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

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Activity and Toxicity of Oxaliplatin Plus Raltitrexed in 5-Fluorouracil Refractory Metastatic Colorectal Adeno-Carcinoma 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). 0250-7005/2004 $2.00+.40 1139 ANTICANCER RESEARCH 24: 1139-1142 (2004) 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. 1140 Laudani et al: Oxaliplatin/raltitrexed
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