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Leucovorin in Metastatic Colorectal Cancer

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Leucovorin in Metastatic Colorectal Cancer ANTICANCER RESEARCH 30: 4325-4334 (2010) Irinotecan/Fluorouracil/Leucovorin or the Same Regimen Followed by Oxaliplatin/Fluorouracil/ Leucovorin in Metastatic Colorectal Cancer HARALABOS P. KALOFONOS1, PAVLOS PAPAKOSTAS2, THOMAS MAKATSORIS1, DEMETRIOS PAPAMICHAEL3, GEORGIA VOURLI4, IOANNIS XANTHAKIS5, GERASIMOS ARAVANTINOS6, CHRISTOS PAPADIMITRIOU7, GEORGE PENTHEROUDAKIS8, IOANNIS VARTHALITIS9, GEORGE SAMELIS2, KOSTAS N. SYRIGOS10, NIKOLAOS XIROS11, MICHALIS STAVROPOULOS12, PARIS KOSMIDIS13, CHRISTOS CHRISTODOULOU14, HELEN LINARDOU15, MARIA SKONDRA11, DIMITRIOS PECTASIDES11, THEOFANIS ECONOMOPOULOS11 and GEORGE FOUNTZILAS5 1Division of Oncology, Department of Medicine and 12Department of Surgery, University Hospital of Patras, Rion, Patras, Greece; 2Oncology Department, Hippokration Hospital, Athens, Greece; 3Bank of Cyprus Oncology Centre, Nicosia, Cyprus; 4Section of Biostatistics, Hellenic Cooperative Oncology Group Data Office, Athens, Greece; 5Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; 6Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece; 7Department of Clinical Therapeutics, Alexandra University Hospital and 11Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, Attikon University Hospital, University of Athens School of Medicine, Athens, Greece; 8Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece; 9Oncology Department, General Hospital of Chania, Crete, Greece; 10Oncology Unit, Third Department of Medicine, Athens Medical School, Sotiria General Hospital, Athens, Greece; 13Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece; 14Second and 15First Department of Medical Oncology, Metropolitan Hospital, Pireaus, Greece Abstract. Background: This study reports the long-term by a 2-week rest period. Treatment continued for 4 cycles. follow-up of patients with metastatic colorectal cancer Patients in arm A were treated with IRI/FU/LV for 4 cycles, (CRC) participating in a randomised phase II study that while patients in arm B were initially treated with IRI/FU/LV compared the efficacy and toxicity of the combination of for 2 cycles followed by sequential administration of 2 cycles irinotecan (IRI), fluorouracil (FU) with leucovorin (LV) (arm of OXA/FU/LV. Results: No significant difference emerged in A) versus sequential chemotherapy with IRI plus FU/LV overall response rate or overall survival. There was a followed by oxaliplatin (OXA) plus FU/LV (arm B) as first difference in progression-free survival (median, 7.3 versus line therapy. Materials and Methods: Intent-to-treat analysis 8.2 months, p=0.040) in favour of arm B. Toxicity profiles was performed on 417 patients (211 in arm A and 206 in were similar in both arms. Conclusion: IRI/FU/LV and arm B). Treatment schedules of weekly IRI 80 mg/m2 or OXA IRI/FU/LV followed by OXA/FU/LV showed comparable 45 mg/m2 plus LV 200 mg/m2 immediately followed by activity with a manageable toxicity profile. intravenous bolus FU 450 mg/m2 for 6 weeks were followed Colorectal cancer (CRC) is a worldwide public health problem, accounting for nearly 800,000 new cases diagnosed each year and approximately 500,000 deaths (1). Significant Correspondence to: H.P. Kalofonos, MD, Hellenic Cooperative advances have been made in the management options for Oncology Group, 115 24, Athens, Greece. Tel: +30 2610999535, Fax: +30 2610994645, e-mail: [email protected], patients with metastatic disease and a median survival of 21- [email protected] 24 months is now frequently reported. Over the past 10 years, three new chemotherapeutic agents Key Words: Colorectal cancer, irinotecan, oxaliplatin, sequence. have been approved for metastatic CRC. These compounds 0250-7005/2010 $2.00+.40 4325 ANTICANCER RESEARCH 30: 4325-4334 (2010) include the topoisomerase I inhibitor irinotecan (IRI), the capecitabine plus OXA or first-line treatment with third-generation platinum analogue oxaliplatin (OXA), and capecitabine plus IRI and second-line capecitabine plus the oral fluoropyrimidine capecitabine. Since 2004, three OXA. The authors concluded that the combination treatment novel biological agents have been approved by the FDA, does not significantly improve overall survival compared namely the anti-epidermal growth factor receptor (EGFR) with the sequential use of cytotoxic drugs in advanced CRC. antibodies cetuximab and panitumumab and the anti-vascular However, in the FOCUS study (15), over 2000 patients were endothelial growth factor (VEGF) antibody bevacizumab (2). randomised to one of five groups: initial FU followed by Several studies have shown a clinical benefit of adding IRI single-agent IRI, initial FU followed by FU with either IRI or OXA to fluorouracil (FU) in the first-line setting (3-6). In or OXA, or initial combinations that consisted of FU with patients with advanced CRC whose metastases are either IRI or OXA. The sequential single-agent strategy gave potentially resectable, immediate treatment with the highest the poorest survival and the authors recommended that this chance for response is desirable. However, in terms of approach should not be advocated. Thus, data are conflicting survival, there does not seem to be an optimum sequence of regarding the use of combination or sequential chemotherapy administration of IRI and OXA (7) and the optimum timing in patients with advanced CRC. and duration of delivery of these agents has not been clearly A phase II study comparing the efficacy and toxicity of defined. OXA and IRI have been directly compared in the combination of IRI plus FU with leucovorin (LV) versus several studies. In a phase III study by Tournigand et al. (8), sequential chemotherapy with IRI plus FU/LV followed by FOLFIRI and FOLFOX6 were compared, in the first-line OXA plus FU/LV as first-line therapy in patients with setting, in patients with metastatic CRC with no differences metastatic CRC was run by the Hellenic Cooperative found in response rates, progression-free survival (PFS) or Oncology Group. Results were presented at the 42th ΑSCO overall survival (OS). At progression, IRI was replaced by meeting in 2006 (16). In the present study, the long-term OXA and OXA by IRI. Not only did this study show an follow-up of these patients is reported. equivalent clinical efficacy between IRI and OXA, but it also demonstrated that there does not appear to be an optimal Patients and Methods sequence of combination regimens, as the OS at the end of both treatment arms was virtually identical. In recent years, In this phase II trial, patients were required to have histologically evidence has emerged on the advantageous use of all three or cytologically confirmed, advanced, recurrent or metastatic cytotoxic drugs during the course of a patient’s illness (9), adenocarcinoma of the colon or rectum, previously untreated, or bi- dimensionally measurable disease located outside of a previously but only 50% to 80% of patients can be exposed to all three irradiated field. Previous palliative radiation therapy was permitted, drugs in a sequential strategy with doublets. Simultaneous provided that <20% of the bone marrow was involved and a target combination chemotherapy can be more effective than single lesion outside the radiation port was present. agents if all drugs can be given at adequate dose levels. Patients were permitted to have received adjuvant cytotoxic However, simultaneous combination chemotherapy of several chemotherapy, provided it was completed ≥6 months before study drugs often requires the dose of each agent to be reduced entry. Eligible patients had to be aged ≥18 years, and have a World from its optimal single-agent level. Health Organization (WHO) performance status (PS) ≤2; no other malignancy, except adequately treated in situ carcinoma of the A solid theoretical framework supports the hypothesis that cervix uteri and basal or squamous cell carcinoma of the skin; no the sequential administration of cytotoxic drugs at adequate other serious illness; and adequate bone marrow reserve (neutrophil doses can maximise cancer cell death and overcome drug count ≥1500/ml and platelet count ≥100000/ml), renal function resistance. However, an important question remains, namely [creatinine ≤1.5 × the upper limit of normal (ULN)] and liver how the active drugs should be sequenced to provide patients function (serum transaminases ≤5 × ULN, serum bilirubin <1.5 with the maximum duration of disease control and acceptable mg/dl and alkaline phosphatase ≤5 × ULN). Exclusion criteria toxicity. Mathematical models support sequential included the presence of central nervous system lesions, as well as bone metastases or pleural effusions, as the sole indication of chemotherapy as being superior to concurrent therapy (10, tumour; pregnant or lactating women; and a high risk of poor 11). Indeed, sequential chemotherapy may allow the delivery outcome due to concomitant non-malignant disease, peripheral of a higher number of drugs with the dose of each drug being neuropathy, active uncontrolled infection or chronic enteropathy. optimised and toxicity therefore reduced. There is now a The clinical protocol and collateral translational research studies growing list of clinical examples in other tumour types in were approved by the Hellenic Cooperative Oncology Group which sequential therapies have outperformed alternating (HeCOG) Protocol Review Committee, by the Institutional Review
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