| Japanese Journal of Clinical Oncology | Pages |
Introduction
Subjects And Methods
Patients
Weekly High-dose 5-FU and LV Treatment
Response Criteria
Evaluation and Follow-up
Results
Response to Therapy
Toxicity
Survival
Discussion
Acknowledgments
References
Weekly 24-Hour Infusion of High-dose 5-Fluorouracil and Leucovorin in Patients with Advanced Colorectal Cancer: Taiwan Experience
Between January 1994 and November 1995, 41 patients with metastatic colorectal carcinoma were enrolled in this study. All these patients had recurrent disease after a prior 5-fluorouracil based adjuvant chemotherapy or failed to achieve response by prior chemotherapy that included 5-fluorouracil. 5-Fluorouracil, 2600 mg/m2, was administered concurrently with 100 mg/m2 leucovorin over 24 hours of continuous intravenous infusion. The treatment was repeated every week until progressive disease was documented. Forty-one patients received a total of 810 courses of treatment. The overall response rate was 17.1% (95% confidence interval 5.6-28.6%). In two patients who achieved complete response, the liver was the metastatic site. The median survival was 18.4 months for responders and 12.6 months for non-responders. Gastrointestinal toxicities including diarrhea, stomatitis, nausea and vomiting were the major side-effects. Sixteen incidences (39.0 %) of grade 2-3 gastrointestinal toxicities were observed. One patient (2.4%) developed a grade 3 cardiac toxicity, and another one (2.4%) had a grade 2 neurotoxicity. Hematological toxicities were minimal with no evidence of severe (grade 2 or more) leukopenia or thrombocytopenia. We conclude that in patients with pretreated metastatic colorectal cancer, weekly 24-hour infusion of high-dose 5-fluorouracil and leucovorin is associated with higher efficacy and tolerable toxicity. This regimen is a good option as a second-line treatment for those whose diseases are recurrent from or refractory to prior 5-fluorouracil, and deserves a longer period of follow-up.
INTRODUCTION
Colorectal cancer is among the leading causes of cancer-related morbidity and mortality in Taiwan. Resection of the primary tumor is the mainstay of treatment for patients in early stages with localized disease and may offer a chance for cure, but for metastatic disease, cure is rarely achieved (1).Treatment of metastatic disease is mainly by chemotherapy. 5-Fluororuacil (5-FU) and leucovorin (LV) has remained the standard recommended chemotherapy (2). The reported response rate of 5-FU and LV in metastatic colorectal cancer varied between institutions, but generally the activity of all these regimens is limited to a response rate of about 20%, with no significant impact on survival (2).
Over the past decades, there have been numerous attempts to increase the efficacy of 5-FU by changing the dose, the schedule, or the route of administration (3). Recently, weekly 24-hour infusion of high-dose 5-FU with LV has become an important regimen in the treatment of various types of adenocarcinoma, including colorectal cancer. Ardalan et al. have conducted a phase II study of weekly 24-hour infusion of a maximal tolerable dose of 5-FU (2600 mg/m2) and LV (500 mg/m2) for treating advanced colorectal carcinoma (4). In their study, 22 patients received a total of 560 courses of treatment to achieve a response rate of 45% (10/22), without excessive toxicity. The response rate was higher than in other reported series. We were interested to know whether this regimen would be effective and tolerable in Chinese patients.
In this study, we report preliminary results on the efficacy and toxicity of weekly 24-hour infusion of high-dose 5-FU and LV in 41 Chinese patients with metastatic colorectal carcinoma.
SUBJECTS AND METHODS
Patients
Between January 1994 and November 1995, 41 patients with metastatic colorectal carcinoma were enrolled in this study. All the patients were diagnosed as having metastatic adenocarcinoma of the colon or rectum. All of them had either recurrent disease after a prior 5-FU based adjuvant chemotherapy or failed to achieve response by prior chemotherapy that included the combination of 5-FU and LV. For a patient to be eligible, the disease had to be measurable in two dimensions by computer tomographic (CT) scan, ultrasound (lesions in liver) or chest X-ray (lesions in lung) or caliper measurement of palpable lesions elsewhere. All patients were required to have a performance status (PS) (Zubrod scale) of 2 or less (5) and to have adequate hematopoietic function as evidenced by leukocyte counts >3000/µl and platelet counts >100 000/µl. Patients with any active infection or previous history of any other malignancy were excluded from this study. Prior radiotherapy was allowed. All patients had normal serum creatinine levels. Patients' characteristics are shown in Table 1.
All patients were hospitalized for treatment. Before the initiation of therapy all patients were required to have a Port-a-Cath in order to accommodate to protracted infusion. 5-FU 2600 mg/m2 and LV 100 mg/m2, admixed in 1000 ml 5% dextrose water, were given concurrently over 24 hours of continuous intravenous infusion with the aid of an infusion pump. We did not observe catheter blockages due to calcium LV crystals. The treatment was repeated every week. No dose escalation was allowed for either 5-FU or LV. If grade 3 hematologic or gastrointestinal toxicities were observed in any course of therapy, the 5-FU dose was reduced to 2100 mg/m2. The treatment was continued until there was objective evidence of disease progression of intolerable toxicity, e.g. severe myelosuppression with sepsis or severe liver function impairment. All patients received a minimum of eight courses of treatment.
Complete response (CR) was defined as complete disappearance of all known lesions documented by two separate observations at least 4 weeks apart and without the appearance of any new lesions. Partial response (PR) required at least a 50% reduction in the cross-sectional area of the indicator lesion (or sum of areas if there was more than one indicator lesion), again documented by two separate observations at least 4 weeks apart, with no individual lesion growing and no new lesion appearing. Stable disease (SD) was defined as <50% reduction or <25% increase in cross-sectional area of all measurable lesions with no appearance of new lesions for at least 4 weeks. Patients were considered to have progressive disease (PD) when any lesion grew >25% in cross-sectional area or when any new lesion appeared.
Table 1
Characteristics
No.
No. of patients
41
Total courses of treatment
810
Age (yr)
Median
62
Range
35-68
Sex
Male
33
Female
8
Status
Adjuvant
18
Refractory
23
Performance status
0
18
1
15
2
8
Primary tumor
Colon
29
Rectum
12
Site of metastases
Liver only
16
Lung only
10
Liver and lung
11
Intra-abdominal, liver or lung
3
Intra-abdominal, liver and lung
1
Disease-free interval
>6 mo
25
>= 6 mo
16
Evaluation and Follow-up
Before treatment, all patients underwent evaluation including a detailed history and physical examination, tumor measurement, chest X-ray, liver imaging (CT and sonogram), complete blood count (CBC), blood chemistry and carcinoembryonic antigen (CEA). All patients were asked to visit the outpatient clinic regularly for monthly physical examination and check-up of CBC, liver and renal functions and serum CEA level during treatment. Chest X-ray and sonogram of liver or CT scan of abdomen was examined every two months. Colonoscopy was performed annually. Adverse effects were evaluated according to the WHO criteria (6). Patients with CR, PR or SD remained in the protocol until progressive disease or unacceptable toxicity was documented.
RESULTS
Response to Therapy
The response data are summarized in Table 2. Forty-one patients who received a total of 810 courses of treatment achieved a response rate of 17.1% (2 CR, 5 PR). The 95% confidence interval is 5.6-28.6%. All responses of involved lesions were confirmed by sonogram, CT scan or chest X-ray.
Table 2
| Response | % |
| CR | 4.9 (2/41) |
| PR | 12.2 (5/41) |
| SD | 36.6 (15/41) |
| PD | 46.3 (19/41) |
Table 3
| Toxicity | Grade | Total (%) | |||
| 1 | 2 | 3 | 4 | ||
| Nausea | 9 | 2 | 0 | 0 | 11 (26.8) |
| Vomiting | 4 | 1 | 0 | 0 | 5 (12.2) |
| Stomatitis | 8 | 4 | 2 | 0 | 14 (34.1) |
| Diarrhea | 6 | 5 | 2 | 0 | 13 (31.7) |
| Leukopenia | 0 | 0 | 0 | 0 | 0 (0) |
| Thrombocytopenia | 0 | 0 | 0 | 0 | 0 (0) |
| Hepatic | 2 | 0 | 0 | 0 | 2 (4.9) |
| Renal | 1 | 0 | 0 | 0 | 1 (2.4) |
| Cardiac | 0 | 0 | 1 | 0 | 1 (2.4) |
| Neurological | 0 | 1 | 0 | 0 | 1 (2.4) |
| Skin | 0 | 2 | 0 | 0 | 2 (4.9) |
| Infection | 0 | 0 | 0 | 0 | 0 (0) |
Toxicity
Toxicities were evaluated and graded according to the WHO criteria (Table 3). These toxicities were generally tolerated by the majority of patients. Gastrointestinal toxicities including nausea, vomiting, stomatitis and diarrhea were the major side-effects, but they were generally tolerable and non life-threatening. Hematological toxicities were minimal with no evidence of severe (grade 2 or more) leucopenia or thrombocytopenia. Two patients developed a transient painful fissuring erythroderma over their palms and soles (the hand-foot syndrome) (7).Mild liver and renal toxicities were occasionally found. One patient developed a grade 3 cardiac dysfunction with clinical manifestation of shortness of breath and cardiomegaly after eight courses of treatment. Another patient developed a transient grade 2 neurotoxicity after 5 courses of treatment with clinical manifestation of somnolence and confusion.
Survival
The median survival was 18.4 months for the responders and 12.6 months for non-responders. Patients who had recurrent disease after a prior 5-FU based adjuvant chemotherapy had a medial survival of 14.0 months, which is similar to 12.9 months for those whose diseases failed to achieve response to prior 5-FU based chemotherapy.
DISCUSSION
Since its discovery by Heidelberger et al. about 30 years ago (8), 5-FU remains the most extensively studied drug and is considered the standard treatment in metastatic colorectal cancer. However, the optimal dose scheduling of 5-FU is still controversial. The most popular method of administration is monthly intravenous (iv) bolus injection, but it is generally accepted that iv bolus injection of 5-FU will produce an objective response rate of only 15-20% in metastatic colorectal cancer (9).These reports were disappointing and prompted us to explore different dose schedules of 5-FU to try to improve the response.
Over the past decades, there have been numerous attempts to increase the efficacy of 5-FU by changing the dose, the schedule or the route of administration. Several non-randomized trials have reported improved response rates when 5-FU is given as a continuous intravenous infusion (10,11).The reported response rates of these trials ranged from 31% to 53%. In a prospective randomized trial comparing continuous infusional 5-FU with a conventional bolus schedule, a higher response rate was achieved in the infusional arm (30% versus 7%, P < 0.001) (12).
A number of studies have indicated that the anti-tumor activity of 5-FU can be enhanced if the intracellular pools of reduced folates are expanded by adding LV (2). Enhanced activity of 5-FU in the presence of reduced folates is most probably a result of stabilization of the ternary complexes between 5-fluorodeoxyuridine monophosphate (FdUMP), thymidylate synthase and 5,10-methylenetetrahydrofolate, which occurs in the presence of 5-10 µmol/l of extracellular folate (4). Houghton et al. have shown that the optimal manner for administering LV is by intravenous infusion over several hours (13). In a phase I study conducted by Ardalan et al., the maximum tolerated dose of 5-FU (2600 mg/m2) and LV (500 mg/m2), infused concurrently over 24 hours every week, was determined (14). They then conducted a phase II study employing 5-FU 2600 mg/m2 and LV 500 mg/m2 over 24 hours intravenous infusion every week in 22 patients with advanced colorectal carcinoma (4). In their study, an overall response rate of 45%, including 3 CR, was noted. Several papers have reported that 5-FU and LV achieved only poor response rates in pretreated cases. In comparison with these papers, Ardalan's study showed a significantly higher response rate, which interested us.
In our study, 41 patients received a total of 810 courses of weekly 24-hour continuous infusion of 5-FU 2600 mg/m2 and LV 100 mg/m2. Two (4.9%) achieved CR while five (12.2%) showed PR. The overall response rate was 17.1%. In comparison with Ardalan's study, our study was not associated with a higher response rate in metastatic colorectal cancer. The probable reason is that all our patients had been previously treated with 5-FU. They had either recurrent diseases after prior 5-FU based adjuvant chemotherapy or failed to achieve response by prior therapy that included 5-FU. In Ardalan's study, only 10 patients had received 5-FU before entering the program, the remaining 12 being 5-FU naive. However, in our study, there were still 7 patients showing a response to the regimen, including 2 CR. The data suggest that weekly 24-hour infusion of high-dose 5-FU and LV will produce a considerable response rate in pretreated metastatic colorectal cancer, and this is considered a good option for second-line treatment for pretreated metastatic colorectal cancer.
The cardiac toxicity of 5-FU was first identified by Dent and McColl in 1975 with the clinical manifestation of angina (15). Labianca et al. have reported a survey of 1083 patients receiving 5-FU; cardiotoxicities were found in 1.1% of all patients and in 4.6% of patients with prior heart diseases (16). 5-FU related cardiotoxicities, including precordial pain, ECG ST-T wave changes, acute myocardial infarction, arrhythmia, ventricular dysfunction and cardiac failure have been reported (17). In our study, a 48-year-old male patient without prior history of heart disease developed a grade 3 cardiac dysfunction with clinical manifestations of chest tightness and shortness of breath after eight courses of treatment. The ECG was not unusual but the echocardiogram revealed global ventricular dysfunction and four-chamber dilation. The chest X-ray showed profound cardiomegaly. The ejection fractions (EFs) of left and right ventricles were 43% and 32% respectively. Chemotherapy was discontinued and medical treatment for heart symptoms included prescription of oxygen and inotropic agents. After 2 weeks of treatment, the symptoms and signs of shortness of breath improved but cardiomegaly persisted and the EFs of both ventricles were 45% and 38% respectively, still below the normal limit. The patient was followed up at our out-patient department for 6 months; the symptoms of shortness of breath persisted and cardiomegaly with reduced EF was still noted.
5-FU related neurotoxicity is relatively rare. Neurological complications, including reversible somnolence, upper motor neuron signs, cerebellar ataxia, acute confusion and pyramidal tract signs may develop in <5% of patients receiving 5-FU (18). The biochemical basis for neurological toxicity secondary to 5-FU has not been elucidated. Previous reports have suggested that this toxicity may be due to further metabolism of the 5-FU catabolite 2-fluoro-beta-alanine to fluoroacetate and fluorocitrate, which are known neurotoxins (19). However, actual formation of fluoroacetate and fluorocitrate from 5-FU have not been documented. Acute confusion caused by 5-FU has been reported. Yeh et al. have reported a patient receiving 5-FU 2250 mg/m2 and LV 500 mg/m2 who developed deep coma, upward gaze and loss of verbal and motor response for about 40 hours (20). In our study, a 64-year-old male patient developed a transient neurotoxicity with clinical manifestations of confusion and somnolence on the fifth course of treatment. Physical examination revealed neither focal neurological symptoms nor sensory or motor function impairment. The pupils were isocoric with prompt light reflex. No pathologic reflex was identified. Oxygen was given via a nasal canula at the rate of 3 liters per minute. The status of confusion and somnolence persisted for about 6 hours, and recovered spontaneously without any neurological sequelae. No further neurological symptoms developed following subsequent treatments. In our study, it seemed that high-dose 5-FU related neurotoxicity was relatively rare, and tolerable in patients with metastatic colorectal cancer.
According to our study, in patients with pretreated metastatic colorectal cancer, weekly high-dose continuous infusion of 5-FU and LV is associated with a relatively higher efficacy and tolerable toxicity. This regimen is a good option as a second-line treatment for those who are recurrent from, or refractory to, prior 5-FU based chemotherapy, and deserves a longer period of follow-up.
Acknowledgments
This work was kindly supported by a grant from the Yen Tjing-Ling Medical Foundation.
References
For reprints and all correspondence: Wei-Shu Wang, Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan
Abbreviations: 5-FU, 5-fluorouracil; LV, leucovorin; CT, computer tomographic; PS, performance status; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CBC, complete blood count; CEA, carcinoembryonic antigen; FdUMP, 5-fluorodeoxyuridine monophosphate; EF, ejection fraction.
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Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1998.
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