Oxaliplatin, Fluorouracil and Leucovorin (FOLFOX) As First-Line Chemotherapy for Metastatic Or Recurrent Colorectal Cancer Patients

Home , FOLFOX, Oxaliplatin

Chinese Journal of Clinical Oncology Dec. 2007, Vol. 4, No. 6 P 397~400 Bing Han et al. 397 [SpringerLink] DOI 10.1007/s11805-007-0397-9

Oxaliplatin, Fluorouracil and Leucovorin (FOLFOX) as First-line Chemotherapy for Metastatic or Recurrent Colorectal Cancer Patients

Bing Han OBJECTIVE To investigate the efficiency and safety of the oxaliplatin, Ruihua Xu fluorouracil (5-FU) and leucovorin regimen (FOLFOX) in previously untreated Yanxia Shi patients with metastatic or recurrent colorectal cancer. METHODS Previously untreated patients with metastatic or recurrent Huiyan Luo 2 Xiaojuan Xiang colorectal cancer received 100 mg/m of oxaliplatin intravenously (IV) over 2 h on day 1, and IV 400 mg/m2 of leucovorin over 2 h followed by a bolus of Yuhong Li 400 mg/m2 of 5-FU. Then 2,600~3,000 mg/m2 of 5-FU was administered by Li Zhang continuous infusion over 46 h. Tongyu Lin RESULTS An evaluated response rate was determined for 97 of 105 Youjian He treated patients. The overall response rate was 35.1%, 9 patients (9.3%) had a complete response and 25 patients (25.8%) a partial response. Thirty- two patients (33.0%) developed stable disease and 32.0% of the patients progressed. The median time to progression (TTP) was 7.7 months and the median overall survival 20.5 months. One and 2-year survival rates were 68% and 32%. Toxic effects based on the National Cancer Institute-Common Department of Medical Oncology, Sun Yat- Toxicity Criteria (NCI-CTC), reaching grade 3/4 were: neutropenia 12.3%, sen University Cancer Center, Guangzhou anemia 11.3%, vomiting 4.1% and diarrhea 7.2%. Grade 3 neuropathy was 510060, China. 5.1%. The overall survival rate of patients who had received a radical resection was superior to the patients who had not received a operation, or had received a palliative resection (P=0.0658). The serum levels of CEA, ALP and LDH had no relationship with survival (P>0.05). CONCLUSION The FOLFOX regimen containing oxaliplatin, 5-FU plus leucovorin was an efficacious regimen with good tolerability in previously un- Correspondence to: Ruihua Xu treated metastatic or recurrent colorectal cancer patients. E-mail: [email protected] KEYWORDS: oxaliplatin, chemotherapy, fluorouracil, leucovorin, colorectal cancer.

Introduction

The incidence and mortality rates of colorectal cancer have increased recently in China. Although surgery is still the primary mode of management, up to 30% of patients lose the opportunity of a resection when diagnosed, and about 40% of the Stage II and III patients will eventually develop a recurrence. Thus chemotherapy for this group of patients should be considered to be of im- portance[1]. Over the last decades, 5-FU has been the mainstay for colorectal cancer chemotherapy. With the utilization of oxaliplatin and irinotecan, the survival of advanced colorectal cancer patients entered a new period. This report focuses on the response rate and toxicity of FOLFOX as first-line chemotherapy for metastatic or Received September 15, 2007, accepted De- recurrent colorectal cancer patients treated in the Cancer Center of cember 3, 2007. Sun Yat-sen University from April, 2002 to September, 2004.

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MATERIALS AND METHODS Assessment of response and toxicity We employed the UICC evaluation system, which in- Clinical data cludes CR (complete response), PR (partial response), A retrospectively compiled database was estab- SD (stable disease) and PD (progressive disease). In lished for 105 patients with metastatic or recurrent addition, we calculated the time to progression time colorectal cancer who underwent FOLFOX first-line (TTP) and overall survival (OS). For toxicity effects, chemotherapy at the Cancer Center of Sun Yat-sen the National Cancer Institute-Common Toxicity Cri- University between April 2002 and September 2004. teria (NCI-CTC) were used, which was scored 0~IV. All diagnoses were confirmed by both histological For the assessment of the effects of oxaliplatin, neu- and imagine examinations, and all evaluations were ropathic toxicity was evaluated according to the spe- [2] obtained using X-ray, B ultrasound or CT scans. This cial criteria established by Levi et al. group of patients was comprised of 70 males and 35 females with a median age of 53 (ranging 21~74) Statistical analysis years. There were 53 colon cancer and 52 rectal can- SPSS 12.0 was used to analyze the data. The Kaplan- cer cases (Table 1). Of the 105 patients, 43 had liver Meier method was employed to calculate the TTP and metastasis, 29 lung metastasis, 21 a local recurrence OS. Statistical significance was set at aP <0.05 level. and the remaining 42 patients had other organ metastasis. All of the patients had at least one evaluable le- RESULTS sion, 39 had 1 lesion, 7 had 2 lesions and 59 multiple lesions. The PS (performance status) was 0~1 without Response rate complication of chemotherapy. Eight of the 105 patients were not evaluated because of their failure to receive 3 cycles of chemotherapy. Table 1. Clinical characteristics. For the remaining 97 patients, the response rate was Parameter Cases % 35.1% (34/97), including CR 9.3% (9/97) and PR 25.8% (25/97) (Table 2). The response rate for liver Total 105 metastatic patients was 32.5% and 20.9% were able Gender to reach SD. Male 70 66.7 Female 35 33.3 Table 2. Objective response to treatment. Age (years) Cases % Median (range) 53 (21~74) Complete response (CR) 9 9.3 Primary site Partial response (PR) 25 25.8 Colon 53 50.5 Stable disease (SD) 32 33.0 Rectum 52 49.5 Progressive disease (PD) 31 32.0 Numbers of evaluatable sites Total 97 1 39 37.1 2 7 6.7 Toxicity >2 59 56.2 Among the 97 patients, the degree of grade III-IV tox- Metastatic or recurrent sites icities were as follows: neutropenia, 12.3%; thrombo- Liver metastasis 43 40.9 cytopenia, 1.0%; anemia, 11.3%; vomiting, 4.1%; and Lung metastasis 29 27.6 diarrhea, 7.2%. Grade III peripheral neuropathy was Local recurrence 21 20.0 only 5.1%, and only developed after the patients had Others 42 40.0 received 10 cycles of chemotherapy amounting to an accumulated oxaliplatin dose of 1,000 mg/m2. About 17.3% of the patients suffered from grade I alopecia Methods (Table 3). One chemotherapeutic cycle consisted of 100 mg/m2 2 of oxaliplatin by a 2 h infusion and 400 mg/m of leu- Survival covorin over 2 h, followed by a 400 mg/m2 of a 5-FU Five of the patients received no follow-up. The mean bolus, then 2,600~3,000 mg/m2 of 5-FU infusion over follow-up time for the total patients was 23.5 months a 46 h period. The cycle repeated every 14 days. We (1.5~44.5 months). By the time of analysis, 45 pa- observed the side effects after each cycle and sched- tients had died of cancer with a median survival of uled an imaging evaluation every 3~4 cycles. Chinese Journal of Clinical Oncology Dec. 2007, Vol. 4, No. 6 P 397~400 Bing Han et al. 399

Table 3. Maximum toxicity per patient (%). OS (P=0.3757 for TTP and P=0.0658 for OS, Figs. Grade I/II Grade III/IV 3 and 4). In addition, the serum level of CEA, ALP Cases % Cases % and LDH before chemotherapy played no role in the prognosis (P>0.05). Nausea 69 71.1 Vomiting 39 40.2 4 4.1 DISCUSSION Diarrhea 30 30.9 7 7.2 Neurologic toxicity 26 26.8 5 5.1 Colorectal cancer is a leading cause of cancer-related Neutropenia 36 37.1 12 12.3 deaths worldwide, and it now ranks third in terms of Thrombocytopenia 30 30.9 1 1.0 the incidence and mortality rates throughout China [3]. Anemia 39 49.3 11 11.3 In the past 40 years, 5-FU has been the mainstay in the chemotherapy of colorectal cancer with a response 20.5 months (95% confidence interval: 17.8~23.2 rate of 10%~15%[4,5]. The widely used biomodulator months) and median TTP of 7.7 months (95% con- leucovorin has successfully increased the response fidence interval: 6.3~9.1 months). The 1 and 2-year rate to 23%, but without improvement in survival[5,6]. survival rates of the entire group were 68% and 32% Oxaliplatin, a third-generation platinum compound, respectively (Figs. 1 and 2 show the TTP and surviv- has improved the response rate and survival of ad- al). The median TTP and overall survival for the liver vanced colorectal cancer patients when combined metastatic patients were 5.7 months and 20.5 months, with 5FU/CF[7-10]. without a significant difference with other metastatic All of the 105 patients in our group received locations or recurrence. If the patients were strati- FOLFOX as first-line chemotherapy. The ratio of fied into 2 groups according to whether or not they males to females was 2:1, which is consistent with the had received radical surgery, the median TTP and OS ratio in China, and the proportion between colon and were 6.8 months and 15.4 months for patients without rectal cancers was 1:1. radical surgery, and 8.1 and 23.5 months for patients De gramont et al.[7] compared the effect of 5-FU/ with radical surgery. There were no significant differ- leucovorin alone or with oxaliplatin as first-line ences between these 2 groups in the terms of TTP and chemotherapy for advanced colorectal cancer. The

1.0 1.0

.8 .8

.6 Survival rate Survival .4 Survival rate Survival .4

.2 Survival Function

0.0 Censored Survival Function 0 10 20 30 40 0.0 Censored 0 10 20 30 40 50 TTP (month) Over survival (months) Over survival (month) Fig. 1. Over survival curve for 97 patients. Fig. 2. TTP survival curve for 97 patients.

Over survival (months)

Fig. 3. Over survival curves for patients with or without radi- Fig. 4. TTP survival curves for patients with or without radical resection. cal resection. 400 Chinese Journal of Clinical Oncology Dec. 2007, Vol. 4, No. 6 P 397~400 Bing Han et al. patients receiving oxaliplatin had a superior response peutic option in China with a promising response rate and progression-free survival. The TTP and rate, survival and a good tolerance. OS were 9.0 months and 16.2 months respectively. The Intergroup N9741 trial[8] and V308 study[10] REFERENCES also showed that oxaliplatin, when combined with 1 Gil-delgado MA, Khayat D, Taieb J. Cancer of the Co- 5FU/CF, had a response rate of 34%~54% in first- lon and Rectum. In: Pollock RE, Doroshow JH, Khayat D et al (Eds). UICC manual of clinical oncology, 2004, line chemotherapy of advanced colorectal cancer 487-504. patients, resulting in an improvement in TTP and OS 2 Levi F, Misser JL, Brienza S, et al. A chronopharmaco- (TTP 8~9 months and OS 16.2~19.5 months). The logic phase II clinical trial with 5 fluorouracil, flolinic response rate, TTP and OS in our group were 35.1%, acid, and oxaliplatin using an ambulatory multichan- nel programmable pump, high antitumor effectiveness 7.7 months and 20.5 months respectively, which is against metastatic colorectal cancer. Cancer 1992; 69: in accord with the reports noted previously. Four of 893-900. the patients were still alive with a follow-up of 44.5 3 Wan DS, Pan ZZ. Carcinoma of Large Intestine. In: Clinical Oncology. Science Publishing House, Beijing. months. Interestingly, 4 patients had liver metasta- 2005, 346-361. sis and underwent a resection or radio-ablation after 4 Cohen AM, Minsky BD, Schilsky RL. Cancer of the Co- chemotherapy, indicating that local liver metastatic lon. In Devita VT Jr, Hellman S, Rosenberg SA (Eds). Principles and Practice of Oncology. Philadelphia, patients may benefit from local treatments including Lippincott-Raven. 1997, 1061-1125. resection and radio-ablation after chemotherapy. In 5 Piedbois P, Buyse M, Rustum Y, et al. Advanced addition, there was a tendency for patients, who had Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced a recurrence or metastasis after receiving radical sur- colorectal cancer: Evidence in terms of response rate. J gery, to have a higher survival compared to those who Clin Oncol 1992; 10:896-903. had not received radical surgery. However, the differ- 6 Lo Bello L, Pistone G, Restuccia S, et al. 5-fluorouracil alone versus 5-fluorouracil plus folinic acid in the ence was not significant (P=0.0658). More investiga- treatment of colorectal carcinoma: Meta-analysis. Int J tions are needed to determine if there is a difference Clin Pharmacol Ther 2000; 38: 553-562. in survival between patients who develop a recur- 7 de Granmont A, Figer A, Seymour M, et al. Leucovorin rence or metastasis after a radical resection, compared and fluorouracil with or without oxaliplatin as first- line treatment in advanced colorectal cancer. J Clin to advanced metastatic patients when diagnosed. In Oncol 2000; 18: 2938-2947. our study, we showed that the serum level of CEA, 8 Goldberg RM, Sargent DJ, Morton RF, et al. A random- ALP and LDH failed to act as prognosis factors. ized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients Oxaliplatin, like other platinum compounds, exerts with previously untreated metastatic colorectal cancer. its cytotoxicity through the formation of platinum- J Clin Oncol 2004; 22:23-30. DNA adducts, which cross-link the strands of the 9 Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treat- DNA double helix, blocking both DNA replication ment of advanced colorectal cancer: a multicenter and transcription[11]. The main toxicity for oxalipla- study of the Gruppo Oncologico Dell'Italia Meridionale. tin was dose-limited peripheral neurotoxicity, which J Clin Oncol 2005; 23:4866-4875. 10 Tournigand C, Andre T, Achille E, et al. FOLFIRI fol- can be aggravated by cold conditions. The incidence lowed by FOLFOX6 or the reverse sequence in ad- rate of grade III peripheral neurotoxicity in our group vanced colorectal cancer. A randomized GERCOR was 5.1%, lower then previous reports[12,13]. One of study. J Clin Oncol 2004; 22:229-237. 11 Mathe G, Kidani Y, Segiguchi M, et al. Oxalato-plati- the possibilities for our lower incidence rate may be num or L-OHP, a third generation platinum complex: the disparity in race and climate. Other grade III~IV An experimental and clinical appraisal and preliminary toxicities included neutropenia, anemia, vomiting and comparison with cis-platinum and carboplatinum. diarrhea, whose incidence rates were in accord with Biomed Pharmacother 1989; 43:237-250. 12 Sorbye H, Glimelius B, Berglund A, et al. Multicenter related reports. phase II study of Nordic fluorouracil and folinic acid In conclusion, the combination of oxaliplatin and bolus schedule combined with oxaliplatin as first-line 5FU/CF (FOLFOX regimen) is well tolerated, and treatment of metastatic colorectal cancer. J Clin Oncol 2004; 22:31-38. it can improve the survival of advanced colorectal 13 Kalofonos HP, Aravantinos G, Kosnidis P, et al. Iri- cancer patients. The results from the 105 patients who notecan or oxaliplatin combined with leucovorin and had undergone the FOLFOX regimen showed that 5-fluorouracil as first-line treatment in advanced colorectal cancer: a multicenter, randomized, phase II this regimen can be used as a first-line chemothera- study. Ann Oncol 2005; 16:869-877.