Original article. P. Rougier 1 *, D. Lepille 2, J. Bennouna 3, A. Marre 4, M. Ducreux 5, L. Mignot 6, A. Hua 7 & D. Méry-Mignard 7.

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1 Original article Annals of Oncology 13: , 2002 DOI: /annonc/mdf259 Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study P. Rougier 1 *, D. Lepille 2, J. Bennouna 3, A. Marre 4, M. Ducreux 5, L. Mignot 6, A. Hua 7 & D. Méry-Mignard 7 1 Hôpital Ambroise Paré, Boulogne; 2 Clinique Pasteur, Evreux; 3 Centre Gauducheau, Nantes; 4 Hôpital, Rodez; 5 Institut Gustave Roussy, Villejuif; 6 Hôpital Foch, Suresnes; 7 Laboratoire Aventis, Paris, France Received 7 November 2001; revised 28 March 2002; accepted 12 April 2002 Introduction Background: We have investigated the efficacy, safety and quality of life profiles of three therapeutic combinations [irinotecan + leucovorin (LV)/5-fluorouracil (5-FU), oxaliplatin + LV/5-FU and irinotecan +oxaliplatin] in patients with metastatic colorectal cancer after failure of a 5-FU-based regimen, or whose disease had progressed within 6 months of the end of treatment. Patients and methods: One hundred and one patients were randomised to receive either: (i) irinotecan 180 mg/m 2 on day 1 followed by an LV 200 mg/m 2 infusion, before a 5-FU 400 mg/m 2 bolus followed by a 5-FU 600 mg/m 2 infusion (LV5FU2 regimen), on days 1 and 2 every 2 weeks; (ii) oxaliplatin 85 mg/m 2 on day 1 followed by the LV5FU2 regimen on days 1 and 2 every 2 weeks; or (iii) oxaliplatin 85 mg/m 2 followed by irinotecan 200 mg/m 2, both on day 1 every 3 weeks. The primary end point was overall response rate (ORR). Results: The intention-to-treat ORRs were 11.4% [95% confidence interval (CI) ), 21.2% (95% CI ) and 15.2% (95% CI ), respectively, in the three arms. Tumour growth control was 60% for all three combinations and overall survivals were 12.2 months (95% CI ), 11.5 months (95% CI ) and 11.0 months (95% CI ), respectively. All patients were evaluable for safety. Main grade 3 4 toxicity was neutropenia (33 to 39% of patients). Conclusions: Thus, second-line treatment with irinotecan/lv5fu2, oxaliplatin/lv5fu2 or irinotecan/oxaliplatin, provides good tumour growth control and survival coupled with an acceptable safety profile. Key words: 5-fluorouracil, irinotecan, metastatic colorectal cancer, oxaliplatin, second-line chemotherapy Colorectal cancer (CRC) is second in the league of cancer deaths worldwide, and the commonest cancer in France with new cases and deaths annually [1]. Primary treatment for CRC is surgical resection, but eventually 50% of patients will develop metastatic disease. For such patients, treatment with 5-fluorouracil (5-FU) has been the only option for over three decades. Optimisation of 5-FU-based therapy, by modulation with folinic acid [leucovorin (LV)] has shown a significant benefit in terms of tumour response rate (RR) when compared with single agent 5-FU (23% versus 11%) [2]. Similarly, continuous intravenous (iv) infusion rather than *Correspondence to: Dr P. Rougier, Hôpital Ambroise Paré, 9 Avenue Charles de Gaulle, Boulogne, France. Tel: ; Fax: ; philippe.rougier@apr.ap-hop-paris.fr bolus administration of 5-FU significantly enhances RRs (22% versus 14%) [3], and decreases haematological toxicity, mainly neutropenia [4]. The LV5FU2 regimen, consisting of high-dose LV administered bimonthly in combination with high-dose 5-FU given as a single bolus together with a continuous infusion, was associated with an improved response rate and progression-free survival compared with a low-dose 5-FU/LV monthly regimen [5]. Therefore, in France, the LV5FU2 or de Gramont regimen was one of the standard palliative chemotherapy regimens for CRC, prior to the development of the newer cytotoxic drugs, which have shown activity in this disease. Overall, 5-FU-based chemotherapy provides median survival times of months in a first-line setting. However, the emergence of two novel anti-neoplastic agents, irinotecan and oxaliplatin, both of which have demonstrated promising activity in the treatment of CRC, has allowed us to consider new therapeutic options for the treat European Society for Medical Oncology

2 1559 ment of patients who fail to respond to a first-line 5-FU-based regimen. Irinotecan, a semi-synthetic derivative of camptothecin, has been shown to exert its cytotoxic action via the potent and specific inhibition of the nuclear enzyme DNA topoisomerase 1 [6]. The cytotoxic effect of this agent and of its main active metabolite, SN-38, is specific to the S-phase of the cell cycle. Published phase II and III studies, have shown irinotecan monotherapy to have activity in both chemotherapy-naive patients and in patients who have failed to respond to prior 5-FU/LV chemotherapy, with an overall response rate (ORR) ranging from 13% to 32% [7 13]. Because combination therapy with non-cross-resistant drugs usually leads to enhanced antitumour activity compared to single-agent therapy, combined administration of irinotecan with the LV5FU2 regimen was assessed in a phase I study by Ducreux et al. [14]. Patients with metastatic CRC received a 90-min infusion of irinotecan, on day 1 every 2 weeks, at doses ranging from 100 to 300 mg/m 2. LV5FU2 was administered on days 1 and 2, commencing 1 h after the end of each irinotecan infusion. In this trial, antitumour activity was reported at almost all dose levels, with an objective response rate reaching 22% in pre-treated patients. Median time to progression and overall survival were 6.3 and 15 months, respectively. More recently, European and American phase-iii trials [15, 16] have shown that a combination of irinotecan with 5-FU and LV is associated with higher RRs and longer times to progression and survivals compared to the widely used regimen using 5-FU and LV in patients receiving first-line therapy for metastatic CRC. These trials led to the registration of this combination for the treatment of metastatic CRC in both Europe and the USA. Oxaliplatin, a diaminocyclohexane platinum compound which acts as an alkylating agent, has a broad spectrum of activity with marked differences from other platinum complexes, and especially with a proven antitumour activity against colon cancer cell lines [17]. The efficacy of oxaliplatin monotherapy has been demonstrated in phase II trials, in both 5-FUtreated and untreated patients, with ORRs ranging between 10% and 24% [18 20]. Evidence of synergism between oxaliplatin and 5-FU in vitro [21] led to numerous clinical trials to assess oxaliplatin in combination with the LV5FU2 regimen. These trials reported increased response rates reaching 18% 51% [22 24], with improvement in time to progression but no statistical benefit in overall survival [24]. This combination has been approved in Europe for first-line treatment of advanced metastatic CRC. Cytotoxic synergism between oxaliplatin and SN-38 (a highly active metabolite of irinotecan) has also been demonstrated in vitro when administered in combination to the human colon cancer cell line HT29 [25]. Results obtained in a number of clinical trials have shown promising efficacy and manageable toxicity profile of the irinotecan/oxaliplatin combination in patients resistant to 5-FU-based therapies [26 30]. However, at the time the present study was initiated, only results obtained with the 3-week combination regimen were available, with a 29% response rate in a single institution phase I II study [26]. To assess the efficacy and safety profile of the three combinations, i.e. irinotecan/lv5fu2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin, we designed a phase II trial in which patients were randomly assigned to receive one of the three combinations after failure of a 5-FU-based regimen. There was no comparison planned between the three arms related to the number of patients in the study. Patients and methods Patient selection To be eligible for this study, patients had to have histologically documented adenocarcinoma of the colon or rectum and metastatic disease with at least one bidimensionally measurable lesion according to World Health Organization (WHO) criteria. All patients had to have been previously treated with a 5-FU-based regimen and to have recorded progressive disease during treatment or after discontinuation of 5-FU, which had occurred <6 months before the first cycle of study treatment. Patients had not to have received more than one palliative schedule of 5-FU-based chemotherapy and the free window between the last antitumour treatment and randomisation had to be of at least 4 weeks for either chemotherapy, surgery or radiotherapy. All patients were required to be between 18 and 75 years of age, and to have a WHO performance status 2 and a life expectancy 3 months. Laboratory data requirements before study entry were as follows: haemoglobin 10 g/dl, absolute neutrophil count (ANC) /l, platelets /l, total bilirubin <1.25 institutional upper normal limit (IUNL), creatinine <1.25 IUNL, and serum glutamic oxaloacetic transaminase (AST) and serum glutamic pyzuvic transaminase (ALT) <3 IUNL (in case of liver metastasis: total bilirubin <1.5 IUNL; AST and ALT <5 IUNL). Exclusion criteria included: tumour type other than metastatic colorectal adenocarcinoma; pregnant or lactating women, patients (both sexes) with reproductive potential not using an adequate contraceptive method; prior chemotherapy with topoisomerase-1 inhibitors or platinum compounds; presence of central nervous system metastasis, current infection, unresolved bowel obstruction or sub-obstruction; uncontrolled Crohn s disease or ulcerative colitis; prior or current history of chronic diarrhoea or severe toxicity under 5-FU; other serious illness or medical condition (including contra-indication to 5-FU); past or current neoplasm other than colorectal carcinoma, except curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix; neuropathy; concomitant treatment with any other experimental drugs or with any other anticancer therapy; and patients who could not be regularly followed for psychological, social, familial or geographic reasons. Before entry and during the study, all patients were required to provide a complete medical history and to undergo a physical examination including assessment of weight, height and WHO performance status. Complete differential blood cell count and biochemical profile were performed 1 week prior to inclusion and on day 1 of each cycle. Blood analysis was conducted each week. Chest radiography and carcinoembryonic antigen test were required within 2 weeks before inclusion. At study entry and throughout the study, tumour assessment was carried out by computerised tomographic (CT) scan on target lesions (abdominal and/or thoracic

3 1560 CT scan) and other examinations if indicated (chest X-ray, ultrasound, clinical examinations). The protocol was approved by the appropriate ethics committee (CCPPRB: Comité Consultatif pour la Protection des Personnes qui se prêtent a une Recherche Biologique, Saint-Antoine Hospital) and conducted in compliance with the latest versions of the Declaration of Helsinki and of the Good Clinical Practices guidelines. All patients provided written informed consent before study entry. Chemotherapy regimens Patients were randomised within a stratification by centre to receive irinotecan/lv5fu2, oxaliplatin/lv5fu2 or irinotecan/oxaliplatin combinations. Each cycle of the irinotecan/lv5fu2 combination consisted of a 90-min infusion of irinotecan 180 mg/m 2 on day 1, followed l h later by the LV5FU2 regimen on day 1 and again on day 2 (120-min folinic acid 200 mg/m 2 infusion, immediately followed by 10-min 5-FU 400 mg/m 2 bolus then 22-h 600 mg/m 2 continuous infusion) every 2 weeks. For the oxaliplatin/lv5fu2 group, each cycle consisted of a 120-min infusion of oxaliplatin 85 mg/m 2 on day 1, immediately followed by the LV5FU2 regimen on day 1 and again on day 2 (see above) every 2 weeks. Each cycle of irinotecan/oxaliplatin was administered as a 120-min infusion of oxaliplatin 85 mg/m 2 followed 1 h later by a 30-min infusion of irinotecan 200 mg/m 2, every 3 weeks. Study treatment was administered for each patient until disease progression, or for a maximum of nine cycles for the irinotecan/lv5fu2 and oxaliplatin/lv5fu2 groups, and for six cycles for the irinotecan/ oxaliplatin group (18 weeks in each arm). Treatment could be discontinued in case of unacceptable toxicity, progressive disease or at the patient s request. After treatment, patients were followed up every 2 months until death. Doses reductions were allowed in the case of severe haematological and/or non-haematological toxicities. Dose adjustments were made according to the system showing the greatest degree of toxicity, with each adverse event being graded using the National Cancer Institute (NCI) common criteria. For haematological toxicities, a maximum of 2 weeks delay in treatment was allowed in case of neutropenia (ANC < /l) and/or thrombopenia (platelet count < /l). Before each cycle, dose adjustments were made according to nadir values. Doses reductions were also recommended in case of grade 3 4 diarrhoea, stomatitis, vomiting and/or in case of grade 3 peripheral neuropathy (according to the Levi scale). For any other non-haematological toxicity that occurred with grade 2, a maximum delay of 2 weeks was allowed to attempt recovery on grade 1. Efficacy assessment The primary efficacy end point was response rate, defined as the sum of complete responses (CR) and partial responses (PR) assessed according to WHO criteria. The assessment of tumour response was performed every 6 weeks (three cycles for the irinotecan/lv5fu2 and oxaliplatin/ LV5FU2 arms, or two cycles for irinotecan/oxaliplatin). Patients who were withdrawn from study before the first evaluation due to disease progression were classified as treatment failures (disease progression). A blinded evaluation of tumour response was made by an external response review committee (ERRC), which comprised a panel of two independent radiologists with particular experience in the evaluation of gastrointestinal tumours, and who were not involved in the study. Secondary efficacy end points included the duration of response and stabilisation, time to progression (TTP; calculated from the start of treatment to the first day of progression or to death due to progression) and overall survival, defined as the period from randomisation to death. Safety evaluation Each patient who received at least one infusion was evaluable for safety (intention-to-treat analysis). For haematological and biological parameters, at least one measure per cycle was required. All adverse events experienced during the study, before each treatment cycle and at the end of the study, were recorded and graded according to the NCI criteria classification or, if not applicable, as mild, moderate, severe or life-threatening. Adverse events were reported regardless of their relationship to the study drug, and the relationship was reported as unrelated, remote, possible or probable. Quality of life analysis Quality of life was evaluated using the European Organisation for Research and Treatment of Cancer (EORTC)-QLQ-C30 questionnaire, which includes 15 key dimensions [31]: five scales for functioning (physical, role, social, emotional and cognitive), one scale for overall health status and nine symptomatic scales (fatigue, pain, nausea/vomiting, dyspnoea, diarrhoea, constipation, anorexia, insomnia and financial difficulties). Patients had to complete questionnaires before each cycle and all questionnaires completed by the patients within 7 days before each treatment cycle were considered evaluable. Evaluation of quality of life was done by a descriptive analysis of evolution of each score from baseline to evaluation under treatment. Statistical analysis All statistical analyses were performed using the SAS software, version Categorical data were listed in contingency tables and continuous data were summarised by their median, minimum and maximum values. For time-related parameters, the Kaplan Meier method was used [32]. Response rates were evaluated in all treated patients and in the evaluable population. The 95% confidence intervals (CI) of response rates were calculated using a binomial estimation [33]. Since the main objective of this clinical trial was to obtain descriptive data on efficacy and safety profiles of the three combinations tested and to assess quality of life in treated patients, no rationale was used to determine the sample size of each group, and a total of 30 patients per combination was planned. Therefore, all analyses were only descriptive and no statistical hypothesis was tested. A stratified randomisation by centre was performed. Results Patient characteristics A total of 101 patients were randomised in 19 centres between June 1997 and August 1998: 35 patients in the irinotecan/ LV5FU2 group, 33 patients in the oxaliplatin/lv5fu2 group and 33 patients in the irinotecan/oxaliplatin group. All patients received at least one cycle of treatment. Baseline patient characteristics are presented in Table 1. Most of them were well balanced among the three groups. More than 90% of patients had a WHO performance status of 0 or 1 at baseline. Approximately 40% to 50% of patients in each group had at

4 1561 Table 1. Main baseline characteristics of the study patients. Characteristics Irinotecan/LV5FU2 group (n = 35) Oxaliplatin/LV5FU2 group (n = 33) Irinotecan/oxaliplatin group (n = 33) All (n = 101) Men/ women, n (%) 23 (66)/12 (34) 25 (76)/8 (24) 14 (42)/19 (58) 62 (61)/39 (39) Median age in years [range] 65.8 [ ] 65.3 [ ] 60.1 [ ] 64.6 [ ] WHO performance status, n (%) 0 20 (57) 19 (58) 19 (58) 58 (57) 1 12 (34) 13 (39) 11 (33) 36 (36) 2 3 (9) 1 (3) 3 (9) 7 (7) Primary tumour site, n (%) Colon 18( 51) 22 (67) 15 (45) 55 (54) Rectum 11 (31) 9 (27) 9 (27) 29 (29) Rectosigmoïd junction 6 (17) 2 (6) 9 (27) 17 (17) No. of organs involved, n (%) N = 1 20 (57) 17 (52) 16 (48) 53 (52) N = 2 11 (31) 13 (39) 13 (39) 37 (37) N 3 4 (11) 3 (9) 4 (12) 11 (11) Sites of metastases, n (%) Lung 12 (34) 11 (33) 12 (36.4) 35 (35) Liver 24 (68) 27 (82) 32 (97) 83 (82) Locoregional 3 (9) 1 (3.0) 4 (4) Lymph nodes 6 (17) 10 (30) 4 (12) 20 (20) Other locations 9 (26) 5 (15) 5 (15) 19 (19) Time between last chemotherapy and first infusion, n (%) <6 months 31 (89) 30 (91) 29 (88) 90 (89) 6 months 4 (11) 3 (9) 4 (12) 11 (11) No. of prior chemotherapies, n (%) (neo-adjuvant or adjuvant or palliative) 2 32 (91) 33 (100) 31 (94) 96 (95) 3 or 4 3 (9) 2 (6) 5 (5) Signs and symptoms Weight loss, grade 1 3; n (%) 6 (17) 2 (6) 7 (21) 15 (15) Respiratory function, grade 1 3; n (%) 6 (17) 7 (21) 13 (13) Pain, grade 1 3; n (%) 15 (43) 15 (45) 14 (42) 44 (44) Asthenia, grade 1 2; n (%) 13 (37) 12 (36) 12 (36) 37 (37) Laboratory abnormalities, n/total (%) White cell count > /l 5/35 (14) 7/33 (21) 13/33 (39) 25/101 (25) Haemoglobin <11 g/dl 4/35 (11) 4/33 (12) 4/33(12) 12/101 (12) Lactate dehydrogenase >2.6 UNL 4/30 (13) 4/26 (15) 10/29 (34) 18/85 (21) Alkaline phosphatase >1 UNL 14/31 (45) 14/32 (44) 20/33 (61) 48/96 (50) UNL, upper limit of normal. least two organs involved, with the liver being the most common site of metastatic disease. The frequency and profile of tumour-related symptoms and laboratory abnormalities were typical of advanced colorectal cancer patients. However, a greater incidence of several symptoms of disease at study entry could be seen for patients randomised in the irinotecan/ LV5FU2 and irinotecan/oxaliplatin groups than for patients included in the oxaliplatin/lv5fu2 group. Weight loss within 30 days before study entry was reported for 17%, 6% and 21% of patients in the irinotecan/lv5fu2 group, oxaliplatin/ LV5FU2 group and irinotecan/oxaliplatin group, respectively. Respiratory function impairment at baseline was noted for

5 % and 21% of patients in the irinotecan/lv5fu2 and irinotecan/oxaliplatin groups, respectively, whereas none was reported for patients randomised in the oxaliplatin/lv5fu2 group. Furthermore, the incidence of laboratory abnormalities at study entry, such as lactate dehydrogenase >2.6 UNL, alkaline phosphatase >1 UNL and white blood cells > /l, usually reflecting poorer prognosis factors [34, 35], was greater for the patients treated with irinotecan/oxaliplatin than in the two other treatment groups. Efficacy results Response rates, the primary end point of our study, evaluated by the ERRC, were provided according to intention-to-treat (ITT) analysis and are shown in Table 2. CT scan data from seven patients (two in the irinotecan/lv5fu2 group, two in the oxaliplatin/lv5fu2 group and three in the irinotecan/ oxaliplatin group) were unavailable for review. Accordingly, these patients were considered unassessable for evaluation by the ERRC, with the exception of one patient who went off study for clinical disease progression. In this latter case, best overall response for this patient was progressive disease. Three patients were classified as unassessable by the ERRC: one in the irinotecan/lv5fu2 group because the only target lesion had been irradiated before first evaluation, and the other two (one in each of the other arms) due to a lack of measurable lesions. The ITT response rates were 11.4% (95% CI ) in the irinotecan/lv5fu2 combination arm (four PRs), 21.2% (95% CI ) in the oxaliplatin/lv5fu2 combination arm (seven PRs) and 15.2% (95% CI ) in the irinotecan/oxaliplatin combination arm (five PRs). Tumour growth control rates [defined as CR + PR + SD (stable disease)] were 60%, 70% and 61% for the irinotecan/ LV5FU2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin groups, respectively. Median durations of response were 8.1, 6.7 and 7.9 months, and median durations of disease stabilisation were 4.4, 4.7 and 6.4 months in each arm, respectively. Median TTP was 3.2 months (95% CI ) in the irinotecan/lv5fu2 group, 4.7 months (95% CI ) in the oxaliplatin/lv5fu2 group and 4.2 months (95% CI ) in the irinotecan/oxaliplatin group. Overall survival in each arm was 12.2 months (95% CI ), 11.5 months (95% CI ) and 11.0 months (95% CI ), respectively. At the cut-off date, median follow-up time was 14.4 months (range months) and two patients were still undergoing treatment with irinotecan/ oxaliplatin. Extent of exposure Exposure to treatment is shown in Table 3. A total of 242 cycles (2-week schedule) was administered to 35 patients in the irinotecan/lv5fu2 group (median 7 cycles; range 1 17). Cumulative doses and median dose intensities were, respectively: irinotecan, 1240 mg/m 2 (range ) and 88 mg/m 2 /week (51 94); and 5-FU, mg/m 2 ( ) and 975 mg/m 2 /week ( ). In the oxaliplatin/ LV5FU2 group, a total of 244 cycles (2-week schedule) was administered to 33 patients (median 9 cycles; range 2 11). Cumulative doses and median dose intensities were, respectively: oxaliplatin, 674 mg/m 2 (range ) and 40 mg/m 2 / week (26 52); and 5-FU, mg/m 2 ( ) and 944 mg/m 2 /week ( ). A total of 178 cycles (3-week schedule) was administered to 33 patients in the irinotecan/ oxaliplatin group (median 6 cycles; range 1 17). Cumulative doses and median dose intensities were, respectively: irinotecan, 1023 mg/m 2 (range ) and 64 mg/m 2 /week (34 70); and oxaliplatin, 496 mg/m 2 ( ) and 28 mg/m 2 / week (19 30). Treatment administration was delayed for >7 days in 6%, 7% and 3% of cycles for patients in the irinotecan/lv5fu2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin groups, respectively. The main reason for treatment delays was haematological toxicity ( 60%) in the first two arms, and delays were Table 2. Efficacy endpoints as assessed by the Expert Panel in the intention-to-treat population Intention-to-treat population Irinotecan/LV5FU2 group (n = 35) Oxaliplatin/LV5FU2 group (n = 33) Irinotecan/oxaliplatin group (n = 33) Partial response [CI 95%] 4 (11.4%) [ ] 7 (21.2%) [ ] 5 (15.2%) [ ] Stable disease 17 (48.6%) 16 (48.5%) 15 (45.4%) Progressive disease 11 (31.4%) 7 (21.2%) 10 (30.3%) Unassessable 3 (8.6%) 3 (9.1%) 3 (9.1%) Tumour growth control rate (RP + SD) Median response duration, months [CI 95%] Median stabilisation duration, months [CI 95%] 60 % 70 % 61 % 8.1 [ ] 6.7 [ ] 7.9 [4.2 not reached] 4.4 [ ] 4.7 [ ] 6.4 [ ] Overall survival [CI 95%] 12.2 [ ] 11.5 [ ] 11.0 [ ] Time to progression [CI 95%] 3.2 [ ] 4.7 [ ] 4.2 [ ]

6 1563 Table 3. Extent of exposure to treatment No. of cycles Irinotecan/LV5FU2 group (n = 35) Oxaliplatin/LV5FU2) group (n = 33) Total Irinotecan/oxaliplatin group (n = 33) Per patient: median [range] 7 [1 17] (cycle every 2 weeks) 9 [2 11] (cycle every 2 weeks) 6 [1 17] (cycle every 3 weeks) Median relative dose intensity per patient [range] Irinotecan 0.98 [ ] NA 0.96 [ ] Oxaliplatin NA 0.94 [ ] 0.98 [ ] 5-FU 0.98 [ ] 0.94 [ ] NA Cycles with dose reduction irinotecan: 6% oxaliplatin: 4% irinotecan: 9% 5-FU: 0.5% 5-FU: 3% oxaliplatin: 3% Cycles delayed by more than 7 days a 6% 7% 3% a Except cycle 1. NA, not applicable. Table 4. Main treatment-related grade 3 4 adverse events reported in the study population: percentage of patients (% of cycles) Neutropenia Irinotecan/LV5FU2 group (35 patients; 242 cycles) Percentage of patients (% of cycles) Oxaliplatin/LV5FU2 group (33 patients; 244 cycles) Grade 3 21 (11) 18 (6) 18 (10) Grade 4 12 (4) 15 (4) 21 (6) With fever 9 (1.2) 6 (0.8) 3 (0.6) Nausea 14 (2) 18 (3) 6 (2) Vomiting 9 (1) 15 (2) 9 (2) Delayed diarrhoea 6 (0.8) 3 (0.4) 33 (8) Asthenia 9 (2) 12 (2) 15 (4) Peripheral neuropathy (grade 2 3) 36 (18) 24 (8) Hand-foot syndrome 3 (0.4) Alopoecia (grade 2) Irinotecan/oxaliplatin group (33 patients; 178 cycles) not related to study treatment for patients in the irinotecan/ oxaliplatin group. The median relative dose-intensity was 0.94 in each arm (see Table 3), regardless of the chemotherapy drug administered. Safety results All patients were evaluable for safety. The incidence of main treatment-related severe toxicities (according to the NCI-CTC scale) is outlined in Table 4, and is listed according to the worst grade observed per patient and by cycle. In each arm, the main grade 3 4 toxicity was neutropenia, which occurred in 33% of patients treated with the irinotecan/ LV5FU2 combination (15% of cycles), 33% of patients treated with the oxaliplatin/lv5fu2 combination (10% of cycles), and 39% of patients treated with the irinotecan/oxaliplatin combination (16% of cycles). The incidence of grade 4 neutropenia was 12%, 15% and 21% of patients in each arm, respectively, with few febrile neutropenia episodes (9%, 6% and 3% of patients in each group, respectively). No infection was observed concomitantly to grade 3 4 neutropenia. The other main toxicities were gastrointestinal, such as delayed diarrhoea and nausea/vomiting, but these were classified as severe in <10% of cycles, regardless of study arm. Grade 3 4 delayed diarrhoea occurred in 6%, 3% and 33% of patients in each group, respectively, with no grade 4 for patients treated in the first two arms and with 9% grade 4 for patients treated with irinotecan/oxaliplatin. Grade 3 4 nausea was reported for 14%, 18% and 6% of patients treated with irinotecan/ LV5FU2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin, respectively. Grade 3 4 vomiting was observed in 9%, 15% and 9% of patients, respectively.

7 1564 Grade 3 4 asthenia was also reported for 9%, 12% and 15% of patients in each arm (irinotecan/lv5fu2, oxaliplatin/ LV5FU2 and irinotecan/oxaliplatin), respectively. More specific adverse events with each drug were also observed. Grade 2 alopecia was experienced by 26% of patients treated with irinotecan/lv5fu2, and by 3% and 58% of patients treated with oxaliplatin/lv5fu2 and irinotecan/oxaliplatin chemotherapy, respectively. Grade 2 3 peripheral neuropathy occurred in both arms containing oxaliplatin: 36% of patients in the oxaliplatin/lv5fu2 group and 24% of patients in the irinotecan/oxaliplatin group, with 12% and 6% of patients experiencing grade 3 peripheral neuropathy, respectively. One treatment-related death occurred after the seventh cycle in the oxaliplatin/lv5fu2 arm, and a total of six patients discontinued treatment due to adverse events: three, two and one in the irinotecan/lv5fu2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin arms, respectively. Two patients, one in the irinotecan/lv5fu2 group and one in the irinotecan/ oxaliplatin group, discontinued due to a worsening of their condition after three and two cycles, respectively. The other four patients discontinued for the following reasons: febrile neutropenia after five cycles (irinotecan/lv5fu2 group), diarrhoea concomitant to infection during cycle 7 (irinotecan/ LV5FU2 group), persistent grade 1 neutropenia after seven cycles (oxaliplatin/lv5fu2 group), and grade 3 vomiting followed by cardiovascular collapse during cycle 7 (oxaliplatin/ LV5FU2 group). Quality of life Four hundred and seventy-six evaluable questionnaires were analysed. Compliance for completion of quality of life questionnaires was >60% for all three arms, except for the last cycle in arm A. Scores were evaluated for each item and each questionnaire, and analysis was realised for the 15 dimensions explored by the EORTC-QLQ-C30 questionnaire. Median changes in domains during treatment were given as the maximum variation compared with baseline. Global health status was stable in each arm during the study. No specific variation was observed in patients treated in the oxaliplatin/lv5fu2 and irinotecan/oxaliplatin groups. In the irinotecan/lv5fu2 group, however, three dimensions emotional, social and role improved with treatment (from baseline) and the symptom fatigue decreased evenly. The analysis also showed, across the three arms, a similar evolution of several items such as nausea/vomiting and diarrheoa, which tended to decrease with treatment, while pain tended to increase. Discussion Progression of CRC after first-line treatment with 5-FU is associated with short survival. The emergence of new drugs such as irinotecan and oxaliplatin, with mechanisms of action that are independent of thymidylate synthase inhibition, led to the development of alternative treatment options after failure of a 5-FU-based regimen. First-line irinotecan or oxaliplatin in combination with 5-FU and LV have already yielded very encouraging results, compared with 5-FU/LV alone, in large phase III studies [15, 16, 24]. Their efficacy as second-line therapy, however, has been reported only in highly specialised centres, and has not been established in an unselected patient population truly resistant to 5-FU in prospective randomised, multicentre studies with independent external review. The present study, of patients with documented 5-FUresistant metastatic CRC, has shown that second-line chemotherapy with combinations such as irinotecan/lv5fu2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin offers effective treatment. The overall response rates (RR) were 11.4% (95% CI ), 21.2% (95% CI ) and 15.2% (CI 95% ) in the above three groups, with response durations of 8.1 months (95% CI ), 6.7 months (95% CI ) and 7.9 months (95% CI 4.2 to not reached ), respectively. These results may be said to be in the same range when both ORR and duration of response are considered together with the overlap in the 95% CI values. The ORRs obtained in the present study, although lower than expected, were consistent with those reported in previous studies in pre-treated patients. RRs obtained in phase I studies for irinotecan/lv5fu2 and irinotecan/oxaliplatin combinations were 22% and 29%, respectively [14, 26]. Two reasons for the lower RR in our study could be the multicentre nature of the trial and the strict ITT analysis. Phase I studies usually include more selected patients and the difference in objective RR might be also due to a higher proportion of patients with poorer prognostic factors in our study. It is noteworthy, for example, that patients treated with the irinotecan/lv5fu2 combination had a smaller proportion of liver metastases and a higher number of other localisations compared with the other groups. Data from two other phase II trials using the irinotecan/lv5fu2 combination were obtained for heavily pre-treated patients (three or more lines), and RRs were 22% and 6% [36, 37], respectively. Recently, in a large phase III trial of sequential treatment by Folfiri/Folfox or inverse sequence in metastatic CRC patients, combinations of irinotecan (180 mg/m 2 ) or oxaliplatin (100 mg/m 2 ) with the simplified LV5FU scheme were evaluated both in first- and second-line therapy. The RR obtained with Folfiri was 56% in first-line and 4% in pretreated patients with the bi-therapy Folfox 6 [38]. In a recent phase II study, Becouarn et al. [30] reported a 23% RR in 5-FU-pre-treated patients treated with the irinotecan/oxaliplatin combination every 3 weeks. In another phase II study of the same combination, Scheithauer et al. reported a higher RR (41%), but with an intensified regimen and a higher doseintensity for oxaliplatin compared with the present study [27]. For the oxaliplatin/lv5fu2 combination, our results are consistent with those reported from two other published phase II studies conducted in pre-treated CRC patients, with RRs of 20% and 21% [22, 23], respectively, and with the recently

8 1565 communicated phase III study where RR was 15% in secondline therapy in patients treated first with the bi-therapy Folfiri [38]. This study also showed a high rate of disease stabilisation in each arm (>50%), leading to overall tumour growth control 60% in patients with documented progression at study entry. Disease stabilisation in metastatic CRC is more and more frequently associated with clinical benefit and survival [10, 34]. Our data in terms of efficacy, including stable disease, seem to be associated with an absence of quality of life deterioration. Indeed the global health status, as evaluated by the EORTC- QLQ-C30 questionnaire, was unchanged during the study whatever the arm, and, furthermore, in the irinotecan/lv5fu2 group, the emotional, social and role dimensions have been improved with treatment, with a decrease in symptoms of fatigue. The analysis also showed, across all three arms, a decrease in the number of adverse events (such as nausea/ vomiting and diarrhoea) with treatment, which could be related to dose adaptations when they occurred. The increase in pain may be due to disease evolution in each arm as all patients were analysed, including those who were discharged for disease progression. The median survival times from the start of study treatment were 12.2 months (95% CI ), 11.5 months (95% CI ) and 11.0 months (95% CI ) in the irinotecan/lv5fu2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin groups, respectively. These results compare favourably with those published for irinotecan or oxaliplatin used as secondline monotherapy, which range from 8.3 to 10.8 months [8 13, 18]. With respect to the new drugs, irinotecan or oxaliplatin, the improvement in patient therapeutic index (especially the non-haematological toxicities) for second-line combination regimens compared with monotherapy encourages consideration of associations of 5-FU with irinotecan or oxaliplatin as a therapeutic option. Furthermore, in our study, although most patients (>90%) had a performance status of 0 or 1, they showed poor prognostic factors such as tumourrelated symptoms, and an increase in lactate dehydrogenase or alkaline phosphatase, especially for patients treated in the irinotecan/oxaliplatin arm and, to a lesser extent, for those in the irinotecan/lv5fu2 and oxaliplatin/lv5fu2 arms. Thus, the overall tumour growth control and survival rates of 1 year obtained in this study, together with the stabilisation of health status, are of particular interest for patients with metastatic CRC who have failed to respond to first-line, 5-FU-based chemotherapy or who have progressed within 6 months of the end treatment. The present study also showed that the three combinations were generally well tolerated, with safety profiles consistent with previous studies. As expected, the main toxicities for the three arms were haematological and gastrointestinal disorders. Overall, grade 3 4 neutropenia was observed in the range of 33 39% of patients. However, the occurrence of complicated neutropenia (febrile neutropenia) was low in the irinotecan/ LV5FU2, oxaliplatin/lv5fu2 and irinotecan/oxaliplatin arms: 9%, 6% and 3% of patients, respectively, without severe infection. Grade 3 4 delayed diarrhoea was observed in 6%, 3% and 33% of patients in the three groups, respectively. The tolerance results of the large phase III study mentioned above, with sequential treatment by Folfiri/Folfox or inverse sequence, showed a similar safety profile for irinotecan or oxaliplatin combined with 5-FU/LV in second-line therapy [38]. The higher frequency of grade 3 4 diarrhoea in patients treated with irinotecan/oxaliplatin could be explained by the known safety profile of each drug administered alone. Despite this, such incidence has not been reported in other studies of this combination used in previously treated patients. Grade 3 4 diarrhoea occurred in 17% and 10% of patients ([26] and [30], respectively) in the 3-week schedule, and was observed in 30% of patients in the 2-week schedule [28]. Furthermore, diarrhoea can easily be managed by good compliance with early anti-diarrhoeal treatment and, if necessary, subsequent dose reduction to improve digestive tolerance in further cycles. The other relevant gastrointestinal toxicities were nausea and vomiting, which occurred in <20% of patients (<5% of cycles) in the three groups, even though no specific recommendations with respect to prophylactic anti-emetic treatment had been made at the time of entry into the study. The known safety profiles of irinotecan and oxaliplatin explain the other nonhaematological toxicities observed in the three arms, such as alopecia in the irinotecan/lv5fu2 and irinotecan/oxaliplatin groups, or peripheral neuropathy in the oxaliplatin/lv5fu2 and irinotecan/oxaliplatin groups. The difference in the incidence of alopecia in the irinotecan/lv5fu2 group compared with the irinotecan/oxaliplatin group could be related to the known safety profile of the schedule administration and to the cumulative toxicity of both drugs in the irinotecan/oxaliplatin group. The occurrence of grade 2 3 peripheral neuropathy was more frequent in the oxaliplatin/lv5fu2 group (36% of patients) compared with the irinotecan/oxaliplatin group (24% of patients), with grade 3 peripheral neuropathy in 12% and 6% of patients, respectively. These results are in agreement with those of previously published trials using the same type of schedule in second-line treatment [22, 23, 26, 30], and can be explained by the higher cumulative dose and dose-intensity of oxaliplatin administered in the oxaliplatin/ LV5FU2 group as a result of the 2-week rather than the 3-week schedule (674 mg/m 2 and 40 mg/m 2 /week compared with 496 mg/m 2 and 28 mg/m 2 /week, respectively). In conclusion, this study showed that at least 60% of patients with metastatic CRC who have progressed after a previous 5-FU-based palliative regimen are likely to benefit in terms of tumour growth control from second-line combination with one or both of the new drugs, irinotecan and oxaliplatin, with manageable safety and promising survival. These results clearly re-enforce the concept of utility of second-line chemotherapy regimens and highlight the need for new trials to improve their efficacy with the addition of other agents.

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