Chemotherapy in elderly patients with metastatic gastric cancer; a single Turkish cancer center experience

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1 ORIGINAL ARTICLE Chemotherapy in elderly patients with metastatic gastric cancer; a single Turkish cancer center experience Cemil Bilir¹, Hüseyin Engin¹, Bekir Hakan Bakkal², Sevil Uygun İlikhan³, Dilek Malkoç³ 1 Department of Medical Oncology, 2 Department of Radiation Oncology, School of Medicine, 3 Department of Internal Medicine; School of Medicine, Bülent Ecevit University, Zonguldak, Turkey ABSTRACT Aim To analyze the results of chemotherapy applied at the Bülent Ecevit University School of Medicine, Department of Medical Oncology, to elderly patients with metastatic gastric cancer (GC). Methods The study retrospectively investigated hospital records including pathological reports, imaging records, chemotherapy regimens, response and toxicity profile. All patients received systemic chemotherapy for pathologically proven metastatic GC at the Bülent Ecevit University School of Medicine, Department of Medical Oncology. Corresponding author: Cemil Bilir Department of Medical Oncology, School of Medicine, Bülent Ecevit University, Zonguldak Sultan Orhan Mh 1145 sk No 14, Gebze, Kocaeli, Turkey Phone: ; Fax: ; cebilir@yahoo.com Original submission: 29 October 2012; Revised submission: 24 December 2013; Accepted: 18 February Results From 2005 to 2012, 23 metastatic GC patients older than 70 years were treated with systemic chemotherapy as a first-line therapy. As the first-line chemotherapy, 17 (74%) patients received polychemotherapy and the remaining six (26%) patients received monotherapy. Overall, 113 cycles were administered. The median progression free survival (PFS) for the first-line chemotherapy was 6 months (95% CI, 0-16) and the median overall survival (OS) was 14 months (95% CI, 3 30). Multivariate analysis revealed that decreased OS was significantly associated with poor Eastern Cooperative Oncology Group (ECOG) performance status (p=0.045), elevated carcinoembryonic antigen (CEA) levels at the diagnosis time (p = 0.040) and decreased number of chemotherapy cycles (p=0.019) with R-Sq (adj) = 41, 6%. One patient had a complete response with docetaxel, cisplatin and fluorouracil combined (DCF) regimen and had 12 months of disease free survival (DFS). Conclusion This is the first study investigating the outcomes of chemotherapy in Turkish elderly metastatic GC patients. Docetaxel, cisplatin and fluorouracil combination were the most common regimen, which is a tolerable and effective choice in elderly patients who had good performance status. Keywords: cancer, stomach, older adults, chemotherapy Med Glas (Zenica) 2013; 10(2):

2 Bilir et al. Chemotherapy in elderly gastric cancer INTRODUCTION Gastric cancer (GC) is a highly lethal malignancy. More than half of all patients diagnosed with GC have an unresectable disease (1). Advanced GC is usually managed palliatively with local and/or systemic measures. Cytotoxic chemotherapy is the most effective treatment choice for patients with metastatic disease (2). There is a limited number of prospective randomized studies comparing chemotherapy and best supportive care (BSC) in advanced disease but each study found that chemotherapy prolonged overall survival (OS) compared to BSC (3). Wagner et al. published a meta-analysis of three trials comparing chemotherapy with BSC, and they found a significant benefit in OS in favor of chemotherapy (hazard ratio [HR] 0.37; 95% CI ) and revealed that there was an improvement in median survival from 4.3 to 11 months (4). However, most patients analyzed in these studies were younger than 70 years (2-4). Very little knowledge is available on the course of the disease in the elderly, or more importantly, on specific treatment policies for elderly cancer patients, including GC (5). Knowledge about treatment methods is mainly based on experience with patients younger than 70 years (2-5). Clinical trials often apply the same age limit (6). Although older patients form the largest number of patients with cancer, they do not receive proportionally the same amount of treatment as younger patients and often the decision as to whether a patient receives chemotherapy is largely based on a patient s chronological age (7-9). The danger is that older patients may forgo worthwhile treatment options because of limited insight into their diagnosis and prognosis, exogenous barriers to receiving care, or perceptions of a low ratio of benefits to risks (5). Conversely, without adequate understanding of prognosis and of the potential outcomes of therapy, patients may receive treatments that are inconsistent with their preferences (5,9). In this context Lim et al. had a study in patients older than 70 year-old with advanced GC (10). The study revealed that Oral S-1 chemotherapy seems to be effective as a first-line treatment regimen for elderly patients with metastatic or recurrent GC (10). In Turkey GC is the fourth common cancer in women and also fifth common in men (11). The aim of this study was to analyze the results of chemotherapy applied to elderly patients with metastatic gastric cancer in Bülent Ecevit University School of Medicine Cancer Center, to contribute to very little information that exists worldwide and also in Turkey related to that already available on this subject. PATIENTS AND METHODS Hospital records of 23 elderly (older than 70 years) patients who had received systemic chemotherapy for metastatic GC at the Bülent Ecevit University School of Medicine, Department of Medical Oncology, between 2005 and 2012 were retrospectively investigated. All patients had pathologically proven metastatic GC. Medical records included physical examination, surgical and pathological reports, imaging records, chemotherapy regimens, response, toxicity profile and dates of progression, last follow up and death. The co-morbidity burden of patients according to the Eastern Cooperative Oncology Group (ECOG) performance status criteria was categorized (12). The study was approved by the Ethical Committee of the Bülent Ecevit University School of Medicine. Chemotherapy The decision for administering first-line chemotherapy depended, in all cases, on the discussions between a physician and a patient. The chemotherapy regimen was used in patients with the ECOG score 0-2 and it was determined by the treating physician. Also chemotherapy regimens dosages were adjusted according to the ECOG performance status. The chemotherapy was usually repeated every days according to the regimen. All tumor measurements and treatment response evaluations were done after every two or three cycles of chemotherapy, using a computed tomography scan and other tests that were used initially to stage the tumor. Responses were classified according to the response evaluation criteria in solid tumors (RE- CIST) 1.0. A partial response (PR) was defined as decrease ( 30%) in the sum of the longest diameter of the target lesions. Progressive disease (PD) was defined as at least 20% increase in the sum of the target lesions. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). The severity of any toxicities not defined in NCI-CTC were graded as 1 (mild), 2 (moderate), 3 (severe), or 4 (very severe). 299

3 Medicinski Glasnik, Volume 10, Number 2, August 2013 Statistical analysis Treatment outcomes were estimated as response rate (RR), disease control rate, OS and progression free survival (PFS). OS was defined as the time between the date of the diagnosis for metastatic disease and the date of death from any cause. PFS was defined as the time from the date of the diagnosis for metastatic disease to the date of disease progression or death from any cause. Also second OS and PFS were defined in the same way after the diagnosis of progression for patients who received second-line chemotherapy. Overall survival was calculated by the Kaplan Meier method by the log rank test. P values as < 0.05 were accepted as significant. Cox proportional hazards regression model was employed in univariate and multivariate analyses to identify the significant independent prognostic factors of various clinical parameters for survival. RESULTS From 2005 to 2012, 23 metastatic GC patients older than 70 years were treated with systemic chemotherapy as the first-line therapy. The median age of the patients was 73 years (range, 70 84), and the male to female ratio was 2.8:1.0. Six patients (26.0%) had diabetes mellitus and eight patients (34.8%) had hypertension. Three patients died while receiving chemotherapy due to febrile neutropenia, septic shock and myocardial infarction (Table 1). Table 1. Baseline characteristics of elderly patients with metastatic gastric cancer Characteristics No (%) of patients Age, Median (range) 73 (70-84) Gender Male 17 (74%) Female 6 (26%) Performance status ECOG 0 8 (35%) ECOG 1 9 (39%) ECOG 2 6 (26%) History of operation Yes 4 (17%) No 19 (83%) CEA, Median (range) 4.3 (1-53) CA 19-9 Median (range, ng/ml) 25 ( ) History of adjuvant chemotherapy Yes 4 (17%) No 19 (83%) Metastasis site Liver 12 (46%) Bone 2 (8%) Lung 2 (8%) Peritoneum 4 (15%) Others 6 (23%) CEA, carcinoembryonic antigen,ng/ml; CA 19-9, cancer antigen; ECOG, Eastern Cooperative Oncology Group As the first-line chemotherapy, 17 (74%) patients received polychemotherapy and the remaining six (26%) received monotherapy as capecitabine (1250 mg/m² twice daily days 1 to 14, every 21 days) (Table 2). Overall, 113 cycles were administered. Among the polychemotherapy regimens were DCF (docetaxel 75 mg/m² IV day 1 + cisplatin 75 mg/m² IV day fluorouracil 750 mg/m² IV days 1 to 5, every 21 days), modified DCF (docetaxel 40 mg/m² IV day 1 + folinic acid 400 mg/m2 IV day fluorouracil 400 mg/ m² IV bolus then 2000 mg/m² 46 hours infusion, cisplatin 40 mg/m² IV day 3 every 14 days), ECF (epirubicin 50 mg/m² IV day 1 + cisplatin 60 mg/ m² IV day fluorouracil 200 mg/m² per day IV daily for up to six months, every 21 days), capecitabine 800 mg/m² per os twice daily on days 1-5 plus cisplatin 30 mg/m² day 1 weekly for 5 weeks also these regimens were given to 17 patients. Irinotecan 180 mg/m² IV day 1 + folinic acid 400 mg/m2 IV day fluorouracil 400 mg/m² IV bolus then 2400 mg/m² over 46 hours infusion (FOLFIRI regimen, every 14 days ) regimen was given as a second line chemotherapy to seven patients. Among 23 patients who received the first-line chemotherapy, one patient had complete response with DCF regimen (overall RR, 4.3%), seven patients had partial responses (30.4%), stable disease was observed in eight patients (34.8%) and progressive disease in seven (30.4%). The overall disease control rate was 69.5%. All 23 patients were included in survival analysis. The median PFS for the first-line chemotherapy was 6 months (95% CI, 0-16) and the median OS was 14 months (95% CI, 3 30). Multivariate Table 2. Treatment summary of elderly patients with metastatic gastric cancer Chemotherapy regimens Drugs used No (%) of patients First-line chemotherapy DCF 12 (52%) regimen Capecitabine 6 (26%) cisplatin - capecitabine 2 (8.5%) modified DCF 2(8.5%) ECF 1 (4%) Post first-line chemotherapy second line chemotherapy 7 (30%) third line chemotherapy 2 (8.5%) Response of first-line chemotherapy CR 1 (4%) PR 7 (30.5%) SD 8 (35%) PD 7 (30.5%) DCF, docetaxel, cisplatin and fluorouracil; ECF, epiribucin, cisplatin, fluorourocil; CR, complete response; PR, partial responses; SD, stable disease; PD, progression; 300

4 Bilir et al. Chemotherapy in elderly gastric cancer analysis revealed that decreased OS was significantly associated with poor ECOG performance status (95 % CI, coef -3.6, p= 0.045), elevated CEA levels at the diagnosis time (95% CI, coef -0.3, p=0.040) and decreased number of chemotherapy cycles (95% CI, coef 1.26 p=0.019) with R-Sq(adj) = 41, 6%. Regression equation to estimate OS was= ECOG - 0,303 CEA levels number of CT cycles. The age, sex, CA 19-9 levels, hemoglobin levels, chemotherapy regimens, radiation therapy were not significant independent prognostic factors. In multivariate analysis increased PFS was associated only with palliative radiotherapy and increased number of chemotherapy cycles (p= and p=0.007, respectively). Single agent capecitabine was used in six patients, and median OS was 12 months, and it was 15 months in remaining 17 patients with the polychemotherapy group (p=0.2). Furthermore, there was no significant difference between the polychemotherapy and capecitabine groups for PFS (median PFS 5.5 months vs. 6 months respectively, p=0.9). One patient had a complete response with DCF regimen and had 12 months of DFS. Eight patients had stable disease, four patients with DCF regimen, three patients on capecitabine treatment and one patient on mdcf. Seven patients had a partial response. Three of them had DCF treatment, two of them capecitabine treatment; one patient on cisplatin-capecitabine and one patient was treated with ECF regimen. Seven patients were treated with FOLFIRI regimen as a second line chemotherapy. The median OS was 8 months (95 % CI, ), median PFS was 3 months (95% CI, 0-5). Three patients were still alive over 12 months by FOLFIRI regimen. The median number of cycles administered in first-line chemotherapy was 5 (1-14). One patient died during the second cycle of DCF due to acute myocardial infarction. One patient died because of febrile neutropenia during the second cycle of DCF, and the third patient had died due to septic shock on the first cycle of mdcf. The most common toxicities were hematological toxicity. Grade 3-4 toxicities included neutropenia in four patients (two patients on DCF, one patient on capecitabine and one patient on mdcf regimen). Grade 3-4 anemia occurred in one patient who had been treated with DCF regimen and one patient had grade 3-4 thrombocytopenia with DCF regimen. The most common grade 1-2 hematologic toxicity was neutropenia and it was determined in 4 patients. Four patients had grade 3-4 reversible nephrotoxicity with DCF regimen. Three patients had grade 1-2 diarrhea with capecitabine, and two patients had grade 1-2 neuropathy with capecitabine. DISCUSSION In the present study, in metastatic GC patients older than 70 years who had been treated with chemotherapy as the first-line therapy, the median OS was 14 months, and median PFS was six months, and these findings are consistent with previous studies conducted in other populations (1, 13). In our study, DCF regimen was the most commonly (60%) used polychemotherapy regimen, and it was both tolerable and effective in elderly patients with metastatic GC. In the literature, most studies were intended for patients less than 65 years old (3). In the Joo Han et al. study researching the effectiveness of S-1 monotherapy in elderly metastatic GC patients 10.8 months OS and PFS of 4.9 months were found (10). In a pooled analysis, 257 patients who were older than 70 years received either a platinumcontaining regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil)+/-mitomycin C (MMC), or FAMTX (14). There were no significant differences between the chemotherapy regimens in terms of OS, PFS and toxicity profiles (14). In one Korean study, clinicopathological characteristics of GC in elderly patients were investigated and compared to young adults. The 5-year survival rates of elderly and young patients did not differ statistically and authors concluded that age itself was not an independent prognostic factor of survival in elderly GC patients (15). Some of these studies found that histological type, nodal involvement and operative curability were significant prognostic factors in elderly GC (13-15). In our study, ECOG performance status, CEA levels and the number of chemotherapy regimen cycles were significant prognostic factors for OS. Age, CA 19-9 levels and the other laboratory parameters had no influence on treatment effectiveness. Bohanes et 301

5 Medicinski Glasnik, Volume 10, Number 2, August 2013 al. also found CEA levels as a prognostic factor for OS in gastric cancer patients (16), as it was found in this study, but our study revealed that CEA could be a prognostic factor in elderly metastatic GC patients. Furthermore, the results of this study showed that number of chemotherapy cycles and palliative radiation significantly affect the PFS. Single agent chemotherapy has been considered to be a good and safe first-line treatment option for elderly patients (1). Ikeda et al. showed the efficacy of doxifluridine for elderly patients (17). Recently, a Korean trial established that both capecitabine and S-1 were safe, well tolerated and efficacious in older patients with advanced GC (18). Seung Tae et al. study on patients received fluoropyrimidine (capecitabine, S-1 or infusion 5-FU) monotherapy and patients treated by doublet or triplet first-line therapy, did not find any significant difference for RR and grade 3 or 4 adverse effects (AE) between patients with combination and single agent as the first-line therapy (1). In our study, six patients received monotherapy (capecitabine) and remaining 17 patients had polychemotherapy Also there were no significant differences for OS and PFS, but it should be remembered that our study population is too small. There is no randomized study for second line chemotherapy for metastatic GC in elderly patients (16). Our study had a small number of patients who had received FOLFIRI regimen and it was comparable OS and PFS with acceptable toxicity profile. The major concern about chemotherapy in elderly cancer patients is toxicity (14). Trumper et al. showed that chemotherapy-related toxicities such as neutropenia, anemia, stomatitis and diarrhea occurred more commonly in the elderly (14). The percentages of grade 3 neutropenia and grade 3-4 non-hematologic toxicities were 19 and 21 respectively (14, 19). In our study population, 17% of patients had grade 3-4 neutropenia like in other studies (1, 13, 14). However, grade 3-4 nephrotoxicity was more common in our study population compared with other studies (13, 14), which developed in four patients (17%), possibly due to more usage of DCF regimen. Careful toxicity monitoring and controlling the dose intensity is needed in these patients. The study had some limitations, such as a limited number of patients, no comparative group that did not receive chemotherapy. Also this study is retrospectively designed. This is the first study investigating the outcomes of chemotherapy in Turkish elderly metastatic GC patients. In conclusion, docetaxel, cisplatin and fluorouracil combined (DCF) regimen was an acceptable regimen in the elderly metastatic gastric cancer patients. In addition, irinotecan, folinic acid, 5- fluorouracil (FOLFIRI) regimen was tolerable and an acceptable regimen with good survival outcomes as second line chemotherapy in elderly patients with metastatic GC. FUNDING No specific funding was received for this study. TRANSPARENCY DECLARATIONS Competing interests: none to declare. REFERENCES 1. Kim ST, Park KH, Oh SC, Seo JH, Shin SW, Kim JS, Kim YH. Is chemotherapy in elderly patients with metastatic or recurrent gastric cancer as tolerable and effective as in younger patients? Asia Pacific Journal of Clinical Oncology 2012; 8: Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 1993; 72: Glimelius B, Hoffman K, Haglund U, Nyren O, Sjoden PO. Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 1994; 5: Wagner AD, Unverzagt S, Grothe W, Kleber G, Grothey A, Haerting J, Fleig WE. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2010; 17:3:CD Montfardini S, Sorio R, Boes GH, Serraino D. Entry and evaluation of elderly patients in European organization for research and treatment of cancer (EORTC) new-drug development studies. Cancer 1995; 76:333-8 Trimble EL, Carter CL, Cain D, Freidlin B, Ungerleider RS, Friedman MA. Representation of older patients in cancer treatment trials. Cancer 1994;74: Fentiman I. Are the elderly receiving appropiate treatment for cancer? Annals of Oncology 1996; 7:657-8 Yancik R, Wesley M, Ries L, Havlik R, Edwards B, Yates J. Effect of age and comorbidity in post menopausal breast cancer patients aged 55 years and older. JAMA 2001; 285:

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