Ifosfamide Containing Regimen for Non-Small Cell Lung Cancer

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1 ORIGINAL ARTICLE Ifosfamide Containing Regimen for Non-Small Cell Lung Cancer D. Behera, A.N. Aggarwal, S.C. Sharma 1, D. Gupta and S.K. Jindal Departments of Pulmonary Medicine and Radiation Oncology 1, Postgraduate Institute of Medical Education and Research, Chandigarh, India ABSTRACT Background. Combination chemotherapy has been demonstrated as one of the best active regimens in patients with non-small cell lung cancer (NSCLC). Methods. A total of 206 patients with advanced unresectable NSCLC stage III B or stage IV were enrolled to receive combination chemotherapy with mitomycin, ifosfamide and cisplatin. About a third of them (n=63) did not continue therapy after the first course either because of toxicity, lack of affordability, or death. The remaining 143 patients (121 males) received two or more cycles of chemotherapy. Results. Nearly half of all followed-up patients showed a partial or complete radiological response. Overall performance status (Karnofsky scale) worsened in 28 (19.6%) and improved in 44 (30.8%). While 50 patients (35%) gained weight, 65 (45.5%) lost weight during follow-up. Overall median survival was 20 weeks [95% confidence interval (CI), 16 to 24 weeks]. However, overall survival improved progressively with the number of chemotherapy cycles administered. Median survival in patients receiving at least three, four and five chemotherapy cycles was 23 (95%, CI, 19-27); 27 (95% CI, 24-30) and 35 (95% CI, 28-42) weeks respectively. Survival at the end of three, six, nine and 12 months was 64.3%, 29.4%, 14.7% and 9.8% respectively. Survival had no association with age of the patient, but was significantly correlated with baseline performance status (Pearson's correlation coefficient 0.29 p<0.01). The cost of each course of chemotherapy was a little over US $100. The side effects were minimal and acceptable, and the regimen was tolerated well by all the patients. Conclusion. Ifosfamide regimen containing mitomycin and cisplatin is a chemotherapeutic combination for treating patients with advanced NSCLC. Key words : Ifosfamide, Mitomycin, Cisplatin, Chemotherapy, Non-small cell lung cancer. [Indian J Chest Dis Allied Sci 2004; 46 : 9-15] INTRODUCTION Lung cancer is a major health problem all over the world, particularly in the industrialized countries 1,2. Non-small cell lung cancer (NSCLC) is a leading cause of death due to cancer worldwide 3. The high death rate is due to the fact that patients with NSCLC usually present at [Received : July 29, 2002; accepted after revision: January 22, 2003] Correspondence and reprints request : Dr D. Behera, Professor, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh , India; Tele. : , Extn 6822 (Off), (Resi); Telefax : ; <dbehera@glide.net.in>.

2 10 Ifosfamide and NSCLC D. Behera et al an advanced stage (IIIB or IV), when a more beneficial form of therapy like surgery or radiotherapy can not be offered. These patients have median survival time of less than a year, and very few survive beyond five years 4. Although the best cure for NSCLC lies in early detection and surgical resection, few patients present with surgically resectable disease; and those who do, frequently relapse and die. Even patients with locally advanced NSCLC frequently die due to recurrent disease, despite curative radiotherapy 5. Given this pattern of failure (extrathoracic systemic relapse), effective systemic chemotherapy seems to be required, if survival is to be improved. In fact, experience over the past two decades has clearly demonstrated that cisplatin-based chemotherapy provides a modest survival advantage 6-9. Further, recent studies indicate that chemotherapy can improve tumour related symptoms and quality of life 10, 11, and even these may be cost effective None of the drugs available so far has shown a significant survival benefit, although they have shown some promise in this direction 15. A dramatic increase in lung cancer has been observed in the developing countries including India in the recent years 16,17. In our own experience, more than 95% patients are inoperable after total clinical, endoscopic and investigative assessment 18. Thus chemotherapy, if possible, is the only hope for a vast majority of cases 19. However, in developing countries like India, significant problems associated with chemotherapy include the cost, toxicity, availability, affordability and acceptability. In the present communication, we share our experience with an ifosfamide-containing regimen in patients with unresectable NSCLC. MATERIAL AND METHODS Two hundred and six histologically proven cases with unresectable (stage IIIB or IV) NSCLC seen at the Lung Cancer Clinic of our institute during the period January 1990 to December 1999 were retrospectively studied. The diagnosis was achieved in each case either by fiberoptic bronchoscopy, biopsy, fine needle aspiration cytology, aspiration/biopsy of the metastatic sites or pleural fluid analysis. All patients willing to receive combination chemotherapy were included in the study. Pretreatment evaluation included a complete medical history and physical examination, a complete haemogram, a standard biochemical profile which included renal and liver function parameters, chest radiograph and computed tomographic scan (CT scan) (whenever possible). Performance status was calculated according to the Karnofsky scale. All patients, irrespective of performance status, were eligible for chemotherapy. Patients were enrolled with an intention to give five to six cycles of chemotherapy, unless disease progressed or unacceptable side effects occurred. Chemotherapy was administered on an outpatient basis as per a standard protocol. Premedication before chemotherapy included intravenous metoclopramide or ondansetron, and intravenous dexamethasone (8 mg). Patients received mitomycin (6 mg/m 2 ) as an intravenous bolus, followed by infusions of ifosfamide (3 g/m 2 ) and cisplatin (60 mg/m 2 ) over three to four hours each. Mesna infusion was given along with ifosfamide (600 mg/g of ifosfamide). During chemotherapy, patients were hydrated using infusion of physiological saline (about one litre), and received additional metoclopramide or ondansetron as required. Oral metoclopramide or ondansetron was continued for the next three days. The cycle was repeated after every 28 days. During each visit detailed medical history was taken and physical examination was completed to document disease symptoms and treatment toxicity. Complete haemogram and biochemical tests as outlined above were repeated before each course of chemotherapy and standard chest radiographs were obtained to assess tumour response. Radioloigcal response was graded as complete (when lesions disappeared completely for at least four weeks); partial (when lesions regressed by at least 50% for at least four weeks) and none (when there was no response or lesions progressed). Followup CT scans or routine bone scans were not performed.

3 2004; Vol. 46 The Indian Journal of Chest Diseases & Allied Sciences 11 Statistical Analysis Data of patients receiving two or more chemotherapy cycles were analysed. Kaplan- Meier survival analysis was performed to assess overall survival. For this purpose, patients lost to follow-up were considered to have died after the last hospital visit. Median survival was calculated for the entire population and comparisons performed between patients receiving different number of chemotherapy cycles and having different performance status. RESULTS Of the 206 patients enrolled for chemotherapy, 63 (30.6%) received only the first chemotherapy cycle and did not continue therapy. Therefore, they were excluded from further analysis. Majority of the remaining 143 patients were men (121, 84.6%) and were aged 50 years or more. Men were significantly older than women (mean age 56.5 ± 11.1 vs ± 11.6 years, p < 0.05). At the time of data analysis, 26 (18.2%) patients were alive and 12 (8.4%) were known to have died. Information on the remaining 105 (73.4%) patients was not available despite repeated efforts to find out their status and they were assumed to be dead. Several patients were lost to follow-up before completion of the entire course; others dropped out due to side effects, death or financial constraints but were followed-up for a variable duration after discontinuing chemotherapy. Evaluable patients received between two and six chemotherapy cycles (Table 1). Additional palliative radiotherapy (1000 rads locally before the start of chemotherapy was administered to 70 (49%) patients. Nearly half of all patients followed-up showed a partial or complete radiological improvement; others showed radiological worsening (Table 1). Overall performance status (measured by Karnofsky scale) worsened in 28 (19.6%) and improved or remained stable in others (Table 2). Fifty (35.0%) patients gained weight during follow-up while 65 (45.5%) had weight loss; the remainder were stable. Table 2. Performance status (measured on Karnofsky scale) initially and after combination chemotherapy Perfor- Number of Performance Status mance Patients After Treatment* Status (baseline) Better Same Worse Total *All patients did not complete the planned five to six cycles of chemotherapy. The proportion of surviving patients decreased at a nearly constant rate as time progressed (Figure 1). Overall median survival was 20 weeks for all the 143 patients irrespective of the number of cycles of chemotherapy [95% confidence interval (Cl) weeks]. Overall survival improved progressively with number Table 1. Radiological response and survival in patients receiving different number of chemotherapy cycles Number Patients Radiological Response Survival (weeks) of Cycles Studied No. (%) None Partial Complete Mean Median 2 25 (17.5%) 17 (68.0%) 6 (24.0%) 2 (8.0%) 8.9 ± (22.4%) 20 (62.5%) 8 (25.0%) 4 (12.5%) 13.2 ± (23.8%) 14 (41.2%) 17 (50.0%) 3 (8.8%) 19.3 ± (31.5%) 19 (42.2%) 14 (31.1%) 12 (26.7%) 35.6 ± (4.9%) 1 (14.3%) 3 (42.9%) 3 (42.9%) 37.3 ± Overall 143 (100%) 71 (49.7%) 48 (33.6%) 24 (16.8%) 22.2 ±

4 12 Ifosfamide and NSCLC D. Behera et al Figure 1. Kaplan-Meier survival plot for the study population. Patients lost to follow-up are assumed to have survived only till the last follow-up visit. Censored data for patients alive at time of data analysis is indicated by (x). of chemotherapy cycles administered, even after making an allowance for four week interval between successive cycles. Most notably, survival improved markedly in patients receiving five or more chemotherapy cycles (Table 1). Median survival in patients received at least 3, 4 and 5 chemotherapy cycles was 23 (95% CI 19-27), 27 (95% CI 24-30) and 35 (95% CI 28-42) weeks respectively. The longest recorded survival was 66 weeks; this 50-year-old gentleman was alive at time of data analysis and had previously received 5 cycles of chemotherapy. There were no significant gender differences in overall survival. Survival did not correlate with the age of patients, but significantly correlated with baseline performance status (Pearson s correlation coefficient 0.290, p<0.01). Overall survival pattern was, however, similar across different strata of performance status, although patients with poorer baseline performance status tended to fare worse (Figure 2). Thus, the number of chemotherapy cycles (more the number, better the survival) and the baseline performance status (more the KPS at the start of therapy, better the survival) were the ultimate predictors of survival. Survival at the end of three, six, nine and 12 months was 64.3%, 29.4%, 14.7% and 9.8% respectively. Overall, patients tolerated chemotherapy Figure 2. Kaplan-Meier survival plots for different categories of performance status (assessed by Karnofsky scale) in the study population. Patients lost to follow-up are assumed to have survived only till the last follow-up visit. There were no significant differences between the various survival patterns. well, although several (91%) reported nausea, vomiting and/or alopecia of varying degrees. Nausea and vomiting persisted for a period lasting for five to seven days and they were managed with additional antiemetics. Alopecia was of temporary nature and growth of hair resumed after discontinuation of chemotherapy. Clinically significant side effects associated with cytotoxic therapy were infrequently observed and included cystitis, mild leucopaenia and mild thrombocytopaenia recorded in nine (6.3%), three (2.1%) and two (1.4%) patients respectively. Cystitis was managed with additional mesna. For leucopaenia and thrombocytopaenia the cycle was delayed by one week till they were normalised or dose modification was made. DISCUSSION The role of systemic chemotherapy in the management of NSCLC, particularly in patients with unresectable tumours, remains a controversial issue 20,21. However, evidence favours a better outcome in patients receiving combination chemotherapy 6,9, although a number of variables decide the final result Of seven prospectively randomised trials on

5 2004; Vol. 46 The Indian Journal of Chest Diseases & Allied Sciences 13 chemotherapy versus best supportive care, three had shown a survival advantage with use of chemotherapy, although the advantage was at best modest 20, The Non-Small Cell Lung Cancer Collaborative Group, which assessed the benefits of chemotherapy for advanced disease in meta-analyses from data available from 1190 patients enrolled in 11 trials of cisplatin-based drug treatment, showed a benefit from chemotherapy with a hazard ratio of 0.73 (p=0.095) 6. Although the overall increase in median survival was only one and half months, there was an absolute increase in one-year survival rate of 10%. This small long-term survival benefit, however, has not been confirmed by all investigators 9. In our own experience, untreated patients with advanced lung cancer managed with single fraction palliative radiotherapy, had a median survival of only five weeks 19. However, with the use of chemotherapy, median survival improved to 31 weeks. With the use of the present regimen, the median survival for those who completed at least five chemotherapy cycles has been 35 weeks. A large proportion of patients also improved their symptoms and performance status. A recent report on nearly 800 patients has also concluded that the mitomycin, ifosfamide, cisplatin regimen provides a significant improvement in symptoms and quality of life in patients with advanced disease 11. At this time, cisplatin or other platinum analogs form the cornerstone of most combination chemotherapy regimens active against NSCLC. Ifosfamide, an alkylating agent, can be used in significantly higher doses than cyclophosphamide, and produces response in over 20% cases when used as a single agent 32,33. Cullen 34 in a study of 66 evaluable patients of NSCLC using mitomycin, ifosfamide and cisplatin, had reported a response rate of 45% and 11% (partial and complete response respectively), with an overall response rate of 56%. Overall median survival was 9.2 months. We have used a similar regimen and the overall response rates (Table 1) are almost similar at 50% for all groups of patients, with higher figures in those receiving four or more cycles. Although the median survival was nearly nine months (35 weeks) for those who could receive five cycles, the overall survival was only 20 weeks. This is because most of our patients could not complete the targeted 5-6 cycles of chemotherapy. Another basic principle of chemotherapy is its easy availability, low toxicity profile and affordability. In the present study, we had a large number of dropouts (almost 30%) soon after the first course of chemotherapy. Although we have not been able to find out the exact cause because of poor follow-up, we believe that, the main cause is lack of affordability or development of unpleasant side effects. Although we have not found any serious drug associated adverse effects in the patients coming back for follow-up, it is possible that such side effects (including toxicity related deaths) may have occurred in other patients not reporting for subsequent chemotherapy cycles. In view of the relatively poor follow-up of patients, we cannot comment further on this aspect. Gastrointestinal side effects can be quite problematic in several patients. Additionally, many patients have underlying iron deficiency anaemia associated with poor nutrition, both due to basic dietary habits and disease-related anorexia. Chemotherapy induced myelosuppression can further worsen anaemia. We administered antiemetics and iron supplements to all our patients to counter both these problems. The cost of the present regimen is a little over US$100, including the investigation costs per cycle. Our institute is a government-run hospital; the hospital charges are almost negligible and the physician fees are nil. Thus, total cost for a full five cycle chemotherapy will not exceed US$600. Thus, this regimen is perhaps one of the cheapest among all combination chemotherapy schedules available in this country with reasonable efficacy. Even this amount is, however, not affordable by several Indian patients. The cost of this regimen is much less than other schedules using newer agents like paclitaxel, docetaxel, gemcitabine, and other agents. Although these drugs are available in this country, the total cost of chemotherapy is at least 10 times the cost of the regimen described

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