Abstract
OBJECTIVE To investigate the efficiency and safety of the oxaliplatin, fluorouracil (5-FU) and leucovorin regimen (FOLFOX) in previously untreated patients with metastatic or recurrent colorectal cancer.
METHODS Previously untreated patients with metastatic or recurrent colorectal cancer received 100 mg/m2 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 400 mg/m2 of 5-FU. Then 2,600~3,000 mg/m2 of 5-FU was administered by continuous infusion over 46 h.
RESULTS An evaluated response rate was determined for 97 of 105 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. Thirtytwo 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 Toxicity Criteria (NCI-CTC), reaching grade 3/4 were: neutropenia 12.3%, anemia 11.3%, vomiting 4.1% and diarrhea 7.2%. Grade 3 neuropathy was 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 untreated metastatic or recurrent colorectal cancer patients.
keywords
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 importance[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 recurrent colorectal cancer patients treated in the Cancer Center of Sun Yat-sen University from April, 2002 to September, 2004.
MATERIALS AND METHODS
Clinical data
A retrospectively compiled database was established for 105 patients with metastatic or recurrent colorectal cancer who underwent FOLFOX first-line chemotherapy at the Cancer Center of Sun Yat-sen University between April 2002 and September 2004. All diagnoses were confirmed by both histological and imagine examinations, and all evaluations were obtained using X-ray, B ultrasound or CT scans. This group of patients was comprised of 70 males and 35 females with a median age of 53 (ranging 21~74) years. There were 53 colon cancer and 52 rectal cancer cases (Table 1). Of the 105 patients, 43 had liver metastasis, 29 lung metastasis, 21 a local recurrence and the remaining 42 patients had other organ metastasis. All of the patients had at least one evaluable lesion, 39 had 1 lesion, 7 had 2 lesions and 59 multiple lesions. The PS (performance status) was 0~1 without complication of chemotherapy.
Clinical characteristics.
Methods
One chemotherapeutic cycle consisted of 100 mg/m2 of oxaliplatin by a 2 h infusion and 400 mg/m2 of leucovorin over 2 h, followed by a 400 mg/m2 of a 5-FU bolus, then 2,600~3,000 mg/m2 of 5-FU infusion over a 46 h period. The cycle repeated every 14 days. We observed the side effects after each cycle and scheduled an imaging evaluation every 3~4 cycles.
Assessment of response and toxicity
We employed the UICC evaluation system, which includes CR (complete response), PR (partial response), SD (stable disease) and PD (progressive disease). In addition, we calculated the time to progression time (TTP) and overall survival (OS). For toxicity effects, the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) were used, which was scored 0~IV. For the assessment of the effects of oxaliplatin, neuropathic toxicity was evaluated according to the special criteria established by Levi et al.[2]
Statistical analysis
SPSS 12.0 was used to analyze the data. The Kaplan-Meier method was employed to calculate the TTP and OS. Statistical significance was set at a P<0.05 level.
RESULTS
Response rate
Eight of the 105 patients were not evaluated because of their failure to receive 3 cycles of chemotherapy. For the remaining 97 patients, the response rate was 35.1% (34/97), including CR 9.3% (9/97) and PR 25.8% (25/97) (Table 2). The response rate for liver metastatic patients was 32.5% and 20.9% were able to reach SD.
Objective response to treatment.
Toxicity
Among the 97 patients, the degree of grade III-IV toxicities were as follows: neutropenia, 12.3%; thrombocytopenia, 1.0%; anemia, 11.3%; vomiting, 4.1%; and diarrhea, 7.2%. Grade III peripheral neuropathy was only 5.1%, and only developed after the patients had 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 (Table 3).
Maximum toxicity per patient (%).
Survival
Five of the patients received no follow-up. The mean follow-up time for the total patients was 23.5 months (1.5~44.5 months). By the time of analysis, 45 patients had died of cancer with a median survival of 20.5 months (95% confidence interval: 17.8~23.2 months) and median TTP of 7.7 months (95% confidence interval: 6.3~9.1 months). The 1 and 2-year survival rates of the entire group were 68% and 32% respectively (Figs. 1 and 2 show the TTP and survival). The median TTP and overall survival for the liver metastatic patients were 5.7 months and 20.5 months, without a significant difference with other metastatic locations or recurrence. If the patients were stratified into 2 groups according to whether or not they had received radical surgery, the median TTP and OS were 6.8 months and 15.4 months for patients without radical surgery, and 8.1 and 23.5 months for patients with radical surgery. There were no significant differences between these 2 groups in the terms of TTP and OS (P=0.3757 for TTP and P=0.0658 for OS, Figs. 3 and 4). In addition, the serum level of CEA, ALP and LDH before chemotherapy played no role in the prognosis (P>0.05).
Over survival curve for 97 patients.
TTP survival curve for 97 patients.
Over survival curves for patients with or without radical resection.
TTP survival curves for patients with or without radical resection.
DISCUSSION
Colorectal cancer is a leading cause of cancer-related deaths worldwide, and it now ranks third in terms of the incidence and mortality rates throughout China [3]. In the past 40 years, 5-FU has been the mainstay in the chemotherapy of colorectal cancer with a response rate of 10%~15%[4,5]. The widely used biomodulator leucovorin has successfully increased the response rate to 23%, but without improvement in survival[5,6]. Oxaliplatin, a third-generation platinum compound, has improved the response rate and survival of advanced colorectal cancer patients when combined with 5FU/CF[7-10].
All of the 105 patients in our group received FOLFOX as first-line chemotherapy. The ratio of males to females was 2:1, which is consistent with the ratio in China, and the proportion between colon and rectal cancers was 1:1.
De gramont et al.[7] compared the effect of 5-FU/leucovorin alone or with oxaliplatin as first-line chemotherapy for advanced colorectal cancer. The patients receiving oxaliplatin had a superior response rate and progression-free survival. The TTP and OS were 9.0 months and 16.2 months respectively. The Intergroup N9741 trial[8] and V308 study[10] also showed that oxaliplatin, when combined with 5FU/CF, had a response rate of 34%~54% in first-line chemotherapy of advanced colorectal cancer patients, resulting in an improvement in TTP and OS (TTP 8~9 months and OS 16.2~19.5 months). The response rate, TTP and OS in our group were 35.1%, 7.7 months and 20.5 months respectively, which is in accord with the reports noted previously. Four of the patients were still alive with a follow-up of 44.5 months. Interestingly, 4 patients had liver metastasis and underwent a resection or radio-ablation after chemotherapy, indicating that local liver metastatic patients may benefit from local treatments including resection and radio-ablation after chemotherapy. In addition, there was a tendency for patients, who had a recurrence or metastasis after receiving radical surgery, to have a higher survival compared to those who had not received radical surgery. However, the difference was not significant (P=0.0658). More investigations are needed to determine if there is a difference in survival between patients who develop a recurrence or metastasis after a radical resection, compared to advanced metastatic patients when diagnosed. In our study, we showed that the serum level of CEA, ALP and LDH failed to act as prognosis factors.
Oxaliplatin, like other platinum compounds, exerts its cytotoxicity through the formation of platinum-DNA adducts, which cross-link the strands of the DNA double helix, blocking both DNA replication and transcription[11]. The main toxicity for oxaliplatin was dose-limited peripheral neurotoxicity, which can be aggravated by cold conditions. The incidence rate of grade III peripheral neurotoxicity in our group was 5.1%, lower then previous reports[12,13]. One of the possibilities for our lower incidence rate may be the disparity in race and climate. Other grade III~IV toxicities included neutropenia, anemia, vomiting and diarrhea, whose incidence rates were in accord with related reports.
In conclusion, the combination of oxaliplatin and 5FU/CF (FOLFOX regimen) is well tolerated, and it can improve the survival of advanced colorectal cancer patients. The results from the 105 patients who had undergone the FOLFOX regimen showed that this regimen can be used as a first-line chemotherapeutic option in China with a promising response rate, survival and a good tolerance.
- Received September 15, 2007.
- Accepted December 3, 2007.
- Copyright © 2007 by Tianjin Medical University Cancer Institute & Hospital and Springer
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