2002-雷替曲塞治疗老年进展期结直肠癌：高效低毒方案

Raltitrexed in the treatment of elderly patients with advanced colorectal cancer: an active and low toxicity regimen J. Feliua,*, J.R. Melb, C. Campsc, P. Escuderod, J. Aparicioe, D. Mene´ndezf, C. Garcı´a Giro´ng, M.R. Rodriguezh, J.J. Sa´nchezi, M. Gonza´lez Baro´na on behalf of Oncopaz Cooperative Group Associated Hospitals aMedical Oncology Service, Hospital La Paz, P� de la Castellana, 261-28046 Madrid, Spain bMedical Oncology Service, Hospital Xeral de Lugo Spain cMedical Oncology Service, H. General de Valencia Spain dMedical Oncology Service, H. Clı´nico de Zaragoza Spain eMedical Oncology Service, H. La Fe de Valencia Spain fMedical Oncology Service, H. Universitario de Santiago de Compostela Spain gMedical Oncology Service, H. General Yagu¨e de Burgos Spain hMedical Oncology Service, H. Sa Marı´a Madre de Orense Spain iUnidad de Estadı´stica de la Universidad Auto´noma de Madrid, Spain Received 9 July 2001; received in revised form 8 October 2001; accepted 21 December 2001 Abstract In spite of the high prevalence of advanced colorectal cancer in the elderly, we have little data on the efficacy and toxicity of chemotherapy in this age group. Raltitrexed is a thymidylate synthetase inhibitor with known activity in the treatment of advanced colorectal cancer. The objective of this study was to analyse the efficacy and tolerance of raltitrexed in elderly patients with advanced colorectal cancer. 92 patients diagnosed with advanced colorectal cancer aged 570 years were entered into the study. Raltitrexed was given at a dose of 3 mg/m2 once every 3 weeks for a minimum of three cycles. A total of 511 cycles were given with a median of five cycles per patient. 20 out of the 90 patients evaluable for response achieved a partial response (PR) (22%, 95% Confidence Interval (CI): 17–36%), 43 (48%) remained stable and 27 showed progression (30%). The mean duration of response was 24 weeks and the progression-free interval was 15 weeks. The overall median survival was 41 weeks. 31 patients (39%, 95% CI: 28–50%) experienced a clinical benefit (improvement of the performance status without a worsening of symptoms or relief of symptoms without a worsening of the performance status). The main toxicities were gastrointestinal and haematological. 12 patients (13%) developed grade 3-4 side-effects: 7 had nausea/vomiting (8%), 6 a transaminase increase (7%), 4 asthenia (4%), 3 diarrhoea (3%), 2 neutropenia (2%), 2 anaemia (2%) and 1 thrombocytopenia (1%). Three toxic deaths occurred (3%). The group of patients with a creatinine clearance 41.08 ml/s was found to have a higher risk of developing grade 3-4 toxicity compared with those with adequate renal function (8/18 versus 4/72; P<0.001). In conclusion, raltitrexed is an active, convenient and low toxicity treatment for the elderly with advanced colorectal cancer. However, it must be used cautiously in elderly patients with a creatinine clearance 41.08 ml/s since they are at a higher risk of suffering grade 3-4 toxicity.# 2002 Published by Elsevier Science Ltd. Keywords: Raltitrexed; Colorectal cancer; Elderly; Chemotherapy; Toxicity 1. Introduction Colorectal cancer is the second most common cause of death from cancer in developed countries [1]. Its incidence increases significantly with age, from 20 cases/ 100 000 habitants/year in men under 65 years old to 337/100 000 in the elderly [2]. In Europe, 40% of patients are over 74 years old at the time of diagnosis [3]. Further- more, considering future demography perspectives, the incidence of colorectal cancer will progressively increase. In spite of the magnitude of the problem, the treatment of colorectal cancer in elderly patients remains a chal- lenge. Several studies have shown that the proportion of 0959-8049/02/$ - see front matter # 2002 Published by Elsevier Science Ltd. PI I : S0959-8049(02 )00005-9 European Journal of Cancer 38 (2002) 1204–1211 www.ejconline.com * Corresponding author. Fax: +34-91-727-7118. E-mail address: oncopaz@ene.es (J. Feliu). patients with this tumour who are operated upon decreases with age (85% of patients under 65 years ver- sus 70% of older patients) [4]. Furthermore, chemo- therapy treatment is also used less frequently in the elderly compared with other age groups, both in the adjuvant [5] and the advanced settings [6]. A number of factors may account for the reluctancy to use chemotherapy in elderly patients. (1) The limited number of studies analysing the efficacy and toxicity of chemotherapy in this age group [7]. (2) Fear that elderly patients may be more susceptible to suffer side-effects that decrease their quality of life, especially diarrhoea, mucositis and myelosuppression [8,9]. (3) Comorbid conditions, that may complicate or even preclude the administration of chemotherapy [10]. However, it is currently accepted that chemotherapy in patients with advanced colorectal cancer prolongs survival time by 5–6 months compared with best sup- portive care [11]. The same benefit is also obtained when early treatment in asymptomatic patients is given com- pared with postponing treatment until the occurrence of symptoms [10]. Furthermore, chemotherapy for advanced colorectal cancer patients has been reported to be effective in maintaining or improving quality of life [10–13]. Although these studies have not specifically been conducted on elderly patients, the benefits might be extrapolated to this age group. The most common treatment has been the association of 5-fluorouracil (5- FU) with leucovorin (LV). However, there is some con- cern that this combination may induce high toxicity in elderly patients: with some exceptions [10,14] this age group has been reported to have a greater risk of mucositis, diarrhoea, hand–foot syndrome and myelo- suppression [8,15], as well as a 9% rate of toxic deaths [8]. These observations were confirmed in a posterior meta-analysis [9]. For that reason, it seems necessary to investigate other regimens that improve the toxicity profile, while maintaining the efficacy of 5-FU-LV. Raltitrexed (ZD1694) is a thymidylate synthetase inhibitor. This enzyme has a fundamental role in the de novo synthesis of the nucleotide thymidine triphosphate, which is essential for DNA synthesis. At a dose of 3 mg/ m2 it is active in a variety of tumours such as breast, pancreatic or refractory ovarian cancers [16], but it is in colorectal tumours where it shows the best activity. Several phase III studies performed in patients with advanced colorectal cancer have demonstrated that its activity is similar to that of the combination 5-FU-LV [17,18]. In a randomisd phase III study that compared 5-FU-LV versus raltitrexed the risk of developing grade 3-4 mucositis and leucopenia was higher in those patients 570 years who received 5-FU-LV, but not in those treated with raltitrexed [19]. The administration as a short intravenous (i.v.) infusion of 15 min every 3 weeks adds value to the efficacy and toxicity profile of raltitrexed. In spite of having included patients aged570 years in these studies, the experience with the use of raltitrexed in elderly patients is very limited. The objective of the present study was to analyse the activity and toxicity of raltitrexed in elderly patients with advanced colorectal cancer. 2. Patients and methods 2.1. Patient eligibility Between July 1997 and December 1999, 92 patients with recurrent or metastatic advanced colorectal cancer and aged570 years were included. They all had at least one lesion histologically confirmed as adenocarcinoma. The inclusion criteria were: (1) a performance status 42, according to Eastern Cooperative Oncology Group (ECOG) scale [20]; (2) life expectancy of at least 3 months; (3) adequate medullar function, that is a granu- locyte count 52�109/L and platelets>100�109/L; (4) adequate hepatic function, that is serum bilirubin <1.25 times the upper normal limit, glutamic oxaloacetic trans- aminase values (SGOT) and glutamic pyruvic transami- nases (SGPT) <2.5 times the upper normal limit in the absence of hepatic metastases or <5 times the upper nor- mal limit in the presence of metastasis; (5) adequate renal function, that is a creatinine value41.25 times the upper normal limit and creatinine clearance >1.08 ml/s. Patients previously treated with chemotherapy were excluded, with the exception of adjuvant chemotherapy that had been finished at least 6 months before. Similarly, patients with cerebral metastases or a history of a previous neoplasia were also excluded, except those with in situ car- cinoma of the cervix or basal cell carcinoma of the skin. All the patients had one or more measurable or eva- luable lesions in accordance with World Health Orga- nization (WHO) guidelines [21]. Patients treated with radiotherapy were included as long as there was at least one evaluable lesion outside the radiation field. All the patients gave their written consent according to the directives of the local ethical committees. 2.2. Pretreatment and Follow-Up studies The diagnostic work-up was performed within 3 weeks prior to the start of the treatment. It consisted of a complete clinical history, physical examination, a blood analysis (haemogram and complete biochemistry) and imaging studies as needed (chest X-ray, computed tomography of the chest, abdomen and pelvis, abdom- inal echography and bone scan). The Charlson comor- bidity scale was used [22]. The ECOG performance status and weight were also recorded. An electro- cardiogram (ECG) was performed in all patients prior to the treatment. Symptom assessment, physical examination J. Feliu et al. / European Journal of Cancer 38 (2002) 1204–1211 1205 and blood biochemistry were repeated before each treatment. The measurements of tumour sizes were performed every three months or sooner if clinically indicated. 2.3. Treatment Raltitrexed is available as a freeze-dried powder. This product has to be reconstituted with 4 ml of sterile water for injections and then diluted in 50 ml of 5% dextrose or 0.9% saline. The dilution thus reconstituted is administered as a short i.v. infusion for approxi- mately 15 min. The dose of raltitrexed was 3 mg/m2 once every 21 days. A minimum of three cycles were given unless a progression of the disease was detected. The concomitant use of vitamin complexes containing folinic acid was not allowed. Prophylaxis with antie- metics was prescribed routinely, although the choice of anti-HT3 drugs or metoclopramide depended on the criteria of the physician. Patients with an objective response or a stabilisation with symptom improvement continued treatment until the occurrence of a progression or unacceptable toxi- city. Patients with stable disease and no symptom improvement received six cycles. Toxicity was recorded before each new cycle and gra- ded according to WHO scales [21]. The administration of chemotherapy was delayed until recovery from toxi- city for a maximum of 3 weeks. In the case of grade 3 or 4 haematological toxicity, the dose of raltitrexed was decreased by 25 or 50%, respectively. If grade 2 or 3 diarrhoea occurred, the dose was reduced by 25 or 50%, respectively; grade 4 diarrhoea led to treatment withdrawal. The Cockcroft–Gault formula [23] was used to calcu- late creatinine clearance before each cycle. If creatinine clearance was between 0.42–1.08 ml/s, the dose of ral- titrexed was reduced by 50% and the next cycle given 4 weeks later. If it was 0.42 ml/s, the treatment was interrupted. 2.4. Definition of response 2.4.1. Response, time to progression, survival The response was assessed at the end of every three cycles of chemotherapy and carried out following WHO directives [21]. For that purpose, both measurable and non-measurable, but evaluable, lesions were considered. A complete response (CR) was defined as the dis- appearance of all clinical and radiological evidence of the tumour assessed through physical examination or radiological explorations or both, for a minimum of 4 weeks. A partial response (PR) was defined as a reduc- tion of at least 50% in the sum of the products of the longest perpendicular diameters of the clearly measur- able tumour lesions during at least 4 weeks without detecting an increase greater than 25% in any lesion or the occurrence of new lesions. Stable disease (SD) indicated a decrease of less than 50% in total tumour size or an increase of less than 25% in the size of one or more measurable lesions. Progression was considered when an increase of at least 25% in the size of one or more measurable lesions or the occurrence of new measurable lesions was detected. Death occurring before the first assessment of response, caused by the progression of the disease or by toxicity, was considered as a therapeutic failure. Progression-free survival was measured from the start of chemotherapy to the date of progression or death without progression. Survival was calculated from the first day of treatment to the date of death or to the date of last follow-up. 2.4.2. Palliative benefits ECOG performance status and the symptoms before each chemotherapy cycle were assessed by the same doc- tor for each patient. The presence of pain, use of analge- sics, anorexia and asthenia were registered. Patients went through a pain stabilisation lead-in period to establish baseline measures. Pain was assessed with the Memorial Pain Assessment (MPA) Card visual analogue scale. Asthenia and anorexia were assessed with a visual ana- logue scale (VAS) of 0–100. In addition, the patient’s weight was measured at each visit. It was considered that a patient could be evaluable for palliative benefits when he/she initially had one of the following signs or symptoms: an ECOG performance status 51, a MPA score 520, a baseline analgesic consumption of 510 morphine-equivalent mg/day, a score on the visual ana- logue scale for anorexia and/or asthenia 520 or a pre- vious weight loss >10% in the previous 6 months. Symptom improvement was obtained when: (1) there was an improvement in the ECOG performance status by at least one score from baseline; (2) there was a weight gain by at least 5% from baseline. Patients with peripheral oedema, ascites or pleural effusion were excluded from this category; (3) there was an improve- ment of 550% from baseline in disease-related symp- toms (pain, use of analgesics, anorexia and asthenia) and in the analgesics consumption (measured weekly in morphine-equivalent milligrams) compared with base- line. All this improvement had to be sustained for at least 4 weeks [18]. Clinical benefit was defined as: (1) ECOG performance status improvement without wor- sening of symptoms or weight loss, (2) weight increment without worsening of ECOG or symptoms, (3) symp- toms improvement without worsening of ECOG per- formance status. 2.5. Statistical methods The dose intensity was calculated for each patient from the total dose of raltitrexed administered during 1206 J. Feliu et al. / European Journal of Cancer 38 (2002) 1204–1211 the entire course of the treatment, and this is expressed as the mean drug dose in milligrams per square metre per week. Univariable analysis was used to compare the inci- dence of grade 3-4 toxicity between the different groups formed according to age (above 75 years or not), gen- der, creatinine clearance (below 1.08 ml/s or not) or Charlson comorbidity scale (0–1 versus52). Wilcoxon rank-sum test was used to compare the quantitative variables and Fisher’s exact test for the percentages were used. Survival time and time to pro- gression were calculated using the Kaplan–Meier method. 3. Results 3.1. Patients characteristics A total of 92 patients with recurrent or metastatic advanced colorectal cancer and aged 570 years were entered into the study. The characteristics of these patients are shown in Table 1. The median age of the series was 77 years (range 71–88 years). There were 39 patients (42%) aged 576 years and 12 patients (13%) aged 580 years. 48 patients were males (52%) and 44 were females (48%). There were 18 patients (20%) with an ECOG performance status of 0, 64 (70%) with 1 and 10 (11%) with 2. In 48 patients (52%), the primary tumour was located in the colon and in 44 (48%) in the rectum. There were 26 patients (28%) who presented with metastasis at the time of diagnosis, in 14 of which (15%) the primary tumour was not resected. 66 of the remaining patients (72%) presented metastases second- ary to a tumour previously resected. Of these patients, 38 (41%) had previously received chemotherapy as adjuvant therapy and 25 (27%) had received chemo- therapy and radiotherapy. Regarding the symptoms, there were 25 (27%) with a weight loss greater than 10% in the previous 6 months, 38 (41%) with a pain score 520, 24 (26%) with a baseline analgesic con- sumption of 510 morphine-equivalent mg/day, 59 (64%) with asthenia 520 on the VAS and 76 (83%) with anorexia 520 on the VAS. Seventy patients (76%) had comorbid conditions, mainly hypertension (25%), obstructive lung disease (17%), ulcer disease (15%), coronary insufficiency (13%) and diabetes (10%). Comorbidity was present in 60% of patients when using Charlson’s scale [22]. According to this scale, 32 patients scored one (35%), 19 scored two (21%) and 4 patients equal to or greater than three (4%). A total of 511 cycles were given with a median of five cycles per patient (range 1–13). 11 patients (12%) received less than three cycles of raltitrexed: 3 (3%) due to toxic death, 4 (4%) due to progression, 2 (2%) due to the patient’s refusal and another 2 (2%) due to death apparently not related to the neoplasia (1 due to an acute stroke and another 1 due to an acute myocardial infarction). Except for these last 2 patients, all of the others were considered valid for the toxicity and response analyses. In 15 patients (16%), the treatment had to be delayed on some occasions: 6 due to an increase of transaminases, 3 due to diarrhoea, 2 due to neutropenia, 1 due to thrombocytopenia and another 3 because of the patient’s request. The median dose intensity was 0.92 mg/m2/week (range 0.75–1 mg/m2/ week). 77 patients (84%) received 90% or more of the planned dose. Table 1 Patients’ characteristics Characteristic n (%) Age (years) (mean and range) 77 (71–88) 70–75 53 (57) 76–80 27 (29) >80 12 (13) Gender Male 48 (52) Female 44 (48) ECOG Performance Status 0 18 (20) 1 64 (70) 2 10 (11) Number of organs with metastasis 1 62 (67) 2 22 (24) 53 8 (9) Metastatic sites Liver 42 (46) Liver plus others 16 (17) Lung 20 (22) Intra-abdominal extension 12 (13) Lymph nodes 10 (11) Others 28 (30) Weight loss None 19 (21) 1–10% 48 (52) >10% 25 (27) Pain score 0–19 53 (58) 20–49 28 (30) 50–100 11 (12) Baseline analgesic requirement (morphine-equivalent mg) <10 66 (73) 10–100 18 (20) >100 6 (6) Asthenia score 0–19 33 (36) 20–49 46 (50) 50–100 13 (14) Anorexia score 0–19 16 (17) 20–49 43 (47) 50–100 33 (36) ECOG, Eastern Cooperative Oncology Group. J. Feliu et al. / European Journal of Cancer 38 (2002) 1204–1211 1207 3.2. Tumour response and survival Out of the 90 patients valid for response, 20 reached a PR (22%, 95% Confidence Interval (CI): 17–36%), 43 (48%) remained with a SD and 27 showed a progression (30%). The median duration of the response was 24 weeks (range 8–57 weeks). The progression-free survival was 15 weeks (range 3–63 weeks). No relationship between the response rate and site of metastases, ECOG performance status and age (70–75 years versus >75 years) was observed. The median survival was 41 weeks (range 2–164 weeks): 56 weeks for patients with a PR, 47 for those with SD and 32 for those who progressed. The actuarial 1-year survival was 30% (CI: 21–91%). Of the patients evaluated, there were 11 who at the time of inclusion did not meet the criteria for assessment of palliative benefits. Therefore, this analysis was con- ducted on 79 patients (Table 2). Considering the per- forma