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Irinotecan in Combination With Fluorouracil in a 48-Hour Continuous Infusion As First-Line Chemotherapy for Elderly Patients With Metastatic Colorectal Cancer: A Spanish Cooperative Group for the Treatment of Digestive Tumors Study

From the Hospital Clínico San Carlos, Madrid; Hospital Santa Creu i San Pau; Hospital Duran i Reynals; Hospital Germans Trias i Pujol; Hospital Clinic i Provincial, Barcelona; Hospital General de Alicante, Alicante; Hospital Carlos Haya, Málaga; Hospital Miguel Servet, Zaragoza; Hospital Reina Sofía, Córdoba; Hospital Juan Canalejo, A Coruña; Hospital Virgen de los Lirios; Hospital General de Elche, Alicante; and Hospital General Universitario, Valencia, Spain

Address reprint requests to Javier Sastre, MD, Servicio de Oncología Médica, Hospital Clínico San Carlos, C/Profesor Martín Lagos, s/n, 28040 Madrid, Spain; e-mail: jsastre.hcsc{at}salud.madrid.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Elderly patients constitute a subpopulation with special characteristics that differ from those of the nonelderly and have been underrepresented in clinical trials. This study was performed to determine the efficacy and safety of irinotecan (CPT-11) in combination with fluorouracil (FU) administered as a 48-hour continuous infusion twice a month in elderly patients.

PATIENTS AND METHODS: Patients 72 years old with metastatic colorectal cancer, Eastern Cooperative Oncology Group performance status of 0 to 1, no geriatric syndromes, and no prior treatment were treated every 2 weeks with CPT-11 180 mg/m² plus FU 3,000 mg/m² in a 48-hour continuous infusion.

RESULTS: By intent-to-treat analysis, in 85 assessable patients, the objective response rate was 35% (95% CI, 25% to 46%), and stable disease was 33% (95% CI, 23% to 44%). Median time to progression was 8.0 months (95% CI, 6.0 to 10.0 months), and median overall survival time was 15.3 months (95% CI, 13.8 to 16.9 months). Toxicity was moderate. Grade 3 and 4 neutropenia, diarrhea, and asthenia were observed in 21%, 17%, and 13% of patients, respectively. Only one case of neutropenic fever occurred. There were two toxic deaths, one was a result of grade 4 diarrhea and acute kidney failure, and the other was a result of massive intestinal hemorrhage in the first cycle. The study of prognostic factors did not reveal any predictive factor of response. Response to treatment and baseline lactate dehydrogenase were the main factors conditioning progression-free and overall survival.

CONCLUSION: Twice a month continuous-infusion CPT-11 combined with FU is a valid therapeutic alternative for elderly patients in good general condition.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Colorectal cancer is one of the most common neoplasms in the elderly population. In Europe, 40% of patients are diagnosed at ages older than 74 years,¹ and the incidence is expected to grow in the future. The therapeutic approach in elderly patients with metastatic disease is currently a challenge. Two phase III studies have established the combination of irinotecan (CPT-11) plus fluorouracil (FU) and leucovorin (LV) as a standard regimen for the treatment of advanced colorectal cancer.^2,3 Nevertheless, elderly patients remain a minority in clinical trials,^4,5 which makes it difficult to extrapolate the results obtained in such trials to routine practice for those patients. The elderly are a special population because of frequent comorbidity, abnormal drug metabolism, and loss of functional capacity, which is associated with a greater risk of cytostatic toxicity.⁶ A multicenter study carried out by Rothenberg et al⁷ using a weekly CPT-11 schedule showed increased toxicity in patients more than 65 years of age.⁷ In contrast, a recent analysis⁸ of activity and toxicity in relation to age, corresponding to the patients of the phase III study published by Douillard et al,² indicates that age is not an adverse prognostic factor for activity or toxicity in patients treated with a combination of CPT-11 + FU-LV. No specific large-scale prospective studies have been conducted in elderly populations with combination chemotherapy. The purpose of this study was to evaluate the activity and tolerability of the CPT-11 + FU combination administered as a continuous infusion every 2 weeks in elderly patients with advanced colorectal cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
This multicenter, prospective study was carried out by the Cooperative Group for the Treatment of Digestive Tumors (TTD group).

Patient Selection
Inclusion criteria included the following: informed consent; metastatic colorectal adenocarcinoma confirmed histologically; absence of previous treatment for advanced disease; interval of more than 6 months from the conclusion of adjuvant chemotherapy; age more than 72 years; measurable disease by Response Evaluation Criteria in Solid Tumors⁹; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; life expectancy more than 3 months; adequate hematologic, hepatic, and renal function (neutrophils 2,000/µL, platelets 100,000/µL, total bilirubin 1x upper limit of normal (ULN), AST and ALT 2.5x ULN or 5x ULN in the case of liver metastases, alkaline phosphatase 2.5x ULN, creatinine 1x ULN or creatinine clearance more than 60 mL/min as calculated by the Cockcroft method, and prothrombin time more than 0.5x ULN); no radiotherapy in the 6 weeks before inclusion; and ability to understand and follow guidelines for the prophylaxis of diarrhea induced by CPT-11. Exclusion criteria included the following: previous treatment with CPT-11 or any topoisomerase I inhibitor; presence of cerebral or leptomeningeal metastases; history of another cancer except for cervicouterine carcinoma-in-situ or basal cell skin carcinoma excised curatively; intestinal obstruction, history of inflammatory enteropathy, or extensive intestinal resection; serious concomitant disease, such as unstable heart disease, acute myocardial infarction in the last 6 months, severe neurologic or psychiatric disorders, uncontrolled active infection, and disseminated intravascular coagulation; presence of geriatric syndromes, such as dementia, delirium in stressful situations, severe depression, frequent falls, spontaneous bone fractures, and neglect; and contraindications for atropine use.

Treatment Schedule
CPT-11 (Campto; Aventis Pharma, Dagenham, UK) was administered in an intravenous infusion lasting 30 minutes at a dose of 180 mg/m², followed by FU 3,000 mg/m² as a continuous 48-hour intravenous infusion, preferably through an implantable Rosenblatt Dual Slimport central catheter (BARD Laboratories, Murray Hill, NJ, and Baxter Healthcare Corp, Chicago, IL). Both drugs were administered at intervals of 2 weeks. Treatment was maintained until either disease progression or unacceptable toxicity appeared, the investigator decided to discontinue treatment, or the patient withdrew consent. Patients received antiemetic prophylaxis as per the routine practice of each center, although use of a guideline for highly emetic chemotherapy was recommended. Atropine premedication was allowed from the first cycle. Patients were given instructions for treating diarrhea by abundant fluid intake, loperamide 2 mg every 2 hours for at least 12 hours, and ciprofloxacin 500 mg/12 h in case of diarrhea lasting more than 24 hours. The prophylactic use of colony-stimulating factors was not allowed. Dose modifications were as follows: in the case of grade 4 neutropenia, neutropenic fever, or thrombocytopenia less than 25,000/µL, the doses of both CPT-11 and FU were reduced by 20%; in the case of grade 3 or 4 diarrhea, both drugs were reduced by 20%; and in the case of grade 3 or 4 hand-foot syndrome, FU alone was reduced by 20%.

Evaluations During the Study
In the 14 days before the first infusion, patients underwent a clinical history and physical examination, blood counts, liver and kidney function tests, and evaluations of electrolyte concentrations and prothrombin time. Carcinoembryonic antigen determination, ECG, chest radiograph, and abdominal computed tomography were performed in the 28 days before treatment commencement. During treatment, blood counts were performed on day 7 of the first two cycles and then at the beginning of each cycle, together with blood biochemistry. Carcinoembryonic antigen determinations and tumor response studies were performed every 3 months (every six cycles).

Evaluation of Efficacy and Toxicity
Tumor response was evaluated by investigators using the Response Evaluation Criteria in Solid Tumors criteria⁹ at 3-month intervals until the disease progressed or the patient died. No evaluation was made by an external radiologic committee. Patients were considered assessable if they had received at least one treatment cycle, in which case they were included in intent-to-treat analysis. The duration of the response was calculated from its appearance until the date that progression was documented. The progression-free survival and overall survival times were calculated from the inclusion of the patient onto the study until documentation of progression and death, respectively. Toxicity was evaluated at the initiation of each cycle using the toxicity scale of the National Cancer Institute Common Toxicity Criteria, version 2.0.

Statistical Analysis
Sample size was calculated using the optimal method designed by Simon.¹⁰ Assuming a minimum efficacy of 15%, which is equivalent to that obtained with fluoropyrimidine therapy alone, we proposed achievement of a 30% response rate with the study combination, at a level of significance of 95% ( error = .05) and a statistical power of 90% (ß error = .10). According to these parameters, a sample size of 82 patients was required. Assuming that 10% of patients would be nonassessable, a total of 90 patients were included. Progression-free survival and overall survival curves were prepared using the Kaplan-Meier method. Ninety-five percent CIs were calculated. Prognostic factors were studied by means of the simple Cox regression procedure for each study variable and a Cox multivariate procedure with a forward stepwise model using an entry significance of 0.1 and an exit significance of 0.15 by the Wald statistic.

	RESULTS

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Between September 2001 and December 2002, 91 patients from 20 centers of the Spanish TTD cooperative group were included. Six patients were excluded from analysis because they did not meet all selection criteria. Eighty-five patients were assessable for toxicity and antitumoral activity. Baseline patient characteristics are listed in Table 1. Median patient age was 77 years. All patients had an ECOG performance status of 0 to 1, and more than half had only one metastatic location. Seventy-two percent of patients presented with one or more concomitant chronic diseases, primarily arterial hypertension (46%), diabetes mellitus (18%), stable heart disease (16%), and chronic pulmonary disease (8%). In 55% of patients, the initial diagnosis was stage IV disease (distant metastases). The main metastatic locations were liver (77%), lung (27%), and lymph nodes (15%). Twenty-eight percent of patients had received adjuvant chemotherapy with FU + LV or oral fluoropyrimidines. Nine patients received previous pelvic radiotherapy (adjuvant, n = 8; and palliative, n = 1).

Safety
The hematologic and nonhematologic toxicities of the patients are listed in Table 2. The main hematologic toxicity was neutropenia, which was grade 3 or 4 in 21% of patients. Only one case of neutropenic fever occurred. Diarrhea was the main nonhematologic toxicity, and grade 3 or 4 diarrhea occurred in 18% of patients. Asthenia, abdominal pain, and emesis were other relevant toxicities. Thromboembolic phenomena occurred in six patients (7%); ischemic cerebral accident occurred in two patients, deep venous thrombosis of the limbs occurred in three patients, and central venous catheter thrombosis occurred in one patient. There were two deaths caused by toxicity; one patient had grade 4 diarrhea associated with acute kidney failure and did not present at hospital or follow the recommended support measures and, subsequently, died at home, and the other patient had a massive gastrointestinal hemorrhage and abdominal pain in the course of the first cycle of treatment. No postmortem studies were performed.

View larger version (12K): [in this window] [in a new window]   Fig 1. Progression-free survival (PFS) curve by the Kaplan-Meier method.

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival (OS) curve by the Kaplan-Meier method.

	DISCUSSION

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To date, we are not aware of the publication of any prospective study of combination chemotherapy in elderly patients with metastatic colorectal cancer. The combination of CPT-11 associated with FU and folinic acid is one of the combinations considered as standard for the treatment of nonelderly patients.^2,3 Primarily, this study demonstrated that multicenter studies of combination chemotherapy in this subpopulation of patients are indeed feasible. We confirm the experience of Aparicio et al,¹¹ who recently published an observational multicenter study in which patients over 74 years of age received combinations of CPT-11 or oxaliplatin in first- and second-line chemotherapy with acceptable activity and toxicity. Unfortunately, in the study by Aparicio et al,¹¹ only eight patients received a combination of CPT-11 with FU-LV as first-line treatment for advanced disease, which is why the findings cannot be compared with our data. It is important to bear in mind that patients included in our study are a subpopulation of elderly patients characterized by their good general state and free of typical geriatric syndromes. The presence of these syndromes is associated with an important loss of independence in activities of daily living, a lower survival, and greater probability of serious chemotherapy-related toxicity.¹² Therefore, the results of this study cannot be extrapolated to the elderly population in general. Although not validated, a consensus protocol for the selection of elderly patients by subgroups in advanced colorectal cancer exists; it is important that future studies include selection criteria based on a comprehensive geriatric evaluation because such an evaluation enables a homogeneous study sample^13-16 to be obtained. Another point to consider is the age that defines the elderly population. Our choice of 72 years or older in this study is obviously arbitrary and based on the exclusion of these patients from other studies of advanced colorectal cancer performed by our group at the same time. Although there is no consensus, it does not seem reasonable nowadays to include patients who are 65 to 69 years of age as being elderly. Most authors accept the cutoff age of 70 years as appropriate for this type of study.

In this study, the administration every 2 weeks of CPT-11 180 mg/m² with high-dose FU 3,000 mg/m² in a 48-hour continuous infusion achieved an overall response rate of 35.3%. This rate is equivalent to the rate of 35.8% obtained by patients 65 years of age and the rate of 31.5% obtained in patients less than 65 years of age with a schedule of CPT-11 plus FU-LV every 2 weeks in the study by Douillard et al,² which was recently analyzed by Rougier et al.⁸ After exclusion of nonassessable patients for response, our response rate reached 41%. On the contrary, our overall response rate is lower than the rate reported by Tournigand et al¹⁷ (56%) for first-line therapy with their folinic acid + FU + irinotecan (FOLFIRI) regimen. They used the same CPT-11 dose and almost the same FU continuous-infusion dose and schedule as we used, but they added high-dose LV and bolus FU on day 1. However, a comparison between the chemotherapeutic schedules used by Douillard² and Tournigand¹⁷ reveals a double FU continuous-infusion dose in the latter schedule.

Although our lower response rate may potentially be attributed to differences in prognostic factors of patients, the role of high-dose LV modulation may not be ruled out. In our schedule, we dispensed with the administration of folinic acid in light of our previous experience in two consecutive phase II studies, which showed that the addition of LV to high doses of FU does not increase activity but does increase toxicity.^18,19 The dose of FU 3,000 mg/m² is the standard dose adopted by the TTD group based on a phase I study of a 48-hour continuous FU infusion.²⁰ The twice a month schedule was maintained because it seemed to be less toxic than a weekly schedule, equally effective, and more comfortable for the patient. Furthermore, in a pilot study with the present schedule in a total of 40 elderly and nonelderly patients that was carried out at two centers by the TTD group and that was presented to the VIII Congress of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica), it was noteworthy that toxicity was low (5% grade 3 or 4 neutropenia and 12% grade 3 or 4 diarrhea) and that preliminary activity was close to 30% (unpublished data). The role of administration of a bolus of FU before continuous infusion of FU is not clear in the literature. Although direct comparison of activity among different phase II studies is not possible, the activity of our schedule seems to be better than the activity obtained by other authors in elderly populations using single-agent schedules of FU, oral fluoropyrimidines, or raltitrexed.^21-27 Except for the 44% response rate reported by Mabro et al²⁸ in a retrospective study with different guidelines for FU modulated with LV, none of these studies achieved an objective response rate of more than 30%. In two consecutive studies of tegafur-uracil with and without LV in a total of 214 patients, our own group obtained response rates of 13% and 18%, respectively.²⁶ The median progression-free survival and overall survival were similar to those of schedules currently considered standards for advanced colorectal cancer in the nonelderly population. Although the recent Tournigand et al¹⁷ study of sequential combination chemotherapy in a nonelderly population has achieved an overall survival time of more than 20 months (which surpasses the 15.3 months obtained in this study), it is important to remember that only 40% of patients received second-line treatment. Two phase II studies of CPT-11 plus FU-LV, one German and the other Nordic, have reported median overall survival times of 13 months and 15.6 months, respectively.^29,30 In the German study, 54% of patients received second-line chemotherapy. In addition, the median overall survival time of 15.3 months that was obtained in our study is higher than the overall survival time reached in prospective studies of elderly patients with single-drug therapy.^22,24-26 There are no phase III studies in elderly populations comparing single-drug chemotherapy to combination chemotherapy. Only one phase III study in elderly patients, including all gastrointestinal tract tumor sites, has demonstrated an increase in survival with chemotherapy as opposed to supportive treatment.³¹

The analysis of predictive factors for response did not find any variable of prognostic significance. The objective response to treatment and a baseline normal LDH value were found to be the only prognostic variables for overall survival. The relationship between objective response and increase in survival has already been demonstrated by the Nordic group³² and, recently, by Louvet et al³³ and the Meta-Analysis Group in Cancer.³⁴ The number of associated chronic diseases was not an adverse prognostic factor for response or survival. Because of recent findings of a negative impact of diabetes mellitus on the evolution of patients with stage II and III colon cancer,³⁵ we analyzed this variable in our population, which had a high prevalence of diabetes, but found no negative effect of diabetes on survival or objective response. A recent analysis of predictive factors of 602 nonelderly patients included in V-302 and V-303 phase III studies has found that weight loss more than 5%, WHO performance status of 0 or 1, two or less metastatic sites, alkaline phosphatase less than 2 x normal, and CPT-11–containing regimen were independent factors for survival.³⁶ LDH was also strongly associated with survival in the univariate analysis, but the value was not available in almost 20% of patients and then was excluded in the multivariate analysis. Köhne et al³⁷ established three prognostic groups according to four baseline clinical parameters: performance status, WBC count, alkaline phosphatase, and number of metastatic sites, but those patients were mainly treated with single-agent or modulated FU. As in the Mitry et al³⁶ analysis, age was not a significant prognostic factor. Nevertheless, the results of our multivariate analysis are limited by the low number of patients for such a study.

The toxicity was moderate and acceptable for the population under study. Grade 3 or 4 neutropenia occurred in 21% of patients, although weekly analyses were made in the first two cycles. Only one case of neutropenic fever was recorded. Grade 3 or 4 diarrhea occurred in 16% of patients, which is a figure similar to that of the population of patients 65 years or older analyzed by Rougier et al⁸ from the phase III study published by Douillard et al.² Treatment was delayed in half of the patients, fundamentally because of asymptomatic neutropenia on day 1 of the cycle, and the dose was reduced in almost one quarter of patients, particularly for nonhematologic toxicity. However, it should be noted that the median dose-intensities attained for CPT-11 and FU were 96% and 96.2% of the planned theoretical doses, respectively. Treatment compliance was good, and all patients had an ECOG performance status of 0 or 1 initially; nevertheless, 12 of 85 patients were unassessable for response because of early discontinuation for various reasons that were not always related to the treatment. This reflects how fragile the elderly population might be and the importance of patient selection for combined chemotherapy.

Despite instructing patients about how to manage toxicity, especially diarrhea and fever, two deaths occurred as a result of toxicity. The first was a result of grade 4 diarrhea associated with acute kidney failure. The patient did not follow the instructions given and did not seek hospital care and, thus, died at home. For this reason, we must emphasize the importance of selecting patients who are fully aware of the toxic effects of treatment and who will cooperate with treatment when regimens with potentially serious side effects are indicated. The other toxic death occurred as a result of massive gastrointestinal hemorrhage, a lethal adverse effect that has been reported in a study by Glimelius et al,³⁰ in which the postmortem study revealed damage to the intestinal mucosa. No postmortem study was performed on our patient. It is worth thinking about the percentage of vascular events found in our series (7%). Vascular syndrome, which is defined as a sudden, unexpected thromboembolic event that occurred during or shortly after receiving chemotherapy, appeared as a major cause of early treatment-induced death in a recent analysis conducted by Rothenberg et al³⁸ in two trials with CPT-11 and FU chemotherapy. Several underlying cardiovascular or thromboembolic conditions, such as diabetes or hypertension, which are common in elderly patients, may contribute to increase the risk of vascular events, and thus, they should be taken into account in patient selection.

Finally, the role of our chemotherapeutic schedule as neoadjuvant treatment before surgery for liver metastases should be noted. Although the age of the treated population was more than 72 years old, seven patients with initially nonresectable metastases localized in the liver alone were able to undergo surgical resection of metastases after treatment. In five of these patients, complete resection of metastasis was possible. In conclusion, the association of CPT-11 with FU as a continuous 48-hour infusion administered every 2 weeks is a well-tolerated, active schedule for elderly patients in good general condition and with no fragility criteria.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Presented previously as a poster at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004 (abstr 3597).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted November 9, 2004; accepted March 8, 2005.

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