteria [9]. Briefly, a complete response (CR) was considered as the complete disappearance of all evident tumor signs as estimated by two observations not less than 4 weeks apart; partial response (PR) was defined as a greater than 50% decrease in the sum of the products of the largest perpendicular diameters of all measurable disease without occurrence of new lesions; stable disease (SD) was considered as a change of less than 25% in the size of disease and progressive disease (PD) as an increase greater than 25% in the area of the measurable tumoral deposits or the appearance of new lesions. Response rates were provided for all patients (intent to treat analysis) and for evaluable patients. Survival, response duration, and time to progression were determined from the date of first treatment until death or last follow-up, and progression. All toxicities were graded according to the NCI Common Toxicity Criteria. If multiple toxicities were observed, the dose administered was based on the most severe toxicity experienced. The dose adjustment schedule was evaluated at the beginning of a new course (based upon laboratory analyses on the scheduled day of treatment and upon maximum toxicity encountered during the previous course). Dose reductions or treatment delays were calculated according to the non-hematological toxicity or myelosuppression recorded at the time of the planned recycling (day 14). The drug dose level was reduced in the case of severe or persistent toxicity; the LV dose remained fixed (100 mg/m 2 ), while CPT-11 was reduced to 150 mg/m 2 (125 for patients with age years), 5FU bolus to 300 mg/m 2 and 5FU c.i. to 500 mg/m 2. In the case of persistent grade 3 toxicity or whenever grade 4 toxicity was recorded, chemotherapy was definitively stopped. In the presence of grade 2 3 hematological toxicity, treatment was delayed for one week or until hematological recovery. If recovery was not reached, the dose level was reduced. For grade 0 2 gastrointestinal toxicity dose administration was 100%, and for grade 3 toxicity, after a one-week delay, the dose level was reduced. Results Patient and Clinical Characteristics Globally, 287 patients were admitted into these trials from the participating centers. The main characteristics of the entered patients are summarized in Table 1. The median age of all patients was 62 years. The majority of patients had a primary colon cancer (68%) and liver metastases (73%). Multiple disease sites were found in 41% of patients.

3 iv58 Table 1. Patient characteristics TOTAL (%) Patients entered (100%) Patients evaluable # 264 (92%) Age (years) Median Range Sex (M/F) 35/33 93/85 28/13 156/131 Median PS (ECOG) Primary tumor site Colon (68%) Rectum (32%) Metastases Synchronous (58%) Metachronous (42%) Metastatic Site* 0 Liver (74%) Lung (27%) Lymph node (15%) Primary tumor (10%) Disease Site Single (60%) Multiple (40%) Stratification ** H+>10 (group 1) (56%) H+<10 (group 2) (17%) H >10 (group 3) (15%) H <10 (group 4) (12%) #3 pts early to evaluate; *measurable disease; **patients stratified according to presence (H+) or absence (H ) liver metastases and size of measurable disease (> or < 10 cm2). Therapeutic Outcome A total of 264 (92%) patients were deemed assessable for response. Three patients in 2301 study are early to evaluate. Overall, 20 patients (4 in 9706, 14 in 9901; 2 in 2301) were considered non-evaluable for the following reasons: five patients because of not-eligibility or protocol violation, nine patients refused to continue the treatment despite low toxicity, five patients for toxicity, one patient for early death unrelated to chemotherapy. Among patients excluded for toxicity one patient presented a cardiac ischemic episode after the second cycle of treatment and two patients died for hematological reasons (one severe treatment-related febrile neutropenia, one patient with disseminated intravascular coagulation). The response rates are listed in Table 2. Twelve CR and 86 PR were observed with an overall response rate of 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was Table 2. Main results Total Patients entered Patients evaluable # 264 Response CR PR SD PD CR+PR Response rate -evaluable 42% 34% 42% 37% (95% CI) 30 55% 27 41% 26 59% 31 43% - intent to treat 40% 31% 39% a 34.5% b (95% CI) 28 52% 25 38% 24 57% 29 40% Median duration (mos) Response (range) TTP 6 7 7,5 7 (range) , Survival (range) a 15/38 pts (3 pts early to evaluate). b 98/284 pts (3 pts early to evaluate); TTP: time to progression. #: 3 pts early to evaluate. 37% (95% CI: 31% to 43%). When also considering SD, the overall tumor growth control rate (CR + PR + SD) was 71% in the intent to treat (ITT) analysis. The median duration of response was 10.5 months, while the median time to progression by ITT analysis was 7 months (range 1 47 months). According to the ITT analysis, the median time of survival resulted 14 months. Globally, about 50% of patients received oxaliplatin after irinotecan and fluorouracil, and in the GOIM 9901 series patients receiving second-line therapy had a median overall survival of 17 months [7]. According to the sites of disease, in the 208 patients with hepatic metastatic disease (3 patients are not evaluable at present in the GOIM protocol 2301) we observed 77 objective responses with an overall response rate (ORR) of 37%. In the 77 patients with lung metastases we obtained 20 objective regressions of the disease, with an ORR of 26%. Response rate in patients with primary rectal cancer was similar to patients with colon cancer. Rectal cancer: 29/91 objective responses (32%); colon cancer: 69/196 (35%) When considering the four stratification groups, the response rates (ITT analysis) were: 33% in group 1, 37% in group 2, 30% in group 3, and 39% in group 4.

4 iv59 Toxicity All but three patients (early to evaluate in GOIM protocol 2301) were evaluable for toxicity. There were two therapyrelated deaths as a result of hematological toxicity (febrile neutropenia); another patient died from a disseminated intravascular coagulation, not related to the treatment because of concomitant progressive disease. The percentages of the observed toxicities, according to the NCI criteria, are outlined in Table 3. Globally, toxicity was mild and grade 3 4 disturbances were uncommon. As expected, loss of hair, hematological and gastrointestinal toxicities (mainly grade 1 2) were the most frequent toxicities. Symptoms related to a cholinergic syndrome occurred in 17% of patients. All these events were manageable. Discussion In recent years, in the treatment of advanced colorectal cancer patients a number of new treatment options have become available. New approaches were clearly needed to improve clinical results. In particular, a bi-monthly schedule of 5FU bolus and continuous infusion combined with high-dose LV (LV5FU2 regimen) was randomly compared to the monthly NCCTG-Mayo Clinic regimen (5FU bolus and low-dose LV). In the 348 patients with measurable disease, this bimonthly schedule obtained better results and fewer grade 3 4 toxicities than the monthly schedule [10]. Therefore, this regimen became the new standard option for advanced colorectal cancer patients in some European countries. Furthermore, the development of new drugs, such as irinotecan (CPT-11), a specific inhibitor of topoisomerase I, has represented another significant progress for the management of colorectal cancer patients. Two large randomized multicenter European trials [11, 12] demonstrated the effectiveness of CPT-11 in second-line treatment of advanced colorectal Table 3. NCI Toxicities (percentages values) 9706* 9901* 2301** Total Total G3-4 Total G3-4 Total G3-4 Total G3-4 Leukopenia Neutropenia Thrombocytopenia Anemia Nausea/vomiting Diarrhea Mucositis Fever Loss of hair Cholinergic syndrome *All entered patients are evaluable. ** 38 evaluable pts (3 pts early to evaluate). cancer patients, with significant improvement in results when this drug was compared to supportive care alone or to FU by continuous infusion. In first-line therapy, phase II trials [6] and large European and American phase III trials [4, 13], confirmed better results with the addition of CPT-11 to FU/LV combination therapy. Therefore, the FOLFIRI regimen according to Douillard et al. [4] schedule represented a standard treatment in European countries. The efficacy and safety of this schedule is confirmed in the experience of the GOIM. 287 patients entered in three consecutive our trials (GOIM protocols 9706, 9901, and 2301) and an overall response rate of 34.5% was observed (37% in evaluable patients). When stable diseases were evaluated together with the objective responses, a high tumor growth control rate (71%) was demonstrated. Median response duration, time to progression and survival were similar to those observed in Douillard study. Furthermore, toxicity was mild with only two therapyrelated deaths as a result of hematological toxicity. In conclusion, our experience confirmed the efficacy of the addition of CTP-11 to LV5FU2 schedule and the mild toxicity of this regimen. FOLFIRI regimen together with FOLFOX combination therapy represent two efficacious first-line choices in the treatment of advanced colorectal cancer patients. Results of our study (GOIM protocol 9901) with a head-to-head comparison between these two regimens (FOL- FIRI and FOLFOX4) showed similar results, with different toxicity profile: more gastrointestinal side effects and alopecia in the FOLFIRI arm, more thrombocytopenia, neurotoxicity and hypersensitivity reactions in the FOLFOX4 arm [7]. Therefore, in the clinical practice the treatment choice must be individually tailored on these bases. The addition of new drugs should be probably improve these results. In particular, cetuximab and bevacizumab demonstrated antitumor activity alone or in combination with chemotherapy in patients with advanced colorectal cancer [14, 15], and some phase II and III trials are ongoing. Acknowledgement The authors wish to thank Dr Antonella Colucci for her assistance in the preparation of the manuscript. References 1. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 1992; 10: Meta-analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: de Gramont A, Bosset JF, Rougier P et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus

5 iv60 continuous infusion for advanced colorectal cancer: a French Intergroup Study. J Clin Oncol 1997; 15: Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet 2000; 355: De Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: Maiello E, Gebbia V, Giuliani F et al. 5-Fluorouracil and folinic acid with or without CPT-11 in advanced colorectal cancer patients: A multicenter randomized phase II study of the Southern Italy Oncology group. Ann Oncol 2000; 11: Colucci G, Gebbia V, Paoletti G et al. Phase III randomized trial of FOLFIRI vs FOLFOX4 in the treatment of advanced colorectal cancer: A multicenter study of the Gruppo Oncologico dell Italia Meridionale (GOIM).J Clin Oncol (in press) 8. Colucci G, Maiello E, Gebbia V et al. 5-Fluorouracil and levofolinic acid with or without recombinant interferon-2b in advanced colorectal cancer patients. A randomized multicenter study with stratification for tumor burden and liver involvement by the Southern Italy Oncology Group. Cancer 1999; 85: Miller AB, Hoogstraten B, Staquet M, Winkler M: Reporting results of cancer treatment. Cancer 1981; 47: de Gramont A, Bosset JF, Rougier P et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French Intergroup Study. J Clin Oncol 1997; 15: Rougier P, Van Cutsem E, Bajetta E et al. Randomized trial of irinotecan versus fluorouracil by coninuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 1998; 352: Cunningham D, Pyrhonen S, James RD et al. Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 2000; 343: Saltz LB, Meropol NJ, Loehrer PJ et al. Phase II of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004; 22: Kabbinavar F, Hurwitz HI, Fehrenbacher L et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21: Appendix The following investigators are members of the Gruppo Oncologico dell Italia Meridionale (G.O.I.M.) and are co-authors of the article: Oncology Institute, Bari: Severino Montemurro, Antonio Cramarossa, Vito Lorusso Centro Oncologico, Catania: Michele Caruso University, Palermo: Maria Rosaria Valerio Cardarelli Hospital, Naples: Teresa Guida M. Ascoli Hospital, Palermo: Biagio Agostara Ospedale Nord, Taranto: Salvatore Pisconti S. Carlo Hospital, Potenza: Gerardo Rosati Miulli Hospital, Acquaviva delle Fonti: Giuseppe Nettis Buccheri La Ferla Hospital, Palermo: Matteo Valdesi Fatebenefratelli Hospital, Benevento: Tonino Pedicini Analysis Center, Catania: Santo Fortunato Centro Riferimento Oncologico, Rionero in Vulture: Nicola Di Renzo G. Panico Hospital, Tricase: Ernesto Durini S. Luigi Hospital, Catania: Stefano Cordio La Sapienza University, Rome: Marisa Di Seri