A randomised trial of two cisplatin-containing chemotherapy regimens in patients with Stage III-B and IV non-small cell lung cancer

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A randomised trial of two cisplatin-containing chemotherapy regimens in patients with Stage III-B and IV non-small cell lung cancer
  LUNG CANCER Lung Cancer 12 (1995) 237-246 A randomised trial of two cisplatin-containing chemotherapy regimens in patients with Stage III-B and IV non-small cell lung cancer Melek Erkisi*“, Figen Doranb, Refik Burgutc, Ali Kocabasd aDepartment of Medical Oncology, Cukurova University Medical School, Balcal 1. Adana. Turkey bDepartment of Pathology, Cukurova University Medical School, Balcal I, Adana. Turkey cDepartment of Biostatistics, Cukurova University Medical School, Balcal 1, Adana, Turkey dDepartment of Chest Disease, Cukurova University Medical School, Balcal I, Adana, Turkey Received 2 October 1994; evision eceived 3 January 995; accepted 1 February 1995 Abstract Seventy-four newly diagnosed atients with histologically proven Stage II-B and IV non- small cell lung cancer were randomized o receive either cisplatin: 20 mg/m’ x day x 5, ifosfamide: 1.8 g/m’ x day x 5, mesna: 1.2 g/m* x day x 5, etoposide: 100 mg/m* day x 5 (ICE) or cisplatin: 20 g/m* x day x 5 and etoposide: 100 mg/m* x day x 5. Response ates were 59 n the ICE and 4O?h n the CE arm with a signi- ficant advantage n response uration and overall survival in the ICE receiving patients (P = 0.03, P = 0.0008). As we used granulocyte colony stimulating actor (G-CSF) very fre- quently, myelotoxicity remained substantial but acceptable. Keywords: Lung cancer; Etoposide; Cisplatin; Granulocyte colony stimulating actor; Chemo- therapy; Ifosfamide 1. Introduction Despite recent improvements in multidisciplinary treatment, the prognosis of Stage III-B and IV non-small cell lung cancer (NSCLC) remains poor. Advances in chemotherapy are associated with some improvement in the prognosis of patients l Corresponding uthor. 0169-5002/95/SO9.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0169-5002(95)00447-Z  238 M. Erkisi et al. /Lung Cancer 12 1995) 237-246 with NSCLC. Low response rates have been reported for different regimens contain- ing some of the most active drugs against this neoplasm. Etoposide is a phase-specific derivative of podophyllotoxin. As a single agent it demonstrates limited benefit in the treatment of NSCLC, but in combination with cisplatin, it has become a comer stone of chemotherapy with a response rate (RR) of 30 in advanced and an average of 50 in limited disease [l]. As a single agent, cisplatin produces a 20 (6-30 ) (RR) [2] but, cisplatin- containing chemotherapy regimens have produced pooled response rates of 30-40 in advanced diseases with a significant survival benefit in responders [3-61. On the other hand, ifosfamide is an oxazophosphorine alkylating agent with a broad spec- trum of anti-neoplastic activity. As a single agent it has achieved 15-30 RR in the treatment of NSCLC, but in combination, 27-46 RR have been reported with various schedules [2,5,7,8]. In the current study, we evaluated the efficacy of a new cisplatin, etoposide, ifosfamide combination. We aimed to assess the benefit if any by the addition of ifosfamide to the cisplatin etoposide combination in the treatment of NSCLC. 2. Materials and methods Seventy-seven newly diagnosed patients with histologically proven Stage III-B and IV NSCLC, who were treated between March 1991 and November 1992, were in- cluded in the study. All the patients were consecutively studied and followed up pro- spectively. A written voluntary informed consent was given by all the patients. After the informed consent, patients were stratified according to the stage of the tumor and then each arm was randomised to receive the chemotherapy with or without ifosfamide. We planned to treat 30 patients in each arm but added five more patients for each complete response. Histopathologic diagnosis was performed according to the New International Staging System (ISS) for lung cancer [9]. All patients had bronchoscopy, chest radiographs, bone scan, and thoraco abdominal computed tomography scan done. Head computed tomography scans were performed when indicated by clinical abnormalities. Patients were reevaluated with pertinent radiographic studies of all previously detectable abnormalities at day 28 and subsequently at least once every 2 months. Besides physical examination, blood chemistry and complete blood counts were also performed routinely. Patients were controlled at regular intervals up to the last visit or death. In the first treatment arm of the CE, the chemotherapy regimen consisted of cis- platin 20 mg/m2 intravenously (i.v.) on days l-5 and etoposide 100 mg/m2 iv. on days l-5. In the second arm of ICE ifosfamide 1.5 g/m2 and mesna 1 g/m2 iv. daily for 5 days were added to the previous regimen. Chemotherapy cycles were repeated every 4 weeks. To prevent nausea and vomiting, patients were premeditated with dexamethasone 8 mg i.v. and ondansetron 4 mg i.v. half an hour before chemother- apy and it was repeated after 8 h. Chemotherapy was started with 1 litre of 0.9 saline + 20 mmol potassium chloride to run 250 ml/h. Cisplatin was infused in 1 litre of saline over 4 h and etoposide was infused in 500 ml of saline over 2 h. Ifosfamide and mesna were infused each in 1 liter of saline over 4 h.  M. Erkisi et al. /Lung Cancer 12 1995) 237-246 239 In the presence of persistent hematologic toxicity, chemotherapy was delayed until the leucocyte count was more than 2500/mm3 and the platelet count at least 100 OOO/mm3. The patients whole blood counts were repeated on the 15th day of the chemotherapy cycles. All the patients with a granulocyte count lower than 1000/mm3 were put on gran- ulocyte colony stimulating factor (r-met Hu G-CSF): 250 kg/m2 x daily sub- cutaneously, until there was a granulocyte recovery. If a Grade 3 or more granulocytopenic episode were to occur then this patient was routinely put on r-met Hu G-CSF: 250 c(glm2 subcutaneously for 5 days following the next chemotherapy cycle. In the first group, the ICE regimen alone was administered to 17 patients, palliative radiotherapy was added in nine, and cytoxan doxorubicin and vincristine (CAV) was given following the ICE in 13 patients. In the other group, only CE regimen was used in 15 patients, palliative radiotherapy was added in six, ifosfamide was added to the CE in nine patients and chemotherapy regimen was changed from CE to CAV in five patients. Response was assessed before each course of chemotherapy. Standard criteria used to evaluate response were as follows: Complete disappearance of all clinical evi- dence of disease for at least 8 weeks was accepted as complete response, 50 or more reduction in the sum of the products of the diameters of all measurable lesions on two separate evaluations lasting at least 8 weeks as partial response. No change in any lesion size was assigned as stable disease and an increase of 50 in the perpen- dicular diameters of measured lesions as progressive disease. Chemotherapy-related toxicity was graded by standard WHO criteria. Duration of response (DOR) was calculated from the date of first treatment until the date of progression and survival was calculated from the first treatment until the death of the patient. 2.1. Statistical methods BMDP statistical software was used for the statistical evaluation (BMDP Statistical Software, Inc., Los Angeles, 1991). Life tables were constructed using the Kaplan-Meier method for censored survival data. Log-rank tests (Generalized Wilcoxon-Breslow) were performed to compare the duration of response (DOR) and overall survival (OS) between the subgroups of patients. The differences between the response rates and toxicity patterns in several histologic types according to the chemotherapy protocols, were assessed by the Pear- son x2-test. All values were two-tailed. 3. Results The study was conducted from March 1990 through November 1992. Of the pa- tients who entered the study, 74 were evaluable. One patient declined chemotherapy after the first course. She has also declined to have laminectomy or even to receive palliative radiotherapy for lumbar spine metastases and two other patients who had achieved partial response, refused to come to our clinic and started on herbal medi- cine after receiving the second course, so that these three patients were excluded  240 M. Erkisi et al. /Lung Cancer I2 1995) 237-246 from the study. Table 1 shows the characteristics of the remaining 74 patients. At the presentation, metastatic sites were bone (19), liver (1 l), adrenal gland (7), extrathoracic lymph nodes (7) and pericardium (4). Twenty-four patients had an ECOG performance status of 0, 32 had a performance status of 1 and 18 had a per- formance status of 2. 3. I. Response Of the 74 patients, 39 received the ICE regimen and 35 the CE. We achieved two complete res-ponses (CR), 21 partial responses (PR) and 10 stable disease (SD) in the ICE receiving arm. Responses were lower in the CE receiving group with one CR, 13 PR and nine SD (P = 0.02). Neither the age of the patients nor the stage of disease seemed to be related with the response rate (RR), duration of response (DOR) or overall survival (OS). The epidetmoid cancer group tended to respond to both chemotherapy regimens with a higher frequency than other histologic types. In the ICE receiving arm, CR + PR rates were 18/27 (66 ) for epidermoid carcinoma, 317 (42 ) for adenocar- cinema and 2/5 (40 ) for other histologies. In the CE receiving arm these values were lo/22 (45 ), 2/7 (28 ) and 2/6 (33 ), respectively. However, the differences were non-significant (P > 0.05). 3.2. Survival At the time of evaluation - June 1994 - , eight patients were still alive: one with local recurrence (LR) at the 30th month, four with progressive disease (PD) with a median duration of 20 months and three patients at CR with a median duration of 48 months. Those were the patients who presented with Stage III-B disease. Duration of response (DOR) was longer in patients who received ICE (P = 0.03, Table 2, Fig. 1). This difference was more significant in patients with well differen- Table 1 Patients’ characteristics Median (years) ge Male/female ratio Histologic type Epidermoid carcinoma Well differentiated Moderately differentiated Poorly differentiated Adenocarcinoma Bronchiole alveolar carcinoma Large cell carcinoma Stage of disease III-B iV CE ICE Total 58 (39-73) 57 (37-80) 56 (31-73) 25110 3217 57117 22 27 49 4 5 9 11 15 26 7 7 14 7 7 14 3 3 6 3 2 5 17 18 35 18 21 39  Table 2 Comparison of survival and response duration between various histologic types of lung cancer Histologic type Chemotherapy progam No. of patients Stage III-B Stage IV Duration of Overall survival response (months) (months) No. of responders (CR + PR + SD) Epidermoid carcinoma Well differentiated Moderately differentiated Poorly differentiated Adenocarcinoma Others ICE CE ICE CE ICE CE ICE CE ICE CE ICE CE 13 14 17.41 f 2.88 II II 13.00 f 2.64 2 3 16.80 l 2.60 2 2 8.00 + 1.00 8 7 20.08 zt 4.698 6 5 20.50 f 4.969 3 4 Il.43 l 2.51 3 4 6.57 f 0.84 3 4 13.75 zt 1.181 3 4 12.00 f 8.00 2 3 9.75 l 3.01 3 3 1.33 f 1.45 21.49 f 2.405 25 16.95 + 3.16 18 5 3 13 8 I I 17.14 l 3.39 4 9.51 zt 2.5 2 15.83 f 3.049 4 8.00 zt 0.058 3 CR, complete response; PR, partial response; SD, static disease.
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