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Japanese Journal of Clinical Oncology Pages 174-179

Factors Predictive of Response and Survival in Patients with Metastatic Colorectal Cancer in Taiwan
Introduction
Materials And Methods
   Patients
   Weekly Bolus 5-FU and LV Treatment
   Biweekly High-dose Continuous Infusion Treatment
   Response Criteria
   Evaluation and Follow-up
   Statistical Methods
Results
   Response to Therapy
   Toxicity
   Factors Affecting Response
   Factors Affecting Survival
Discussion
Acknowledgements
References

Factors Predictive of Response and Survival in Patients with Metastatic Colorectal Cancer in Taiwan

Factors Predictive of Response and Survival in Patients with Metastatic Colorectal Cancer in Taiwan Wei-Shu Wang, Frank S. Fan, Ruey-Kuen Hsieh, Tzeon-Jye Chiou, Jen-Kou Lin, Tzu-Chen Lin, Chueh-Chuan Yen, Jin-Hwang Liu, Hung Hsu and Po-Min Chen

Division of Medical Oncology, Department of Medicine, Division of Colorectal Surgery, Department of Surgery, Veterans General Hospital-Taipei, and National Yang-Ming University School of Medicine, Taipei, Taiwan

5-Fluorouracil in combination with leucovorin has been shown to be active in therapeutic trials of metastatic colorectal carcinoma. In this study, we administered these drugs to 72 patients with metastatic colorectal carcinoma. Thirty-six of them without previous exposure to 5-fluorouracil were treated with weekly bolus injections of 5-fluorouracil (425 mg/m2 ) and leucovorin (25 mg/m2 ) supplemented with oral levamisole. Another 36 patients with or without prior 5-fluorouracil treatment received 5-fluorouracil 3,000 mg/m2 and leucovorin 300 mg/m2 in a 48-hour continuous infusion every two weeks. Clinical efficacy and toxicity were assessed by WHO criteria. Variables were tested for relations to response and survival by univariate and multivariate analysis. The response rate was 19.4% in weekly bolus arm and 13.9% in biweekly high-dose infusion arm (P =0.527). Median survivals in the two arms were 18.4 months (weekly) and 21 months (biweekly) respectively (P =0.708). Gastrointestinal side effects including nausea, vomiting, diarrhea and mucositis were the major toxicities of these regimens. By multivariate analysis, the only factor to influence response rate was the site of metastases (P =0.009). The only factor to affect survival was performance status of the patient (P =0.0001). We concluded that the two 5-fluorouracil based regimens are well-tolerated and shown to have a response rate comparable with previous reports of similar regimens in patients with metastatic colorectal cancer. Only liver metastases seemed to have a better response to therapy. Performance status is the most important prognostic factor in patients with metastatic colorectal cancer.

Keywords: 5-fluororacil - leucovorin - metastatic colorectal cancer - prognostic factor

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 the 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 to 5-FU and LV of metastatic colorectal cancer varied between many 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 ).

Patients' characteristics do influence prognosis in advanced colorectal cancer. The hemoglobin level, disease-free interval, performance status, body weight loss, serum lactate dehydrogenase level and lung involvement have been reported as being important prognostic factors in advanced colorectal cancer (3 -6 ). Other prognostic factors often studied are age and sex of the patient, location of the primary tumor, number and site of metastases, serum CEA level and response to chemotherapy (3 ,7 ) In this study, we examined 72 patients with metastatic colorectal carcinoma. These patients received either weekly bolus injections or biweekly 48-hour continuous infusion of high-dose 5-FU and LV. The primary aim of this study was to identify the activity and toxicity of the two 5-FU based regimens. The second aim was to assess the prognostic factors for response and survival.

MATERIALS AND METHODS

Patients

Between September 1990 and November 1995, 72 patients with metastatic colorectal carcinoma were enrolled in this study. All the patients were diagnosed as having metastatic adenocarcinoma of the colon or rectum. To include an eligible patient, 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 caliber measurement of palpable lesions elsewhere. Patients were required to have a performance status (PS) (Zubrod scale) of 2 (bedridden <50% of the time) or less and to have adequate hematopoietic function as evidenced by leukocyte counts >3000/[mu]l and platelet count >100 000 /[mu]l. Patients with any active infection or previous history of any other malignancy were excluded from this study. Prior treatment with radiotherapy was allowed. All patients had normal serum creatinine levels.

Patients' characteristics are shown in Table 1 . All were to be followed for the remainder of their lives.

Weekly Bolus 5-FU and LV Treatment

Between September 1990 and August 1992, 36 patients without prior exposure to 5-FU were assigned to receive weekly bolus 5-FU and LV. Initially, a loading dose of 5-FU 425 mg/m2 with LV 25 mg/m2 was administered as a daily intravenous bolus injection on five consecutive days. After a two-week interval, weekly therapy with the same as the previous daily doses of 5-FU and LV was begun. Levamisole 50 mg was given by mouth three times a day for a period of three days every two weeks. The therapy lasted as long as the patients remained in complete remission, partial remission or stable disease.

Table 1. Patients' characteristics
Characteristics Weekly bolus Biweekly infusion
No. of patients - 36 36
Sex
  male 28 23
  female 8 13
Age (yr)
  median 63 63
  range 23-78 34-77
Performance status
  0 24 24
  1 5 7
  2 7 5
Primary tumor
  rectum 20 19
  colon 16 17
Initial Dukes' stage
  B, C 24 15
  D 12 21
Site of metastases
  liver 23 21
  extra-hepatic 13 15
Pre-chemotherapy CEA
  >30 ng/dl 15 21
  <30 ng/dl 21 15
Disease-free interval
  >6 months 20 13
  <6 months 16 23
Serum albumin level
  >3.5 g/dl 25 19
  <3.5 g/dl 11 17
CEA, carcinoembryonic antigen; Weekly bolus, weekly bolus injection arm; Biweekly infusion, biweekly high-dose continuous infusion arm.

Table 2 . Response to chemotherapy
Response Weekly bolus Biweekly infusion
CR 13.9% (5/36) 0
PR 5.5% (2/36) 13.9% (5/36)
SD 27.8% (10/36) 19.4% (7/36)
PD 52.8% (19/36) 66.7% (14/36)
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Biweekly High-dose Continuous Infusion Treatment

Between September 1992 and November 1995, 36 patients with or without prior exposure to 5-FU were enrolled in the study. 5-FU 3000 mg/m2 with LV 300 mg/m2 in 1000 ml 5% dextrose was given through a continuous intravenous infusion over 48 hours every 2 weeks. All patients were hospitalized for treatment. The treatment continued until disease progression was documented.

Response Criteria

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 were 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.

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 CEA. All patients visited 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-rays and sonograms of the liver or CT scans of the abdomen were examined every 2-3 months. Colonoscopy was scheduled on a yearly basis. Side effects was evaluated according to the WHO criteria. Patients with CR, PR or SD remained in the protocol until progressive disease was documented.

Statistical Methods

In the initial stage of the data analysis, each variable was evaluated separately by the [chi]2 test (8 ) to assess its association with tumor response.Survival curves were constructed by the Kaplan-Meier product limit method (9 ) and the data were analyzed using the log-rank test (10 ) through a microcomputer. A multivariate analysis by the Cox's proportional hazards regression model (11 ) was then performed to determine the most important predictors of survival among all of the possible variables.

Table 3 . Treatment-related toxicities, graded according to WHO criteria
Toxicity   Weekly bolus Biweekly infusion
  Grade 1 2 3 4 1 2 3 4
Mucositis   2 3 2 0 6 3 0 0
Nausea   9 4 1 0 3 8 2 0
Vomiting   3 5 0 0 2 6 0 0
Diarrhea   4 6 2 0 5 3 1 0
Leukopenia   0 0 0 0 1 0 0 0
Thrombocytopenia   0 0 0 0 0 0 0 0
Infection   0 0 0 0 0 0 0 0
Liver   3 0 0 0 2 1 0 0
Renal   1 0 0 0 2 1 0 0
Neurological   0 0 0 0 0 0 0 0

Table 4 . Analysis of variables influencing response to therapy
  P
Factors Variables No. CR+PR Univariate Multivariate
Regimen
  weekly bolus 36 7 0.527 0.676
  biweekly infusion 36 5    
Sex
  male 51 10 0.297 0.609
  female 21 2    
Age (yr)
  >63 46 8 0.826 0.586
  <63 26 4    
Performance status
  0 48 11 0.044 0.065
  1, 2 24 1    
Primary tumor
  rectum 39 7 0.751 0.242
  colon 33 5    
Initial Dukes' stage
  B, C 39 8 0.341 0.784
  D 33 4    
Site of metastases
  liver only 44 11 0.017 0.009
  extra-hepatic 28 1    
Pre-chemotherapy CEA
  >30 ng/dl 36 8 0.206 0.085
  <30 ng/dl 36 4    
Disease-free interval
  >6 months 33 8 0.113 0.247
  <6 months 39 4    
Serum albumin level
  > 3.5 g/dl 44 8 0.665 1.000
  <3.5 g/dl 28 4    

RESULTS

Response to Therapy

The response data are summarized in Table 2 . Thirty-six patients treated with weekly bolus injection of 5-FU and LV achieved a response rate of 19.4% (5 CR, 2 PR). The 95% confidence limit is 6.5-32.3%. Another 36 patients treated with biweekly 48-hour infusion of 5-FU and LV achieved a response rate of 13.9% (5 PR). The 95% confidence limit is 2.6-25.2%. There was no significant difference between these two regimens (P = 0.527). All responses of involved lesions were confirmed by sonogram, CT scan or chest X-ray.

Toxicity

Toxicities in these two arms are summarized in Table 3 . These toxicities were well-tolerated by the majority of patients. Gastrointestinal toxicities including stomatitis, nausea and vomiting and diarrhea were the major side effects, but they were generally tolerable and were not life-threatening. Hematological toxicities were minimal with no evidence of severe (grade 2 or more) leukopenia and thrombocytopenia. One patient receiving biweekly 48-hour continuous infusional treatment developed a transient painful fissuring erythroderma over his palms and soles (the hand-foot syndrome) (12 ).Mild liver and renal function impairment was occasionally found. There was no cardiac or neurological complication.

Factors Affecting Response

Each variable was tested separately to assess its association with tumor response (Table 4 ). The regimen, sex, age, location of primary tumor, initial Dukes' stage at diagnosis, serum CEA level before treatment, disease-free interval and serum albumin level did not affect response rate. By univariate analysis, performance status of the patient (P =0.044) and site of metastases (P = 0.017) both affected the response rate, but on multivariate analysis, the only factor to affect response rate was the site of metastases. Patients with metastases confined to the liver had a better response to treatment (P = 0.009).

Factors Affecting Survival

In our study, the only factor to affect survival was the performance status of the patient. As previously reported, performance status did have significant influence on survival (5 ). The median survival for patients with a performance status of 0 was 24.7 months, with 9.4 months for those who had a performance status of 1 or 2 (P = 0.0001) (Fig. 1 ). By multivariate analysis, performance status was still an important determinant in predicting survival (P = 0.0001) (Table 5 ).


Figure 1. Survival probability according to performance status (PS) of the patients. Patients with a PS of 0 (---, n = 48) had a significantly longer survival than those with a PS of 1 or 2 (-[circle]-, n = 24, P = 0.0001).

Table 5 . Analysis of factors prognostic for survival
  P
Factors Variables Survival Univariate Multivariate
Regimen
  weekly bolus 18.4 0.708 0.162
  biweekly infusion 21.0    
Sex
  male 21.9 0.040 0.556
  female 14.5    
Age (yr)
  >63 20.7 0.647 0.281
  <63 17.9    
Performance status
  0 24.7 0.0001 0.0001
  1, 2 9.4    
Primary tumor
  rectum 18.2 0.358 0.721
  colon 21.9    
Initial Dukes' stage
  B, C 21.8 0.218 0.549
  D 16.9    
Site of metastases
  liver 20.6 0.761 0.525
  extra-hepatic 16.6    
Pre-chemotherapy CEA
  >30 ng/dl 17.5 0.391 0.804
  <30 ng/dl 22.0    
Disease-free interval
  >6 months 23.8 0.027 0.184
  <6 months 16.1    
Serum albumin level
  >3.5 g/dl 21.0 0.267 0.146
  <3.5 g/dl 17.7    

DISCUSSION

Since its discovery by Heidelberger et al. about 30 years ago (13 ), 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. However, 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 (14 ). These reports were disappointing and prompted us to explore different dose schedules of 5-FU in an attempt to improve the response.

Levamisole is a synthetic orally active agent that has anti-helminthic and immunomodulatory properties. In combination with 5-FU, it has been associated with a one-third reduction in recurrence rate and risk of death in patients with surgically resected Dukes' stage C colon cancer (15 ).However, its role in the management of metastatic colorectal cancer remains unknown. In this study, we administered weekly iv bolus 5-FU and LV plus oral levamisole to 36 previously untreated patients. Five (13.9%) achieved CR while two (5.5%) showed PR. The overall response rate in this group was 19.4%. The median survival was 18.4 months.

Several nonrandomized trials have reported an improved response rate when 5-FU is given as a continuous intravenous infusion (16 -18 ). The reported response rates of these trials ranged from 31% to 53% (19 ). 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) (19 ). In this study, 36 patients with or without prior exposure to 5-FU were assigned to receive a 48-hour continuous infusion of 5-FU and LV. No patient achieved a CR but five (13.9%) had a PR. The median survival of these patients was 21 months. The response rate was similar between the bolus arm and the infusional arm (19.4% versus 13.9%, P = 0.527). The median survival was still similar in the two 5-FU based regimens (21.0 months versus 18.4 months, P = 0.708). However, we should keep in mind that in this study the two different regimens were compared historically, not in a randomized fashion, and they may be influenced by patients' backgrounds. This subject deserves a large, prospective randomized trial to compare the two regimens.

The performance status of the patient has been reported as being the most important prognostic factor in advanced colorectal cancer and many other malignancies (1 ,3 ,4 ). In our study, the importance of performance status in prognosis was confirmed again. By univariate analysis, patients with a performance status of 0 had a significantly longer median survival than those with a performance status of 1 or 2 (P = 0.0001). In stepwise multivariate analysis by Cox's regression model, a longer survival was still found in patients with a performance status of 0 (24.7 months versus 9.4 months, P = 0.0001).

Location of the primary tumor is commonly studied in clinical trials to evaluate its influence on response and survival. Previous studies have reported that the survival was not significantly different in patients with primary tumor located in the rectum or in the colon (3 ,6 ), but in the study conducted by Kemeny et al. (6 ), patients with a primary tumor located in the left colon had a significantly longer survival than those with primary tumors in the right (9.5 months versus 2 months, P < 0.002). In their study, the reason for this difference was not clear. In our study, the response rate and survival were not significantly different between patients with a primary tumor located in the colon or in the rectum (P = 0.751 and 0.358 respectively).

An elevated preoperative serum carcinoembryonic antigen (CEA) level is associated with early recurrence and poor prognosis in patients with colorectal carcinoma (7 ). Slentz et al. further reported that failure in bringing a pre-operative elevated CEA to a normal range following a curative resection implied a poor prognosis (22 ). Some investigators have reported that in patients with hepatic metastases from colorectal cancer, an increased serum CEA level is associated with a shortened survival (6 ,21 ). However, in a study of 227 patients with colorectal liver metastases, serum CEA <39 ng/ml or >50 ng/ml did not affect survival (P = 0.056) (4 ). In our study, serum CEA level above or below 30 ng/dl was not found to have a significant influence on survival (17.5 versus 22.0 months, P = 0.804). The relations between serum CEA level and survival in patients with metastatic colorectal cancer deserves further studies.

Disease-free interval had been rejected as a prognostic determinant by a previous study (21 ), but in a study of 340 patients conducted by Graf et al., patients with a disease-free interval of >365 days had a longer survival than those whose disease relapsed within 365 days (P < 0.01) (3 ). In our study, by univariate analysis a disease-free interval of >6 months had a median survival of 23.8 months, which is longer than 16.1 months for those with a <6 months interval (P = 0.027), although on multivariate analysis there was no difference between these two groups (P = 0.184). The role of disease-free interval in predicting survival for patients with metastatic colorectal cancer is still not clear.

A poor nutritional status has been reported as being associated with poor survival in patients with advanced colorectal cancer (1 ). Finan et al. had reported a series of 90 patients with hepatic metastases from colorectal cancer. The median survival in patients with serum albumin level >30 g/l was significantly longer than those whose albumin level was <30 g/l (P = 0.02) (20 ), but in our study, patients' serum albumin level >3.5 g/dl was not associated with a longer survival (21.0 months versus 17.6 months, P = 0.146).

The only factor to affect response to therapy on multivariate analysis is the site of metastases. In our study, patients who had metastases confined to the liver had a higher response rate than those who had extra-hepatic metastases (25% versus 3.6%, P = 0.009), although in a previous study conducted by Graf et al., hepatic metastases seemed to decrease the probability of a response (3 ).The difference in response rate between hepatic metastases only and extra-hepatic disease deserves further studies.

According to our study, these two 5-FU based regimens were well-tolerated in patients with metastatic colorectal cancer, but their efficacy was still disappointing. It deserves further studies to determine the optimal dose scheduling. Patients who had metastases confined to the liver seemed to have a higher response to chemotherapy. Performance status is still the most important determinant in predicting survival for patients with metastatic colorectal cancer.

Acknowledgements

This work was kindly supported by a grant from the Yen Tjing-Ling Medical Foundation.

References

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Received October 21, 1996; accepted December 11, 1996
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

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