Response to Cisplatin-Etoposide Treatment and Survival in Patients with Small-Cell Lung Cancer in North Lebanon

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1 Original Paper Med Princ Pract 2003;12: DOI: / Received: November 10, 2001 Revised: July 28, 2002 Response to Cisplatin-Etoposide Treatment and Survival in Patients with Small-Cell Lung Cancer in North Lebanon Wassim Khalil Kalaajieh Public Health Faculty, Lebanese University, Tripoli, Lebanon Key Words Small-cell lung cancer W Staging W Metastases W Response rate W Lebanon W Cisplatin etoposide Abstract Objective: To study the clinical features of small-cell lung cancer (SCLC) cases diagnosed in adults in North Lebanon. Patients and Methods: Descriptive analysis of 125 SCLC cases diagnosed in a tertiary care hospital in North Lebanon. Results: One hundred and twenty-five patients diagnosed with SCLC comprised the study group; 109 male and 16 female patients aged from 35 to 84 years with a mean age of 56 B 7.4 years. 95.4% of male and 31.2% of female patients were current smokers. The most frequent symptoms were cough, dyspnea, and chest pain in 24.8, 18.4, and 16.8%, respectively. Staging procedures were performed in all patients: 49 (39.2%) patients had limited stage (LS) and 76 (60.8%) patients had extensive stage (ES) disease. Metastasis was most frequent to bones (40.8%) followed by liver (24.8%) and brain (14.4%). The response rates, including both complete and partial responses to therapy, were 80, 41.5, and 52% for LS, ES, and overall patients, respectively. Median survival was 311, 163, and 201 days for LS, ES, and overall patients, respectively. Conclusion: Clinical features of the patients were very similar to those reported in the literature except that there were lower median survival values and response rates to treatment, including both complete and partial responses for both LS and ES disease. The results should be considered preliminary with regard to the activity of the chemotherapy regimen, given the statistical limitation of the small number of patients. Introduction Copyright 2003 S. Karger AG, Basel Primary carcinoma of the lung is a major health problem with a generally grim prognosis. Lung cancer accounts for 32% of all cancer deaths in men and for 25% of deaths in women and it is the leading fatal cancer. Smallcell lung cancer (SCLC) makes up about 20% of all the lung cancer cases [1, 2] and remains the most lethal form of this disease [3]. SCLC is initially a chemosensitive disease for the majority of patients and combination chemotherapy has prolonged the survival of patients with limited or extensive disease. When combination regimens containing a platinum compound and etoposide are used, response rates of 60 90% with 10 50% complete responses are usually achieved, resulting in a median survival of patients with limited and extensive stage of months and 7 10 months, respectively [4 7]. Although partial and complete responses to combination chemotherapy ABC Fax karger@karger.ch S. Karger AG, Basel /03/ $19.50/0 Accessible online at: Dr. Wassim Kalaajieh PO Box 1528 Tripoli (Lebanon) Fax , Mobile wkalajie@ul.edu.lb

2 are common, SCLC remains an incurable disease for most patients due to the emergence of resistant clones that are refractory to further treatment. Clinical studies on cancer in Lebanon are limited [8, 9]. In the absence of exact vital population statistics and a national population-based cancer registry, the review and analysis of data from various large hospitals should provide useful data on cancer epidemiology in Lebanon. In this study, we evaluated the clinical features of SCLC cases diagnosed in a tertiary care hospital in North Lebanon between January 1, 1995 and December 31, Patients and Methods Criteria for Eligibility Eligibility criteria included histologically or cytologically documented SCLC, limited stage (LS) or extensive stage (ES) disease, no prior chemotherapy, performance status by World Health Organization (WHO) ^2 and the presence of bidimensionally measurable and not previously irradiated disease. In addition patients had to have adequate organ function with absolute neutrophil count 61,500/Ìl, platelet count 6100,000/Ìl, serum creatinine! 1.5 mg/dl, serum AST and ALT values ^1.5 times the upper limit of normal, serum bilirubin! 1.5 mg/dl, absence of active infection or malnutrition and no history of any other malignancy in the preceding 5 years. Patients with second- or third-degree heart block bundle-branch block, or a history of ventricular arrhythmias or angina pectoris were excluded. Pretreatment and Staging Procedures Each patient underwent the following staging procedures to assess the presence or absence of metastatic disease: chest X-ray (posterioranterior and lateral views), computed tomography (CT) scans of the chest, the brain and the abdomen, radionuclide bone scan, and bone marrow aspiration and biopsy in patients with apparently limited disease. Pretreatment assessment also included hematological and biochemical tests, including the measurement of serum lactic dehydrogenase level and an ECG. Patients were considered to have LS disease when cancer was not detectable outside the hemithorax, with or without ipsilateral, mediastinal, hilar, or supraclavicular fossa (stage I IIIB limited disease, LS). Patients were considered to have ES disease when detectable cancer occurred beyond the sites listed for LS. Patients with malignant pericardial or pleural effusion were considered to have ES disease (stage IV extensive disease, ES). Data Collection The medical records included name, sex, admission date, marital status, smoking status, occupation, and place of residence in Lebanon. The history of disease was completed by the attending physician including chief complaint, symptoms, past medical history and family history. Treatment Modalities Chemotherapy. Each course of chemotherapy consisted of the administration of cisplatin (Platinol; Bristol-Myers Squibb, Princeton, N.J., USA) 80 mg/m 2 i.v. on day 1 and etoposide (Vepesid; Bristol-Myers Squibb) 120 mg/m 2 i.v. on days 1 3 every 4 weeks. Patients received prophylactic 50 Ìg/m 2 of recombinant human granulocyte macrophage-colony stimulating factor administered subcutaneously on days 4 13 with subsequent cycles when febrile neutropenia or grade 4 neutropenia developed. Treatment cycles were repeated every 28 days. Pre- and posthydration with normal saline was administered for cisplatin and antiemetic prophylaxis consisted of ondansetron plus dexamethasone. Patients with stable disease, complete remission or partial remission received six cycles. Doseadjustment criteria were based on toxicity and included 25% dose reduction of all drugs in case of febrile neutropenia or grade 4 neutropenia or thrombocytopenia lasting more than 5 days or any 6 grade 3 nonhematological toxicity; in the absence of fever, all drugs were reduced by 15% if the nadir absolute neutrophil count was below 500/Ìl and platelets less than 50,000/Ìl. Dose reductions were maintained for all subsequent cycles of treatment. Toxicity and Response Evaluation A complete medical history was obtained and a thorough physical examination was performed with a complete blood count, biochemical profile and an ECG before each treatment cycle. During treatment, a complete blood count with differential was performed weekly. In cases of grade 3 4 neutropenia or thrombocytopenia or febrile neutropenia it was performed daily until hematological recovery. Response to treatment was assessed in all patients by physical examination and chest X-rays after each cycle, and by CT scans or ultrasound after every three cycles of chemotherapy or sooner if clinically indicated. Any staging investigation that previously yielded abnormal results was repeated after every three cycles of chemotherapy. Imaging studies were reviewed by a panel of independent radiologists. A complete response was defined as the disappearance of all malignant lesions documented by clinical, radiological, and endoscopic methods lasting at least 1 month without any new tumor lesion. A partial response was defined as a decrease 650% in the size of all measurable lesions lasting at least 1 month without any new tumor lesion. Progressive disease was defined as 125% increase of the cross-sectional area of one or more lesions or development of new lesions irrespective of responses elsewhere. Stable disease was defined as the criteria that fall in between partial response and progressive disease. Toxicities and response to treatment were scored according to standard WHO criteria [10]. Radiotherapy Limited stage disease patients were scheduled to receive thoracic radiation (50 Gy in 25 fractions) after the completion of chemotherapy. The effect of thoracic radiation was not considered in the evaluation of response. Patients with limited disease achieving a complete response were also recommended to receive prophylactic brain radiation after the completion of chemotherapy (30 Gy in 10 fractions over 14 days using 2 lateral fields). Radiotherapy was scheduled to start within 2 months of the completion of chemotherapy. Statistical Analysis All clinical data were collected and analyzed using the Statistical Package for Social Science (SPSS) program version 8.0 statistical software. Analysis was performed on an intent-to-treat basis provided that the main inclusion criteria were satisfied. The duration of response was measured from the day of the first documentation of response to chemotherapy until disease progression. The time to dis- 118 Med Princ Pract 2003;12: Kalaajieh

3 Fig. 1. Age and sex distribution of SCLC patients registered between January 1, 1993 and December 31, ease progression was measured from study entry until the day of the first evidence of disease progression. Follow-up was available only in 90 patients. Overall survival was measured from study entry to death. Survival was estimated by the method of Kaplan and Meier [11]. Results One hundred and twenty-five patients were diagnosed to have SCLC between 1995 and The age range was from 35 to 84 years with a mean age of 56 B 7.4 years; 109 (87.24%) were male and 16 (12.8%) were female patients, all Lebanese born. The ratio of males to females was 6.8/1. Among the study group, 8% were in the years age group, 19.2% were in the years age group, 46.4% were in the years age group, 16% were in the years age group and 10.4% in the years age group. Figure 1 shows this data by gender. Of the 125 patients included in this study, 44 (35.2%) were drivers, 30 (24%) were factory workers and 18 (14.4%) were farmers. Data regarding the habitual use of tobacco was available on 114 patients and revealed that 95.4% of males and 31.2% of females were current smokers, with a median cumulative cigarette consumption of 61 pack-years. Two females were passive smokers. There was no history of other risk factors for SCLC. Physical examination revealed superior vena cava syndrome in 8 (6.4%) patients and Claude Bernard-Horner syndrome in 4 (3.2%) patients. Table 1. Chief complaints of SCLC patients admitted between January 1, 1993 and December 31, 2000 Chief complaints Patients Cough Dyspnea Chest pain Extrathoracic pain Fatigue Anorexia Hemoptysis Weight loss Total The most frequent chief complaints were cough, progressive dyspnea and chest pain reported by 24.8, 18.4 and 16.8% of patients, respectively (table 1). Both chest X-ray and thoracic CT findings were evaluated for all 125 patients. A hilar mass with mediastinal widening was the most common abnormality on chest X- ray. Thoracic CT scans mostly revealed a centrally located solid mass of irregular borders and ipsilateral hilar and/or mediastinal lymphadenopathies. Cavitations were detected in only 1 patient and also there was neither chest wall invasion by the tumor nor solitary pulmonary nodules. Cisplatin-Etoposide Treatment in Patients with Small-Cell Lung Cancer Med Princ Pract 2003;12:

4 Table 2 shows the detailed documentation of diagnostic procedures. Adequate specimens were obtained using fiberoptic bronchoscopy in the majority of cases (87.2%). Only 4 (3.2%) patients required transthoracic biopsy. In the remaining patients, diagnosis was determined by other methods. All patients underwent staging using different methods: thoracic, abdominal and cranial CT scans, bone scintigraphy, and if the above-mentioned procedures were negative for metastasis, unilateral bone marrow biopsy was performed. It was determined that 49 (39.2%) patients were in the LS while 76 (60.8%) patients were in the ES. Metastasis was most common in bone in 51 (40.8% of patients), followed by liver in 31 patients (24.8%) and brain in 18 patients (14.4%). Table 2. Distribution of diagnostic procedures in SCLC patients Procedure Patients Fiberoptic bronchoscopy Transthoracic biopsy CT-guided Extensional lymph node biopsy Bone marrow Pleural biopsy Liver biopsy Total Toxicity was evaluated in all patients and all treatment cycles (table 3). Sixteen (13%) patients developed grade 4 neutropenia and 4 (3%) grade 3 4 thrombocytopenia. Febrile neutropenia developed in 9 (7%) patients requiring hospitalization for a median of 6 days (range 4 18). Grade 3 4 diarrhea developed in 1 patient and grade 3 4 asthenia in 7 (6%) patients. There was no relationship between toxicity and type of metastasis. More importantly, there were 3 deaths not related to the disease or treatment (due to a ruptured aortic aneurysm, a pulmonary embolism and a gastrointestinal hemorrhage from gastric ulcer without associated thrombocytopenia). Follow-up was available in 90 patients. Complete response was reached in 35.1, 15.1 and 23.4% of LS and ES groups and overall patients, respectively. Partial response was 45.9, 26.4 and 34.4% of LS, ES, and overall patients, respectively. Thus 81, 41.5 and 57.8% of the patients in the LS, ES, and overall categories had either a complete of partial response to therapy (table 4). The median time to relapse after the last chemotherapy course was 8 weeks (range 5 30 weeks). After the completion of chemotherapy, relapse occurred in 16.2, 34.1 and 26.7% of LS, ES, and overall patients, respectively. Intrathoracic relapse was the most common site (45.8%), followed by cranial (33.3%) and hepatic (20.8%). Survival could be evaluated for 90 patients and was calculated from the day of diagnosis using the method of Kaplan and Meier. The median survival was 311, 163, and 201 days for LS, ES, and overall categories of patients, respectively. Table 3. Hematological and nonhematological toxicity profile of cisplatin-etoposide regimen Toxicity Highest WHO toxicity grades grade 1 grade 2 grade 3 grade 4 Neutrophils Hemoglobin Platelets Nausea/vomiting Diarrhea Mucositis Asthenia Constipation Neurotoxicity Fluid retention syndrome Hypersensivity reaction Number and percent of patients are given. 120 Med Princ Pract 2003;12: Kalaajieh

5 Discussion The most common cancer seen in men in Lebanon is lung cancer [8, 9]. The incidence of lung cancer among women remains relatively low; however, it will need to be monitored over the upcoming years and correlated with habits among the Lebanese population [12]. Our study revealed that the male-to-female ratio was approximately 7 to 1, a ratio higher than in industrial countries, but consistent with that of developing countries [13, 14]. The mean age of our patients was 56 B 7.4 years, a finding similar to previously published studies [1, 15]. Smoking has been implicated as the main cause of almost 90% of deaths from lung cancer [1, 15, 16]. The potency of tobacco smoke to induce cancer is probably related to the large number of toxic compounds that constitute smoke, including some 42 accepted or suspected human carcinogens [17 20]. Like all the other lung cancers, SCLC is linked to environmental tobacco smoke [15]. In our study, 95.4% of males and 31.2% of females were current smokers with a median cumulative cigarette consumption of 61 packyears. It is interesting to note that, in addition to cigarette smokers, there were 5 males (4.8%) and 2 females (12.5%) with a history of chronic water pipe smoking (nargileh). The most common chief complaints of our patient population were cough, dyspnea and chest pain, in decreasing order, and the most frequent radiologic abnormality was an irregularly bordered hilar mass with mediastinal widening. Fiberoptic bronchoscopy was the sole means of diagnosis in about 90% of the patients. These findings are consistent with previous reports on SCLC. The staging procedures divided the patients into two categories: 49 patients (39.2%) with LS, whereas 76 patients (60.8%) had ES, with bone, liver and the brain being the most common targets of metastasis. In comparison with previously published data from Lebanon [8], rates for bone metastasis were almost identical (39.3 vs. 40.3%) whereas liver metastasis rates were higher in North Lebanon than rates reported from other studies form Lebanon (36.4 vs. 17.6%). The reverse was true from brain metastasis rates, which were lower than those reported from other Lebanese studies (14.4 vs. 33.3%). Our study found rates of metastases to the different organs similar to those reported in other international studies [21, 22]. The percentage of patients presenting with ES was somewhat higher than in other parts of the world [2, 23]. This is probably due to a delay in presentation of the patients to clinics. SCLC remains an incurable disease for the majority of patients, with little progress made in the last 20 years of clinical research. Patients with limited disease have a 10 15% chance of survival at 5 years and have benefited from the multimodality approach combining chemotherapy with thoracic radiotherapy [6]. On the other hand, patients with distant metastases have a 3-year survival rate of less than 5% and no new drug combination has been shown to be superior to the classic regimen of a platinum compound combined with etoposide [5]. When combination regimens containing a platinum compound and etoposide are used, response rates of 60 90% with 10 50% complete responses are usually achieved, resulting in a median survival of patients with LS and ES disease of months and 7 10 months, respectively [4 6]. The response rates for both of LS and ES were lower in our study than the values mentioned above, although standard treatment protocols were applied. The median survival rates of 311 days (11 months), 163 days (5 months), and 201 days (6.5 months) for LS, ES, and overall patients, respectively, are lower than those reported in previous studies [24 28]. Table 4. Response rate to treatment in SCLC patients Response LS ES Total Complete response Partial response Stable disease Progressive Total Number and percent of patients are given. Cisplatin-Etoposide Treatment in Patients with Small-Cell Lung Cancer Med Princ Pract 2003;12:

6 Conclusion Clinical features of our SCLC patients were nearly the same as those reported in the literature except for lower response rates, including both partial and complete response, for both of LS and ES disease categories as well as lower median survival values. However, the conclusions drawn from our study regarding the activity of the chemotherapy regimen should be considered as preliminary given the statistical limitation of the small number of patients at the time of termination of the study. References 1 Neoplastic disease of the lungs; in Fraser RG, Pare JAP, Pare PD, Miller AB (eds): Diagnosis of Diseases of the Chest, ed 3. Philadelphia, Saunders, 1989, pp Ihde DC, Glatsteineg EJ, Pass HI: Small-cell lung cancer; in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 5. Philadelphia, Lippincott-Raven, 1997, pp Hoffman PC, Mauer AM, Vokes EE: Lung cancer. 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