ANTICANCER RESEARCH 24: 1139-1142 (2004)

Activity and Toxicity of Oxaliplatin Plus Raltitrexed in 5-Fluorouracil Refractory Metastatic Colorectal Adeno-Carcinoma

AGATA LAUDANI1, VITTORIO GEBBIA2, VITA LEONARDI1, GIUSEPPINA SAVIO1, NICOLA BORSELLINO3, MARIA PIA CUSIMANO1, CATERINA CALABRIA1, ROSARIA STEFANO1 and BIAGIO AGOSTARA1

1Division of Medical Oncology, Oncological Hospital "M. Ascoli", Palermo; 2Medical Oncology, University of Palermo, and Medical Oncology Unit, La Maddalena Clinica for Cancer, Palermo; 3Medical Oncology Unit, Ospedale Fatebenefratelli Buccheri - La Ferla, Palermo, Italy

Abstract. Background: This study evaluated the antitumor and/or metastatic disease. These patients are therefore efficacy and safety of a novel oxaliplatin/raltitrexed potential candidates for palliative chemotherapy. combination in pretreated advanced colorectal cancer Until recently these patients had few therapeutic options, patients. Patients and Methods: Forty-five patients with 5- mainly represented by 5-fluorouracil (5FU) as a single agent fluorouracil-refractory metastatic colorectal cancer received or in combination with folinic acid (FA) or methotrexate raltitrexed 3.0 mg/m2 as a 15-minute intravenous (i.v.) (2,3). Now regional treatments and various new infusion, followed 45 min later by l-OHP 130mg/m2 iv as 2-h chemotherapeutic agents have become clinically available. venous infusion on 1 day every 3 weeks. All patients had In fact the bimonthly combination of bolus plus continuous histologically proven metastatic colorectal cancer, age 18-75, venous infusion of 5FU and FA, and combination of 5 FU measurable disease and normal baseline biological values. with new cytotoxic agents such as oxaliplatin (l-OHP) and Most patients (60%) had >2 disease sites. All patients were irinotecan have been shown to be superior to modulated assessed for safety and also for response according to an intent- 5FU in terms of time to progression and, for the latter, to-treat fashion. Results: The overall response rate was 29% overall survival (4-7). (95% CL 16%-44%) including one CR (2%) and 12 PR Clinical trials investigating innovative chemotherapeutic (27%). Six patients (16%) showed a stabilization of disease agents have shown that l-OHP and raltitrexed demostrated for a tumor growth control rate of 45%. The median time to significant single agent activity as first- and second-line progression was 4 months (range 1-12+) and median overall treatment (8-12). Raltitrexed is a thymidylate synthase (TS) survival was 9 months (range 1-29+). Conclusion: These data inhibitor, that blocks the production of thymidine confirm that this oxaliplatin/raltitrexed combination is effective monophosphate from deoxyuridine monophosphate in a against metastatic colorectal carcinoma, well tolerated with reaction- specific manner. Although one trial showed a low grade toxicity and easy to administrer. Further evaluation survival advantage in favour of 5FU/FA, raltitrexed has of this regimen seems warranted as an alternative to demonstrated antitumor activity comparable with bolus fluoropyrimidine-based combinations. FU/LV regimens with similar response rates in 4 randomized phase III trials (13-15). Colorectal carcinoma is one of the most common cancer L-OHP is a third generation platinum-compound types in the Western world, with more than 30% of cases derivative that principally forms intra-strand DNA adducts. diagnosed at advanced stage (1). Approximately 50% of all L-OHP has shown activity in both chemotherapy-naive and newly diagnosed patients ultimately will develop recurrent FU/FA-pretreated patients with advanced colorectal cancer (16). In a phase III trial, l-OHP in combination with 5FU achieved a response rate of 51% and time to progression of 9.0 months (3). Since preclinical and clinical data suggest Correspondence to: Dr. Vittorio Gebbia, Divisione di Oncologia the existence of at least an additive effect of raltitrexed and Medica, Via Alessandro Paternostro 48, 90133 Palermo, Italia. Tel: ++39-091- 6806710, e-mail [email protected] l-OHP in various tumor types, the combination of these drugs with different mechanisms of action and toxicity Key Words: Colorectal cancer, metastases, raltitrexed, oxaliplatin. profiles seems particularly attractive (17,18).

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The aim of our study was to evaluate the activity of this Table I. Patients characteristics. combination in patients with advanced colorectal cancer N. enrolled patients 45 (100%) failing 5FU-folinic acid regimens and to confirm its favorable toxicity profile. Sex (male/female) 26/19

Patients and Methods Median age (range) 61 (44-75)

Eligibility criteria. Patients with histologically proven metastatic or Median ECOG PS (range) 1 (0-2) locally recurrent colorectal adenocarcinoma and bidimensionally measurable disease according to the WHO criteria were considered Histology (adenocarcinoma) elegible for this study. All patients must have developed progressive disease after palliative fluoropyrimidine-based - grade 1 4 (8%) - grade 2 21 (47%) chemotherapy or within 3 months since the completion of adjuvant - grade 3 13 (29%) chemotherapy. Other eligibility criteria included: age between 19 - nos 7 (16%) and 75 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, life expectancy of at least 3 months, Site of primary disease (colon/rectum) 28/17 (62%/38%) adequate bone marrow function (leucocyte count >3,500/ÌL, platelet count> 100,000/ÌL), adequate renal (BUN < 50 mg%, Previous treatments serum creatinine < 1.2 mg%) and hepatic (serum transaminases < 2 times the normal value, serum total bilirubin < 1.2 mg%) - Surgery 45 (100%) functions and geographical accessibility in order to guarantee a - Adjuvant radiotherapy 13 (29%) close follow-up. - Radiotherapy for advanced disease 2 (4%) Exclusion criteria included the presence of central nervous - Adjuvant chemotherapy 18 (40%) system metastases, serious or uncontrolled concurrent medical - Chemotherapy for advanced disease 42 (93%) illness, peripheral neuropathy and a history of other tumors, with the exception of adequately excised uterine cervical or basal skin Sites of disease carcinomas. Informed consent according to institutional regulations was obtained from all patients prior to study entry. - Liver 33 (73%) - Lung 19 (42%) Study design. The primary end-point of the study was response rate - Pelvic mass 14 (31%) evaluated according to WHO criteria and analysis of side-effects - Node 14 (31%) recorded according to the NCI Common Toxicity Criteria. - Pleura 4 (8%) Secondary efficacy end-points included the duration of response as - Peritoneum 4 (8%) measured from onset of the best response to date of disease - Bone 3 (7%) progression, progression- free survival as calculated from the - Adrenals 2 (4%) starting date of treatment to the time of progression or relapse, and overall survival.

Treatment. All patients received raltitrexed 3.0 mg/m2 as a 15-minute intravenous (i.v.) infusion, followed 45 min later by l-OHP 130mg/m2 employed as needed. Disease response was assessed every three i.v. as a 2-h venous infusion on 1 day every 3 weeks. Prophylactic treatment cycles. Briefly, tumor response was defined as complete anti-emetic treatment with 5HT3 antagonists plus dexamethasone response (CR) when all tumoral lesions disappeared completely for was systematically administered. In the case of grade 3 hematological at least 4 weeks without the appearance of any new lesion; partial toxicity, dose reductions were not recommended and treatment was response (PR) if there was a > 50% reduction in the sum of the delayed by one week. In case of grade 4 hematological toxicity or any products of the longest perpendicular diameters of tumoral lesions; other severe organ toxicity, the doses of both drugs were reduced by stable disease (SD) as < 50% decrease or < 25% increase in the 25%. L-OHP was discontinued if persisting paresthesia associated size of neoplastic deposits, and progressive disease as a >25% with pain and/or functional impairment occurred, or if a patient increase in the size of metastases and/or the appearance of any new experienced any other kind of severe neurotoxicity. Short course lesion. Complete blood cell counts with platelet and differential radiotherapy to bone tumors for pain control was the only counts were performed weekly during treatment, and biochemistry concomitant anticancer treatment permitted during the study. analyses were repeated before every cycle. Subjective symptoms, Patients with complete response after six cycles or disease performance status, adverse events and physical examination were progression did not receive further chemotherapy. Patients with recorded before each treatment cycle. The above-reported partial response or stable disease continued chemotherapy until examinations were repeated for restaging as needed. progression, unacceptable toxicity or refusal. Statistics. The distribution of time to progression and overall Disease assessment. Prior to chemotherapy, all patients were survival were calculated from the start of chemotherapy until the assessed by medical history, physical examination, date of death or last follow-up using the Kaplan-Meier product- hemocromocytometric analysis, blood chemistry tests, chest x-rays. limit method. Responses were reported as relative rates with their and imaging evaluation (CT scan, MRI, ultrasound). Endoscopy was 95% confidence limits.

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Table II Response rates.

Type or response No of patients Percent

Overall response rate 13 29% Complete response 1 2% Partial response 12 27% Stable disease 6 13% Progression 26 58%

Results

Patient characteristics. Between February 2000 and May 2002, a total of 45 patients entered this bi-institutional trial : all patients were considered assessable for toxicity, whereas 42 patients were considered assessable for response. The Figure 1 Time to progression and overall survival curves. demographic and disease history characteristics of enrolled patients are shown in Δable I. The median age was 61 years (range 44-75 years), with 26 men (60%) and 19 women (40%). The large majority of patients had an ECOG Toxicity. All 45 patients were assessable for toxicity. performance status of 0 - 1. In 62 % of patients the primary Hematological toxicity was generally mild to moderate and disease site was the colon, while 38 % of patients had rectal fully reversible within one week in all patients. Grade 1 carcinoma. All patients had previous surgery for primary leukopenia occurred in 2 patients (5%). One patient (3%) disease and 5 patients also had liver surgery for metastatic developed grade 3 anemia requiring packed RBC disease. Previous treatments also consisted of adjuvant transfusion. No patient suffered from thrombocytopenia. radiotherapy in 29% of cases and adjuvant chemotherapy in Among non-haematological adverse reactions, transient, 40% of patients. Two patients had radiotherapy for pain mild to moderate gastrointestinal toxicities commonly control due to bone metastases. Overall 42 patients (93%) developed. However grade 3 nausea/vomiting was observed in had received previous front-line 5FU-based chemotherapy 3 patients (8%), grade 2 in 10 (25%); grade 3 diarrhea and 8 patients (18%) also a second-line chemotherapeutic occurred in only 3 patients (8%) and grade 2 in 3 (8%), treatment. transient grade 1-2 transaminitis occurred in 5 patients (13%). All but 14 patients had multiple metastases involving 2 or Asthenia, a side-effect characteristic of raltitrexed, was more organ systems. The sites of metastases were liver severe in 5 patients (13%). L-OHP-induced peripheral (73%), lung (42%), pelvic region (31%), node (31%), neurosensory toxicity was observed in 5 patients (13%), but pleura (8%), peritoneum (8%), bone (7%) and adrenals only 2 experienced moderate to severe neuropathy. Minor (4%). A total of 178 courses of chemotherapy were side-effects were fever, abdominal pain, renal toxicity, administered to the 40 patients, with a median number of 4 hypotension and stomatitis. cycles/patient (range 1-10). Discussion Response to therapy. Overall 42 out of 45 patients (93%) who entered this study had an adequate follow-up and were Advanced colorectal carcinoma (ACRC) has been fully assessable for both response and toxicity. One patient traditionally considered as a cancer resistant to systemic had early progression and two patients refused to continue chemotherapy; nevertheless new therapeutic approaches chemotherapy after the second cycle. Antitumor responses have changed the natural history of advanced colorectal are shown in Table II. The overall response rate was 29% cancer. Innovative 5FU schedules and new active drugs (95% CL 16%-44%) including one CR (2%) and 12 PR offer patients first- and second-line treatments with a higher (27%). Six patients (16%) showed a stabilization of disease. chance of achieving an objective response and hopefully The site of tumor involvement in one patient who longer survival than standard modulated 5FU regimens. experienced CR was the liver. Figure 1 shows time to Response rates as single-agent are of only 15-25%, but progression and overall survival curves. The median time to greater interest is observed when these agents are disease progression was 4 months (range 1-12+). Median administered in combination with 5FU and leucovorin, with overall survival was 9 months (range 1-29+). significant improvement in OR and median survival.

1141 ANTICANCER RESEARCH 24: 1139-1142 (2004)

This bi-institutional phase II study analyzed the toxicity and 9 Scheithauer W, Kornek GV, Schuell B et al: Second-line treatment efficacy of the combination of raltitrexed and l-OHP in with oxaliplatin plus raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorin based chemotherapy. patients with pretreated ACRC, following the interesting Ann Oncol 12: 709-714, 2001. results reported with this regimen in medical literature 10 Cascinu S, Graziano F, Ferraù F et al: Raltitrexed plus oxaliplatin (8,9,19). The schedule employed in this trial had already been (TOMOX) as first-line chemotherapy for metastatic colorectal tested in phase I study by other authors (8,17,19). In this study cancer. A phase II study of the Italian Group for the Study of a major objective response was achieved in 13 patients for an Gastrointestinal Tract Carcinomas. Ann Oncol 13: 716-720, 2002. overall response rate of 29% (95% CL 16%-44%), including 11 Seitz JF, Bennouna J, Paillot B et al: Multicenter non randomized phase II study of raltitrexed (Tomudex) and oxaliplatin in non- one CR (2%). Six patients (16%) showed a stabilization of pretreated metastatic colorectal cancer patients. Annals of disease for a tumor growth control rate (CR+PR+SD) of Oncology 13: 1072-1079, 2002. 45%. The median time to progression was 4 months (range 1- 12 Neri B, Doni L, Fulignati F et al: Raltitrexed plus oxaliplatin as 12+), while median overall survival was 9 months (range 1- first-line chemotherapy in metastatic colorectal carcinoma: a 29+). Palliation of cancer-related symptoms, i.e. reduction of multicentric phase II trial. Anti-Cancer Drugs 13: 719-724, 2002. 13 Cunningham D, Zalcberg JR, Rath U et al: Tomudex (ZD1694): pain , improvement of performance status and increase of results of a randomized trial in advanced colorectal cancer body weight, was observed in 60% of symptomatic patients. demonstrate efficacy and reduced mucositis and leucopenia. The These results are in the range reported by other Tomudex Colorectal Cancer Study Group. Eur J Cancer 31A: investigators for pre-treated patients (8, 19-21). Compared 1945-1954, 1995. to other studies using the same regimen, we observed less 14 Harper P: Advanced colorectal cancer: results from the latest raltitrexed (tomudex) comparative study Abstract Proc Am Soc Clin hematological toxicity and fewer non-hematological adverse Oncol 16: 228a, 1997. events including diarrhea and vomiting when compared to 15 Pazdur R and Vincent M: Raltitrexed (Tomudex) versus 5- CPT-11 or continuous venous infusion 5FU-based regimen. fluorouracil and leucovorin (5FU+LV) in patients with advanced These data are in agreement with previous report (22). colorectal cancer: results of a randomized, multicenter, North In conclusion our data suggest that the oxaliplatin/ raltitrexed American trial. Proc Am Soc Clin Oncol 16: 228a, 1997. 16 Cvitkovic E and Bekkarda M: Oxaliplatin: a new therapeutic option combination may be considered an effective and easily in colorectal cancer. Semin Oncol 26: 647-662, 1999. manageable salvage regimen without severe toxicity in patients 17 Fizazi K, Ducreux M, Ruffie P et al: Phase I, dose finding, and with progressive advanced colorectal cancer pretreated with pharmacokinetic study of raltitrexed combined with oxaliplatin in FA-modulated 5FU. This combination should be compared as patients with advanced cancer. J Clin Oncol 18: 2293-2300, 2000. front-line therapy for clinical efficacy, toxicity and quality of life 18 Douillard J, Michel P, Gamelin E et al: Raltitrexed (Tomudex) plus oxaliplatin. An active combination for first-line chemotherapy in to other active chemotherapeutic regimens such as FOLFOX patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol or FOLFIRI in future prospective randomized trials. 19: 250a, 2000. 19 Comella P, De Vita F, De Lucia L, Casaretti R, Avallone A, References Orditura M, Rivellini F, Palmeri S, Catalano G and Comella G: Oxaliplatin and raltitrexed combined with leucovorin-modulated 5- 1 Landis SH, Taylor M, Bolden S and Wingo PA: Cancer statistics. fluorouracil i.v. bolus every two weeks: a dose finding study in CA Cancer J Clin 48: 6-29, 1998. advanced previously treated colorectal carcinoma. Southern Italy 2 Meta-Analysis Group in Cancer: Efficacy of intravenous continuous Cooperative Oncology Group. Ann Oncol 11 :461-468, 2000. infusion of fluorouracil compared with bolus administration in 20 Martoni A, Mini E, Pinto C, Gentile AL, Nobili S, Dentico P, advanced colorectal cancer. J Clin Oncol 6: 301-308, 1998. Marino A, Scicolone S, Angelelli B and Mazzei T: Oxaliplatin plus 3 Bertino GR: Chemotherapy of colorectal cancer: history and new raltitrexed in the treatment of patients with advanced colorectal themes. Semin Oncol 24 (Suppl.18): S18-37, 1997. cancer: a phase II study. Anticancer Res 23: 687-691, 2003. 4 Saltz L, Cox JV, Blanke C et al: Irinotecan plus fluorouracil and 21 Comella P, Casaretti R, Crucitta E, De Vita F, Palmeri S, Avallone leucovorin for metastatic colorectal cancer. Irinotecan Study Group. A, Orditura M, De Lucia L, Del Prete S, Catalano G, Lorusso V and N Engl J Med 343: 905-914, 2000. Comella G: Oxaliplatin plus raltitrexed and leucovorin-modulated 5 Douillard JV, Cunningham D, Roth A et al: Irinotecan combined 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer with fluorouracil compared with fluorouracil alone as first-line patients. Br J Cancer 86: 1871-1875, 2002. treatment for metastatic colorectal cancer: a multicenter 22 Volk J, Reinke F, van Kuilenburg AB, van Gennip AH, Schlichting randomised trial. Lancet 355: 1041-1047, 2000. C, Ganser A and Schoffski P: Safe administration of irinotecan, 6 De Gramont A, Figer A, Seymour M et al: Leucovorin and oxaliplatin and raltitrexed in a DPD-deficient patient with metastatic fluorouracil with or without oxaliplatin as first-line treatment in colon cancer. Ann Oncol 12: 569-571, 2001. advanced colorectal cancer. J Clin Oncol 18: 2938-2947, 2000. 7 Giacchetti S, Zidani R, Perpoint B et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first line treatment of metastatic colorectal cancer. J Clin Oncol 18: 136-147, 2000. 8 Scheithauser W, Kornek GV, Ulrich-Pur V et al: Oxaliplatin plus Received August 19, 2003 raltitrexed in patients with advanced colorectal carcinoma: results Revised November 10, 2003 of a phase I-II trial. Cancer 91: 1264-71, 2001. Accepted February 3, 2004

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