A phase II study of Tomudex alternated with methotrexate, 5-fluorouracil, leucovorin in first-line chemotherapy of metastatic colorectal cancer

Annals of Oncology 10: 985-987, 1999. © 1999 Kluwer Academic Publishers. Primed in the Netherlands.

Short report A phase II study of Tomudex alternated with methotrexate, 5-fluorouracil, leucovorin in first-line chemotherapy of metastatic colorectal cancer S. Cascinu,1 R. R. Silva,2 R. Labianca,3 S. Barni,4 R. Mattioli,5 G. Martignoni,6 L. Frontini,7 G. Gasparini,8 V. Catalano,1 A. M. Baldelli,1 L. Giuliodori,2 R. Agostinelli1 & G. Catalano1 Unita Operativa di Oncologia Medica, Aiienda Ospedaliera 'Ospedale S. Salvatore', Pesaro; Unita Operativa di Oncologia Medica, Ospedale Profiii, Fabriano, 3 Unita Operativa di Oncologia Medica, Ospedali Riuniti, Bergamo: " Unita Operativa di Radioterapia ed Oncologia Medica, A zienda Ospedaliera 'S Gerardo' Monza; 5 Unila Operativa di Oncologia Medica, Ospedale di Fano: 6 Unita Operativa di Oncologia Medica, Aztenda Ospedaliera 'S. Carlo Borromeo, Milano; 1 Unita Operativa di Oncologia Medica, Azienda Ospedaliera 'Ospedale S. Paolo', Milano; Unita Operativa di Oncologia Medica, Azienda Ospedaliera 'Bianchi-Melacrino', Reggio Calabria, Italy

whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three Purpose: This multicenter phase II study was designed to peritoneal carcinomatosis. Four patients achieved objective assess the efficacy of the alternating schedule of tomudex with responses (one complete and three partial), for an overall methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) response rate of 12% (95% CI: 0%-22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival in first-line chemotherapy for metastatic colorectal cancer. Patients and methods: Patients with histologically proven for all patients was 13 months. Two patients experienced grade metastatic colorectal cancer and at least one bidimensionally 3 WHO neutropenia while hepatotoxicity was reported in 13 measurable lesion, aged 18-70, with performance status =S 2, patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting normal baseline biological values, and no prior chemotherapy, that this combination could increase hepatic toxicity in comwere selected. Treatment was tomudex 3 mg/m2 and, after two parison to tomudex or MTX/5-FU alone. weeks, MTX, 200 mg/m2 by 30' infusion after hydration with Conclusions: Our results suggest that this regimen does not 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m2 warrant further investigation in advanced colorectal cancer and leucovorin, orally, 15 mg for six times every 6 hours, patients, at least not with this schedule and doses. beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles. Key words: alternating regimens, colorectal cancer, methoResults: Thirty-four patients were enrolled in this study, of trexate/5-fluorouracil combination, Tomudex Summary

were the case, Tomudex could replace the 5-FU infusional part of the hybrid regimen developed by our group In spite of its limited efficacy, 5-fluorouracil (5-FU) is [5]. However, the combination of the two regimens still the mainstay of chemotherapy for colorectal malig- could also determine the theoretical risk of an overlap nancies. In recent years the addition of modulated agents or potenzialization of toxicity, especially hepatotoxicity, (methotrexate (MTX) or leucovorin (LV) to 5-FU has leading to significant dose reductions of drugs. An improved the outcome of treatment of colon cancer, approach which would avoid such an overlap and would even though an objective clinical response is obtained in make it possibe to design a trial with a full dose of each no more than 20% of patients with advanced disease [1]. single agent, is to alternate delivery of the drugs. The Recently, new drugs, such as Tomudex, CPT-11 or aim of this phase II study was therefore to assess the oxaliplatin, have appeared to be promising. Tomudex is combination of tomudex given every other cycle altera direct and specific thymidylate synthase (TS) inhibitor nating with the regimen of MTX/5-FU/LV in advanced [2]. After the first promising results, however, no more colorectal cancer. than 20% of patients usually achieve a clinical response to this drug [3]. The resistance of the majority of the patients can be explained by mutations or increased Patients and methods levels of TS [4]. Because the combination of MTX/5-FU works Patient selection through a different pathway by the inhibition of RNA synthesis, an alternating administration of tomudex and Patients with histologically verified unresectable metastatic disease MTX/5-FU could result in increased cytotoxicity. If this were eligible for the study. The eligibility criteria included: measurable Introduction

986 disease, age less than 70 years, performance status (ECOG) 0-2, life expectancy > 3 months, and no serious concomitant disease affecting liver, heart, kidney. Exclusion criteria were prior chemotherapy, the presence of CNS metastases and severe concomitant non-malignant diseases. Written informed consent was obtained from all patients, as were Ethics Committee approvals in ac cord with local requirements.

Chemotherapy regimen All patients were treated with tomudex 3 mg/m 2 and, after two weeks, MTX, 200 mg/m 2 by 30' infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m 2 and LV, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Treatment was to be administered for up to six alternating cycles or until the appearance of disease progression or unacceptable toxicity, or patient refusal.

Assessment of response and toxicity The primary efficacy end points assessed were the objective response rate and toxicity. Evaluation of response was performed after three alternating cycles, while toxicity was evaluated weekly according to standard WHO criteria [6], Secondary efficacy end points included response duration and overall survival.

Table 1. Patient characteristics. Number of patients Sex Male Female Age Median Range Performance status (ECOG) 0 1 2 Primary tumor location Colon Rectum Sites of disease Liver Lymph nodes Lung Peritoneum Local relapse

Results From November 1997 to June 1998, investigators from 8 institutions treated 34 advanced colorectal cancer patients with this regimen. The characteristics of the patients are listed in Table 1.

26 8 62 43-69 10 16 8 24 10 24 5 4 3 9

Table 2 Toxicity: worst grade per patient across all cycle Toxicity

Statistical methods A two-stage design was used with a minimum of 17 patients and a maximum of 34 patients, so that the trial could be stopped early if the combination did not produce a response rate of at least 40%. The probability that the trial would be stopped early, i.e., two or fewer responses in the first 17 patients, was aproximately 3% if the true response rate was at least 40%. The regimen would have been considered promising if at least 10 responses were achieved in 34 patients. The probability that 10 or more responses would be observed if the true response rate was 40%, was 82% while there was an only 6% probability of observing 10 or more responses if the true response rate was 20% [7].

34

Hepatic Neutropenia Diarrhea Mucositis Renal Nausea/vomiting

MTX/5-FU toxicity grade

Tomudex toxicity grade 1

2

3

4

1

2

6 2

2 2

3 1

_ -

4 2 2 3

1

_ -

1 -

1 _ 2

3

1 1 2 1 1

4 _ -

represented the most common and severe side effect (Table 2). In fact it was reported in 13 patients (38%), with four patients presenting grades 3 and 4 hepatic toxicity. Furthermore, of the three patient hospitalizations two were due to hepatic toxicity and the third to neutropenia. Hematological toxicity was mild with only two patients developing grades 3 and 4 neutropenia. No drug-related deaths were reported.

Discussion Tumor response Objective tumor response was seen in 4 of 34 patients (12%, 95% CI: 0%-22%), with 1 complete response. Fourteen patients had stable disease and sixteen progressed on therapy. The duration of responses was: nine, six, six, and five months. With a median follow up of 18 months, the median progression-free survival was 5 months, and the median survival was 13 months. Toxicity A total of 130 cycles of tomudex and 128 of MTX/5-FU/ LV were administered during the study. Hepatotoxicity

Sobrero et al. showed that the mechanism of cell kill by 5-FU differs depending on its mode of administration, whether short-term infusion or continuous infusion [8]. It was hypothesized that combining these two different schedules of administration would result in an enhancement of cytotoxicty of 5-FU [9]. In the clinical setting, sequential MTX/5-FU/LVand 5-FU continuous infusion were chosen as the two components of the combined regimen because they satisfied the concept of scheduleoriented biochemical modulation. In fact, while 5-FU given by continuous infusion inhibits TS, pretreatment of 5-FU with MTX has been shown to enhance the amount of fluorouridine triphosphate incorporated into RNA

987 [5]. A phase II study showed particularly encouraging results in terms of response rate, which were subsequently confirmed in a randomized trial regarding the time to progression and survival [5, 10]. Tomudex is a direct and specific TS inhibitor, more potent than 5-FU [3,4], Because of its convenient dosing schedule of a single i.v. injection once every three weeks, tomudex was thought to be an appropriate replacement for the 5-FU infusional part of the hybrid regimen developed by Sobrero et al. in an attempt to simplify the schedule. The objective of this multicenter phase II study was to assess the efficacy of the alternating combination of Tomudex with MTX/5-FU/LV in thefirst-linetreatment of metastatic colorectal cancer. With four objective responses, this alternating schedule yielded the disappointing response rate of 12%, much lower than that obtained with the original regimen including 5-FU continuous infusion [5,10]. Some aspects of the schedule selected for this study, rather than comprising a failure of the hypothesis of the schedule-oriented biochemical modulation, could explain these disappointing results. The interval between the drugs could not be optimal: four weeks for each one instead of two weeks for MTX/ 5-FU/LV and three weeks for Tomudex. Better results could have been obtained by using these two regimens sequentially, as first- and second-line treatments and not in an alternating fashion from the beginning, so that the interval between the administration of the same regimen could be the one suggested by previous studies. Furthermore, the combination of MTX/5-FU/LV with Tomudex, even with an alternating regimen, can increase hepatic toxicity, leading to delays or dose reductions, without increasing the activity. Longo et al. showed that Tomudex can enhance 5-FU cytotoxicity, given by bolus when tomudex is given before 5-FU, whereas simultaneous drug exposure or the opposite sequence produced less-than-additive effects [11]. Thus, the alternating administration of the two drugs could result in no advantage but only in a higher incidence of side effects. In spite of the disappointing results in terms of response rate, the median survival of 13 months could be considered encouraging. However, it might be due to the favourable characteristics of the patients enrolled in this phase II study (26 patients had PS 0-1; two-thirds

of patients had liver metastases and about 50% of them had only one metastatic site) rather than to an effect of treatment. In conclusion, the alternating combination of Tomudex with MTX/5-FU/LV does not seem to be more effective than the original schedule including 5-FU, while toxicity is more severe. In our opinion, this regimen does not deserve further investigation, at least not with this schedule. References 1. Seymour MT. Colorectal cancer: Treatment of advanced disease. Cancer Treat Rev 1998; 24: 119-31. 2. Tuoroutoglu N, Pazdur R. Thymidilate synthase inhibitors. Clin Cancer Res 1996; 2: 227-43. 3. Sobrero AF. The potential role of Tomudex in the treatment of advanced colorectal cancer. Tumori 1997; 83: 576-80. 4. Johnstone P, Behan K, Allegra C. Fluorouracil: Active in ZD1694 (Tomudex) resistant cell lines with markedly elevated thymidilate synthase levels. J Natl Cancer Inst 1995; 87: 1558-9. 5. Sobrero AF, Aschele C, Gulgielmi AP et al. Schedule-selective biochemical modulation of 5-fluorouracil: A phase II study in advanced colorectal cancer. Clin Cancer Res 1995; 1. 955-60. 6. Miller AB, Hoodgstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-14. 7. Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10: 1-10. 8. Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal cancer - a tale of two drugs: Implications for biochemical modulation. J Clin Oncol 1997; 368-81. 9. Sobrero AF, Aschele C. Guglielmi AP et al. Synergism and lack of cross-resistance between short-term and continuous exposure to fluorouracil in human colon adenocarcinoma cells. J Natl Cancer Inst 1993; 85: 1937^44. 10. Sobrero AF, Frassineti GL, Giuliani R et al. Randomized comparison between sequential MTX/5-FU and schedule specific biochemical modulation in advanced colorectal cancer. Ann Oncol 1998; 9 (Suppl 4): 157. 11. Longo GSA, Izzo J, Chang YM et al. Pretreatment of colon carcinoma cells with tomudex enhances 5-fluorouracil cytotoxicity. Clin Cancer Res 1998; 4: 469-73. Received 23 February 1999; accepted 27 May 1999. Correspondence to: Prof. S. Cascinu Oncologia Medica Azienda Ospedaliera 'Ospedale S.Salvatore' 61100Pesaro Italy