Efficiency and tolerability of 5- fluorouracil-based adjuvant chemotherapy in elderly patients with colorectal carcinoma

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1 Turkish Journal of Cancer Volume 34, No.4, Efficiency and tolerability of 5- fluorouracil-based adjuvant chemotherapy in elderly patients with colorectal carcinoma LHAN ÖZTOP 1, ARZU YAREN 1, IfiIL SOMAL 2, OKTAY TARHAN 1, U UR YILMAZ 1 1 Dokuz Eylül University, Institute of Oncology, Department of Medical Oncology, 2 Atatürk Research and Training Hospital, Department of Medical Oncology, zmir-turkey ABSTRACT The benefit and tolerability of adjuvant chemotherapy for surgically treated colorectal cancer is less well defined in elderly patients. We reviewed data of 51 patients who received adjuvant chemotherapy for colorectal cancer between October 1993 and December 2002, and were 65 year-old at the first cycle of chemotherapy. Fifty-one elderly patients with colorectal cancer received 5-FU based adjuvant chemotherapy. Twenty-four patients (47.0%) had stage II, 25 (49.0%) had stage III, and 2 (3.9%) had stage IV disease (completely resected liver metastasis). Fourteen patients (27.5%) were treated with bolus 5-FU, while 37 patients (72.5%) were treated with infusional 5-FU. The most commonly observed grade 3-4 toxicities were myelosuppresion (17.6%) and diarrhea (15.6%), and they were more frequently seen in patients who received 5-FU bolus regimens (p<0.001 and p<0.005, respectively). The 3-year DFS and OS rates were 77.7% and 83.5%, respectively. Twenty-nine patients who were 70-year-old were also evaluated. The most commonly grade 3-4 toxicities observed in this age group were myelosuppresion (6.9%) and diarrhea (6.9%), and they occurred in patients who received 5-FU bolus regimens. In survival analyses, the 3-year DFS and OS were 80% and 80.7%, respectively. In elderly patients, the use of 5- FU based adjuvant chemotherapy for colorectal cancer was well tolerated, and advanced age is not an obstacle for the adjuvant chemotherapy of colorectal cancer. [Turk J Cancer 2004;34(4): ] KEY WORDS: Colon cancer, elderly patients, 5-fluorouracil INTRODUCTION The incidence of colorectal cancer increases with advancing age, and in elderly patients with this disease, the cancer is still the major cause of death. Randomized clinical trials demonstrated that adjuvant chemotherapy with 5- fluorouracil (5-FU) based regimens was able to reduce the risk of disease recurrence and mortality in patients with stage III colorectal cancer. Elderly patients were not adequately included to these trials because of traditional age limits of inclusion criteria. Meanwhile, adjuvant chemotherapy in colorectal cancer has minimal toxicity which permits the administration of the planned treatment to the vast majority of patients and reduces the risk of death by one third, as compared with surgery alone (1-4). There is no reason to consider that elderly patients with early colorectal cancer are deprived of a similar benefit in terms of disease control and survival. Due to the low toxicity profile of regimens used in the adjuvant treatment of colorectal cancer, patients with advanced age can receive the adequate treatment, but there are limited data on the risks and benefits of cancer treatment in older patients, because patients of this age group were less involved in clinical trials (5-9).

2 140 Adjuvant 5-FU Based Chemotherapy in Elderly Patients with Colorectal Carcinoma The improvement of preventive and therapeutic health services as well as of socio-economic conditions resulted in an important prolongation of life expectancy in developed countries. As a result of this, the proportion of elderly people has increased as a whole. These persons with advanced age are nowadays in better conditions, and a better health care is delivered to them. Thus, patients with colorectal cancer in advanced age are left without treatment in a lesser degree. In accordance with this trend in developed countries, no age limit was adopted in decisions for adjuvant treatment of patients with surgically treated early stage colorectal cancer and adjuvant chemotherapy was proposed to each one irrespective of age in our department. In order to evaluate the feasibility and tolerability of the adjuvant treatment of elderly patients in early stage colorectal cancer, the records of all patients treated during the last ten years in our department of medical oncology were analyzed and reported below. MATERIALS AND METHODS We reviewed the data of patients with colorectal cancer aged 65 years or older referred to our department of medical oncology for adjuvant treatment following curative surgery from October 1993 to December This included patients with stage II, III and also stage IV with completely resected liver metastasis. The choice of chemotherapy regimen changed during the period and were based on 5- FU as bolus (weekly 5-FU, 5-FU + Levamisol, Mayo) or late as bolus plus infusion (LV5FU2) (Table 1). The first chemotherapy cycle was initiated within two to eight weeks following the surgery. Basic criteria for the administration of chemotherapy were adequate blood counts (WBC 4.000/mm 3, Hb 11 g/dl, PLT /mm 3 ) and serum biochemistry (creatinine 1.5 mg/dl, AST and ALT 2 x upper limit of normal (ULN), bilirubin 2.0 mg/dl) as well as good performance status (ECOG 2) and absence of significant systemic disease. For each patient, the stage of disease (TNM), degree of tumor differentiation, co-morbidities and the type of chemotherapy regimen were recorded. The chemotherapy toxicity and the outcome of the disease and patients were analyzed. The toxicity of chemotherapy was graded according to the Common Toxicity Criteria of World Health Organization (10) and the highest grade observed was recorded for each kind of toxicity. Table 1 The chemotherapy regimens administered to the patients Mayo Clinic regimen 5-FU 425 mg/m 2 (IV bolus) d1-5 Folinic acid 20 mg/m 2 (IV bolus) d1-5 (To be repeated every 4 weeks during 6 months) LV5FU2 regimen 5-FU 400 mg/m 2 (IV bolus) d mg/m 2 (IV 22 h inf) d1+2 Folinic acid 200 mg/m 2 (2 h inf) d1+2 (To be repeated every 2 weeks) 5-FU + Levamisole 5-FU 425 mg/m 2 (IV bolus) d1-5 then weekly x 1 y Levamisole 50 mg t.i.d. PO d1-3 three days per week, every other week Weekly 5-FU 5-FU 425 mg/m 2 (IV bolus) d1 (Weekly)

3 Öztop et al. 141 Statistical Methods Comparisons of the distribution of qualitative parameters among subgroups were made using the chi-square test or Fisher s exact test when it is more adequate. Means were compared with student t-test. Disease-free survival (DFS) and overall survival (OS) were estimated with Kaplan-Meier method. The DFS was defined as the time from the first day of chemotherapy until the first evidence of disease recurrence, and OS was defined as the time from the first day of chemotherapy until death. The survival was also analysed as adjusted survival (AS) censoring non-cancer related deaths at the time of death. Subgroups were compared with log-rank test. SPSS 10.0 for Windows was used for all statistical analyses. The most commonly observed grade 3 and 4 toxicities were myelosuppresion (17.6%) and diarrhea (15.6%), and they were more frequently seen in patients who received 5-FU as bolus regimens (p<0.001 and p<0.005, respectively). Nausea and vomiting were also more frequent in the bolus group (p<0.05) (Table 3). Grade 3-4 myelosupression was also more frequently observed in female patients (6 of 19; 31.5%) compared to males Table 2 Characteristics of elderly (65 and older) patients with colorectal carcinoma who received adjuvant chemotherapy after surgical resection RESULTS Adjuvant chemotherapy for colorectal cancer following surgical resection was started from October 1993 to December 2002 in 155 patients of all ages. Fifty-one among these patients were aged sixty-five years or older at the time of start the chemotherapy and they are the subject of this analysis. The total number of patients in this age group referred after surgery was 55, but four of them did not receive chemotherapy; three patients refused the treatment while one patient was left without chemotherapy because of inadequate performance status. These four patients were not included to this analysis. About two third of the patients were male and the median age was 70 (range years). Approximately half of the patients had stage II disease (47.0%). This analysis included also two patients who received adjuvant chemotherapy after resection of liver metastases at the same time as primary tumor. Only 13 patients (25.5%) had rectal cancer and they also received radiation therapy before or after surgical resection. Characteristics of 51 patients who were analyzed are summarized in table 2. All patients received 5-FU based adjuvant chemotherapy. Fourteen patients (27.5%) were treated with different regimens of bolus 5-FU ± folinic acid, while 37 patients (72.5%) were treated with 5-FU as bolus combined by longer infusion, and high dose folinic acid (LV5FU2). No initial dose reduction was performed for advanced age. Patient characteristics Number of patients (%) Median age (year) 70 Sex Male 32 (62.7) Female 19 (37.3) Performance status 0 12 (23.5) 1 29 (56.8) 2 10 (19.7) Stage II 24 (47.0) III 25 (49.0) IV (metastectomy) 2 (4.0) Comorbidity 0 34 (66.6) 1 10 (19.6) 2 7 (13.8) Localisation of cancer Colon 38 (74.5) Rectum 13 (25.5) Tumor grade Well differentiated 7 (13.7) Moderately differentiated 33 (64.7) Poorly differentiated 3 (5.9) Unkown 8 (15.7) Chemotherapy Bolus 14 (27.5) Infusional 37 (72.5)

4 142 Adjuvant 5-FU Based Chemotherapy in Elderly Patients with Colorectal Carcinoma (3 of 32: 9.4%), but the difference did not reach statistical significance (p>0.05). A Dose reductions were performed in 4 (7.8%) patients as a result of hematological toxicity and in one patient, the chemotherapy was interrupted at month 2 because of hematological toxicity in spite of dose reductions. The chemotherapy dose intensity was defined as the ratio of the dose planned to the dose delivered. The median dose intensity was 92%. The patients who were alive at the end of analysis were followed for a median duration of 26.5 months (range: 2-114). The 3-year DFS and OS were 77.7% and 83.5% respectively (Figure 1). Nine patients were dead during the follow-up and four of these deaths were not related to colorectal cancer. When the survival data was adjusted censoring non-cancer deaths, the median survival was 74 months and 3-year adjusted survival (AS) was 92.5%. Sex, presence of comorbidity, location of tumor, differentiation of tumor, stage, and type of chemotherapy regimens did not have statistically significant effect on DFS, OS and adjusted survival. Twenty nine patients who were seventy years or older were also evaluated separately. The median age was 74 and most of patients (24 of 29 patients) had good performance status (ECOG 0-1). The most commonly grade 3-4 toxicities observed in this age group were myelosuppresion (6.9%) and diarrhea (6.9%), and they occurred in patients who received 5-FU bolus regimens. In survival analyses, the 3-year DFS, OS and AS were 80.0%, 80.7 % and 92.7%, respectively. DISCUSSION The adjuvant chemotherapy for surgically treated colorectal cancer in fifty-one patients being 65 years or older at the beginning of first cycle, were analyzed retrospectively. B Figure 1. Kaplan-Meier estimates for (A) overall and (B) disease free survival among elderly (65 and older) patients who received adjuvant chemotherapy as 5-FU Different, but all 5-FU based chemotherapy regimens were administered. The treatment was well tolerated with only one disruption of treatment because of toxicity. There was no treatment related mortality. The 3-year disease free survival, overall survival and cancer related survival were found 77.7%, 83.5% and 92.5%, respectively. This figure was 80.0%, 80.7% and 92.7%, respectively in patients who were seventy years and older. Table 3 Grade 3-4 toxicity of adjuvant chemotherapy in 65 age and older patients All patients Myelosuppression Diarrhea Stomatitis Handfoot Whole group 17.6% 15.6% 7.8% 3.9% Bolus 5-FU 15.6% 13.6% 7.8% - Bolus + Infusional 5-FU 2.0% 2.0% - 3.9%

5 Öztop et al. 143 These data concern patients of relatively new and developing medical oncology department and most of patients were seen in last years of the analysis period. This fact explains why median follow up is as short as 26.3 months beside an analysis period of 10 years. Otherwise, the inclusion of stage II patients contributed to the good prognosis of the whole group. The adjuvant treatment of colorectal cancer concerns also the radiotherapy when the tumor is localized in the distal rectum. In this context, the use of the radiotherapy in patients is also to be evaluated. This was not done in this analysis because of small number of patients who received adjuvant radiotherapy and lack of adequate data. It has been demonstrated that adjuvant chemotherapy can reduce the risk of disease recurrence and death in patients with stage III colon carcinoma by approximately 40% and 33%, respectively (4). The benefit of adjuvant chemotherapy in stage II is controversial. The choice of the physicians in this department was in favor of the administration of adjuvant chemotherapy also in stage II. Treatment regimens found efficacious in this context are generally well tolerated. Moreover, these studies demonstrated that adjuvant therapy can be administered with minimal toxicity and that the vast majority of patients are able to complete treatment (11,12). Although elderly persons make the majority of the population with cancer, older patients have been less likely to receive standard cancer treatments, even when such treatments are potentially curative and usually well tolerated (8,13,14). Newcomb and Carbone showed that, nearly 50% of patients who have various malignancies at an age under 65 were offered chemotherapy as a treatment option, but only 35% of those over 65 were given the same option. The rate of patients who rejected the chemotherapy was higher among older patients because of fear from side effects (15). In our study, 51 of 55 patients (92.7%) referred in our department were given adjuvant chemotherapy and only three of them refused the treatment despite the opinion of the physician. This high rate of patient compliance despite the age can be explained by the fact that, most patients had good performance status and especially in our country, patients leave the treatment decision to the physician. Clinicians have rational arguments not to use treatments with a high rate of toxicity in patients with advanced age. These include coexisting morbid conditions, lower level of tolerance against adverse effects, declining functional and mental status with advanced age and lack of social support. However, most people older than 75 are independent, and their life expectancy without cancer is 10 to 12 years in western countries and this is increasing towards this level in Turkey (16). Because colorectal cancer typically recurs mostly within five years after diagnosis, it is reasonable to consider adjuvant chemotherapy to prevent recurrence in elderly patients including octogenarians. In a pooled analysis of individual patient data from seven phase III randomised trials, in which the effects of postoperative 5-FU plus leucovorin (five trials) or plus levamisole (two trials) were compared with the effects of surgery alone in elderly patients with stage II or III colon cancer. It was concluded that adjuvant treatment had a significant positive effect on both overall survival and time to tumor recurrence. The 5-year OS was 71% for those who received adjuvant therapy, as compared with 64% for those untreated (8). Another population-based cohort study resulted in favor of a survival benefit of adjuvant 5-FU in elderly patients with stage III colon cancer (17). Furthermore, the survival benefit did not appear to diminish with patient age. Other studies also reported similar survival rates (18-20). The survival analysis in our study showed that the 3- year DFS and OS were 77.7% and 83.5%, respectively. These results were similar to the studies reported elsewhere. Many studies have shown that age was not associated significantly with survival (4,8, 18-22). Conversely, in some studies, there was a trend in favor of an improved clinical outcome for the elderly. In addition to this, Moertel et al. (4) found that older patients with colon carcinoma had a greater survival benefit from 5-FU based adjuvant therapy compared to younger patients. In some studies, patients with advanced age receiving 5-FU based chemotherapy for colorectal cancer experienced increased grade 3-4 toxicities as leukopenia and mucositis (9,23,24). However, a meta-analysis of 19 trials have found no convincing evidence that chemotherapy was more toxic or less beneficial for elderly cancer patients who were aged 70 years and over (12). A secondary analysis of several phase II trials in advanced cancer also found no evidence of increased toxicity in those over age 65 (25). We have found that the most commonly observed grade 3-4 toxicities were myelosupression (17.6%) and diarrhea

6 144 Adjuvant 5-FU Based Chemotherapy in Elderly Patients with Colorectal Carcinoma (15.6%) and they were more frequently seen in patients who received 5-FU bolus regimens. These rates are comparable to rates varying from 9 to 30% observed elsewhere during the adjuvant treatment of colorectal cancer. The toxicity is in general less severe when 5-FU was administered as longer duration infusion (17,18,24,25). We have also compared these patients age 65 years with the 104 patients age < 65 years who received adjuvant chemotherapy in the same context during the study period of our department. In younger group, forty-four patients (42.3%) had stage II and 60 (57.7%) had stage III. Thirtyseven patients (35.6%) were treated with bolus 5-FU, while 67 patients (64.4%) were treated with infusional 5-FU. Grade 3-4 hematological toxicity and diarrhea were observed more frequently in bolus group than infusional group (7.3 vs 2.6% and 6.8 vs 3.2%, respectively). The dose reduction was performed in 6 patients in both group. In survival analysis, there was not any significant difference between bolus and infusional treatment group. The 3-year diseasefree survival and overall survival rates were 76.4% and 79.7% in whole group. Although both age group had a similar survival rates, the hematological toxicity and diarrhea were observed more frequently in patients age 65 years than the patients age < 65 years. The association of gender and toxicity with 5-FU-based adjuvant chemotherapy for patients with colon carcinoma, especially in older patients, has been controversial. The North Central Cancer Treatment Group (NCCTG) recently reported a meta-analysis of 6 NCCTG-cancer-control trials involving 786 patients receiving 5-FU based chemotherapy for colorectal carcinoma (26). Including the effect of age in a logistic regression analysis showed that women who received 5-FU based therapy experienced greater severe toxicity than men. Altered pharmacokinetics in female patients as gender-related differences in dihydropyrimidine dehydrogenase (DPD) activity have been described by Milano and colleagues (27) and are likely to be responsible for the increased toxicity seen in females. We have also found that female patients have experienced grade 3-4 toxicites than male patients, however this was not statistically significant. In our analysis, patients aged 70 years or older were analyzed separately. The survival data and toxicity rates were not much different than those of the whole group. So, when the age limit is increased, there is no change implying different therapeutic decisions. Our analysis showed that elderly patients with colorectal cancer can receive 5-FU based adjuvant chemotherapy with a mild increase in toxicity compared to their younger counterparts. So, we believe that older patients with stage II or III colorectal cancer or resectable metastatic disease should be both offered adjuvant chemotherapy, especially infusional regimens of 5-FU are preferable because of lower toxicity rates unless there are no medical and psychosocial contraindications.

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