INTRODUCTION. Jpn J Clin Oncol 2005;35(9) doi: /jjco/hyi140. Gil Medical Center, Incheon, Korea

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1 Oxaliplatin, Folinic Acid and 5-Fluorouracil (FOLFOX-4) Combination Chemotherapy as Second-line Treatment in Advanced Colorectal Cancer Patients with Irinotecan Failure: A Korean Single-center Experience Se Hoon Park 1, Ju Young Sung 1, Sang-Hoon Han 1, Jeong Heum Baek 2, Jae Hwan Oh 2, Soo-Mee Bang 1, Eun Kyung Cho 1, Dong Bok Shin 1 and Jae Hoon Lee 1 1 Department of Internal Medicine and 2 Department of Anorectal Surgery, Gachon Medical School Gil Medical Center, Incheon, Korea Jpn J Clin Oncol 2005;35(9) doi: /jjco/hyi140 Received May 1, 2005; accepted June 19, 2005; published online July 18, 2005 Objective: This study was designed to determine the effectiveness and tolerance of oxaliplatin, folinic acid (FA) and infusional 5-fluorouracil (5-FU) (FOLFOX-4) chemotherapy when used as a second-line treatment in patients with advanced colorectal cancer for whom an irinotecancontaining regimen failed. Methods: Thirty-eight patients with measurable colorectal cancer, progressive after previous irinotecan-containing chemotherapy for metastatic disease, were registered in this trial. Oxaliplatin was administered on day 1 at the dose of 85 mg/m 2 as a 2 h infusion, concurrently with FA 200 mg/m 2 /day, followed by bolus 5-FU 400 mg/m 2 and a 22 h infusion of 5-FU 600 mg/m 2 for two consecutive days. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred or until a patient chose to discontinue the treatment. Results: For 34 patients treated, a total of 183 chemotherapy cycles were administered. In an intent-to-treat analysis, six patients (16%) achieved a partial response that they maintained for 5.4 months. The median progression-free and overall survivals were 2 and 5 months, respectively. Frequently encountered toxicities were peripheral neuropathy and gastrointestinal side effects including diarrhea. Although there was one early death, toxicity profiles were generally predictable and manageable. Conclusion: Second-line FOLFOX-4 is a feasible regimen with modest activity for colorectal cancer patients with irinotecan failure. Further clinical trials incorporating novel biological agents are warranted. Key words: colorectal cancer oxaliplatin chemotherapy INTRODUCTION Colorectal adenocarcinoma is the fourth most frequently diagnosed malignancy in Korea, accounting for 12% of newly diagnosed cancer cases. According to the Ministry of Health and Welfare, the incidence of colorectal cancer has been increasing in both males and females during the past two decades (1). Until recently, the standard therapy for patients with recurrent or metastatic disease was chemotherapy with 5-fluorouracil (5-FU), usually modulated by folinic acid (FA), which typically yielded a median survival of <1 year (2,3). Two recently introduced drugs active in the treatment of advanced colorectal cancer (ACC) are irinotecan and oxaliplatin. Both drugs have For reprints and all correspondence: Dong Bok Shin, Division of Hematology and Oncology, Department of Internal Medicine, Gachon Medical School Gil Medical Center, Incheon , Korea. dbs@gilhospital.com been shown to have synergistic effects with 5-FU and FA on colorectal cancer cell lines (4,5). Since irinotecan and oxaliplatin were introduced to ACC treatment, the efficacy of palliative chemotherapy for ACC has improved considerably. Irinotecan inhibits topoisomerase I, thus impeding DNA uncoiling leading to double-stranded DNA breaks (6). Firstline treatment with irinotecan and either bolus or infusional 5-FU/FA significantly improved outcomes compared with 5-FU/FA (7,8). These results established irinotecan in combination with 5-FU as a standard first-line chemotherapy for patients with ACC. Oxaliplatin is a platinum analog that blocks DNA replication and transcription (9). This agent is particularly attractive because of its activity against cisplatin-resistant colon cancer cell lines (4). Combination of oxaliplatin and infusional 5-FU/FA (FOLFOX) significantly increased the response rate and the time to progression compared with 5-FU/FA (10). # 2005 Foundation for Promotion of Cancer Research

2 532 Salvage FOLFOX-4 for CRC Although median survival was longer for those treated with FOLFOX, statistical significance was not reached. When this study was initiated, there were few data regarding the efficacy of any other chemotherapy regimen after failure of irinotecan. Therefore, we initiated a phase II study to assess the efficacy and the safety of oxaliplatin, FA and infusional 5-FU (FOLFOX-4) in patients with ACC who did not respond or whose disease progressed after first-line treatment with irinotecan-containing regimens. PATIENTS AND METHODS ELIGIBILITY Patients with ACC for whom irinotecan-based first-line chemotherapy (primary or secondary after initial response) had failed within 1 year before their registration were enrolled in this study. The patients were required to be aged at least 18 years and to have bidimensional measurable disease; life expectancy of 12 weeks or more; Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower; and adequate hematological (neutrophil count >1500/mm 3 and platelet count > /mm 3 ), hepatic (serum total bilirubin level <1.5 mg/dl and AST/ALT <3 ULN) and renal (serum creatinine level <1.5 mg/dl) functions. Any previous antitumor treatment had been completed at least 4 weeks before entering this study. This study protocol was reviewed and approved by the Gil Medical Center institutional review board, and signed informed consent was obtained from all patients before their enrollment. STUDY DESIGN The combination of oxaliplatin with FA and intravenous infusion of 5-FU (FOLFOX-4), as described by de Gramont et al. (10), was used. In brief, FA was given at the dose of 200 mg/m 2 /day followed by bolus 5-FU 400 mg/m 2 and a 22 h infusion of 5-FU 600 mg/m 2 for two consecutive days. Oxaliplatin was administered on day 1 at the dose of 85 mg/m 2 as a 2 h infusion, concurrently with FA. The treatment was repeated every 2 weeks until disease progression, unacceptable toxicity, patient s decision to discontinue treatment or a maximum of 12 cycles. Dose modifications were performed based on the hematological parameters and the degree of non-hematological toxicities. Patients were assessed, before starting each 2 week cycle, using the National Cancer Institute common toxicity criteria. Chemotherapy was delayed until recovery if neutrophils decreased to <1500/mm 3 or platelets decreased to < /mm 3 or for significant persisting non-hematological toxicity. The 5-FU dose was reduced by 25% after grade 3 or 4 diarrhea, stomatitis or dermatitis occurred. Oxaliplatin was reduced for grade 3 or 4 neutropenia and in cases of persistent (14 days or longer) paresthesia or temporary (7 14 days) painful paresthesia or functional impairment. In cases of persistent (14 days or longer) painful paresthesia or functional impairment, oxaliplatin was omitted from the regimen until recovery. PATIENT EVALUATION Tumor response was evaluated according to the World Health Organization criteria (11) and was assessed with an abdominopelvic computed tomography scan or with the same tests used initially to stage the tumor. All tumor measurements were recorded by a gastrointestinal radiologist in millimeters in two dimensions in all measurable lesions. Responses were assessed every four courses of chemotherapy, or earlier in the case of clinical deterioration. Toxicity grading was based on the National Cancer Institute Common Toxicity Criteria (version 2.0). STATISTICAL CONSIDERATIONS Thirty-three patients were required in a single-stage phase II clinical study (12), assuming that the expected overall response rate would be 30% and the threshold rate was 10% (alpha 0.05, beta 0.1). The starting point of various time intervals was the first day of chemotherapy. Response duration was the time between the initial response and the date of progression. The date of disease progression or death from causes other than ACC was used in calculating progression-free survival (PFS). Time to death, whatever the cause, was used to calculate the overall survival (OS). The Kaplan Meier product-limit method was used to estimate the survival rates, and all analyses were performed using SPSS for Windows RESULTS PATIENTS Among a total of 38 patients enroled into the study between June 2001 and March 2003, four were ineligible or never received protocol therapy. Detailed characteristics of the patients are listed in Table 1. The median age was 52 years (range years) and most of the patients (92%) had a good performance status (0 or 1 on the ECOG scale). The liver and lung were the most common sites of metastases. All the patients had been pretreated with the irinotecan-containing regimen for metastatic disease and had received a median number of six cycles of such therapy (13). Responses to the prior chemotherapy were as follows: one complete response and 17 partial responses, for an overall response rate of 49% [95% confidence interval (CI), 34 66%]. TREATMENT OUTCOMES Patients received a total of 183 cycles of chemotherapy, with a median number of four per patient (range 0 12). According to the intent-to-treat principle, the overall response rate was 16% (95% CI, 4 27%), which has maintained for a median of 2.0 months (95% CI, months). Taking into account nine patients who had stable diseases, 15 patients (39%) achieved clinical benefit, defined as response or stable disease. After a

3 Jpn J Clin Oncol 2005;35(9) 533 Table 1. Patient characteristics No. % Patients Evaluable for response and survival 38 Treated Male gender ECOG performance status Primary site Colon Rectum Prior anticancer therapy Surgery Radiotherapy Adjuvant chemotherapy Chemotherapy for metastatic disease Prior chemotherapy for metastatic disease Irinotecan and capecitabine Irinotecan, 5-FU and FA 4 11 Irinotecan, 5-FU and methotrexate 2 5 Site(s) of metastatic disease* Liver Lung Lymph node 9 24 Peritoneum 4 11 Bone 2 5 Pelvic local recurrence 6 16 Age: median 52 years; range years Interval from the last cycle of prior chemotherapy: median 1.4 months; range months *Because patients could have metastases at multiple sites, the total number of metastases is greater than the number of patients. median follow-up of 35 months (95% CI, months), median PFS was 2.0 months (95% CI, months), while median survival was 5.0 months (95% CI, months). The estimated 1 year survival rate was 16% (Fig. 1). At the time of current analyses, all patients had died due to the progressive course of their ACC. A total of 29% of patients were salvaged with oral fluoropyrimidines or with a continuous infusion of 5-FU. SAFETY Given planned dose intensities of oxaliplatin 42.5 mg/m 2 /week and 5-FU 1000 mg/m 2 /week, the relative dose intensities of each drug were 88 and 90%, respectively. Dose reduction was required in 18 cycles (10%). Toxicity data were available for Figure 1. Progression-free and overall survival. Table 2. Worst toxicity in evaluable patients all patients and 183 chemotherapy cycles. One patient died of respiratory failure shortly after the completion of the second cycle, for which the possibility of disease progression could not be completely excluded as the cause. The patient, who initially presented with multiple pulmonary nodules and bilateral pleural effusion, complained about increasing dyspnea and suffered a sudden respiratory arrest. Frequently encountered toxicities were peripheral neuropathy and gastrointestinal side effects including diarrhea (Table 2). Even if all patients were pretreated with cytotoxic chemotherapy, only one episode of febrile neutropenia occurred. Hematological toxicity was infrequent and none received hematopoietic growth factors. Abnormality of liver enzymes, although transient and reversible with rest, was observed in two patients; one of these patients was known to have hepatitis B-related chronic liver disease prior to enrollment. Treatment was delayed in 25 cycles (14%) of chemotherapy. DISCUSSION Grade 1, 2 per 38 patients (%) Neutropenia 5 3 Thrombocytopenia 5 5 Nausea/vomiting Stomatitis Diarrhea Hepatic 5 Fatigue 16 8 Peripheral neurotoxicity Skin 3 Pulmonary 3 Grade 3, 4 per 38 patients (%) This small phase II study was designed to assess the activity and safety of the FOLFOX-4 regimen in a group of patients

4 534 Salvage FOLFOX-4 for CRC with ACC who had been pretreated with an irinotecancontaining regimen as first-line chemotherapy. The evolution of treatment using irinotecan and oxaliplatin in combination with 5-FU regimens has resulted in a significant prolongation of life in patients with ACC. Since both drugs have demonstrated similar activity in first- and second-line settings, the optimal chemotherapy regimen and schedule to use in patients with ACC is still undecided (14). In Korea, the irinotecan-containing regimen was approved in the year 2000 for the first-line treatment of ACC. In a salvage setting, FOLFOX has been shown to be beneficial in the treatment of patients with ACC progressing after irinotecan/ 5-FU/FA (IFL regimen) (15). Second-line FOLFOX, in this setting, achieved an objective response rate of 10% and a median time to progression of 4.6 months. Patients treated with FOLFOX experienced a higher incidence of clinically significant toxicities, but these toxic effects were predictable and manageable. Treatment sequences are of increasing importance in terms of judging the efficacy of palliative chemotherapy of ACC. Because oxaliplatin was not readily available as first-line chemotherapy when this study was initiated, most patients received oxaliplatin after failure of irinotecan. In a recently published study comparing the efficacy of the alternative sequence of administration of the FOLFOX and FOLFIRI regimens in the treatment of ACC (16), second-line treatment with FOLFOX achieved a 15% response rate with a 4.2 month median PFS. Overall, median survival time of 21 months has been achieved by means of palliative chemotherapy with FOLFOX FOLFIRI and FOLFIRI FOLFOX, respectively. The FOLFOX regimen has recently been reported to be active and comparatively safe and is now recommended as the standard first-line chemotherapy for patients with ACC (17). OS was improved for FOLFOX in this study, but this result may be in part related to the availability of alternative therapy to patients failing protocol therapy. Fifty-two percent of patients treated initially with FOLFOX were moved over to an irinotecan-containing regimen, but only 17% of those treated with IFL were able to receive oxaliplatin as second-line treatment. Thus, improved OS may depend on the sequential use of different, partially non-cross-resistant regimens in the same patient. In our study, the median PFS and OS were 2 and 5 months, respectively. Although there was one possible treatmentrelated death, toxicity profiles in our study were generally predictable and manageable. A low percentage of patients experienced toxicity leading to treatment discontinuation. Nevertheless, these results are lower than those expected for the same regimen in previously reported phase II/III studies. Rothenberg et al. reported a response rate of 10% and a median PFS of 4.6 months with second-line FOLFOX (15). In two large randomized phase III studies (16,17), FOLFOX administered in patients pretreated with an irinotecan-based regimen resulted in response rates up to 15%. FOLFOX proved to be effective even in a third-line setting (18). Caution is required when making comparisons between different studies. This discrepancy could be attributable to patient selection, but the small size of our study and differences in the manner of assessing and reporting outcomes are contributing factors. Neither PFS nor OS favors the current regimen in the second-line setting, although they cannot be reliably evaluated in a single-arm clinical study. The second-line FOLFOX did not seem to impact effectively on OS, and alternative and more effective drugs are sought for second-line treatment. A recent randomized phase II study demonstrated the superiority of the epidermal growth factor receptor (EGFR) targeted agent cetuximab in a second-line setting (19); a response rate of 23% and a median time to progression of 4.1 months were achieved with cetuximab and irinotecan combination. Tyrosine kinase inhibitors directed to EGFR, such as gefitinib and erlotinib, have shown promising results in patients with pretreated ACC, particularly in combination with FOLFOX (20,21). Another novel approach in the treatment of ACC involves therapeutic agents that inhibit the neovascularization process of growing tumors. Bevacizumab is a recombinant humanized antivascular endothelial growth factor monoclonal antibody that is being clinically evaluated in many tumor types including ACC. 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