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Efficacy of Low-Dose Paclitaxel and Cisplatin in Patients with Advanced Non-Small Cell Lung Cancer

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Efficacy of Low-Dose Paclitaxel and Cisplatin in Patients with Advanced Non-Small Cell Lung Cancer Cancer Research and Treatment 2001;33(6):469-473 Efficacy of Low-dose Paclitaxel and Cisplatin in Patients with Advanced Non-Small Cell Lung Cancer Byung S u Kim, M.D., Do-Youn Oh, M.D., Yo-han Jo h, M.D., Do Ye un Kim, M.D., Jee Hyun Kim, M.D., Se Hoon Lee , M.D., Dae Ho Lee , M.D., Tae -You Kim, M.D., Dae Se og He o, M.D., Yung-Jue Bang, M.D. and Noe Kye o ng Kim, M.D. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea Purpose: To evaluate the efficacy and toxic ity of hype rs e ns itivity (1) and s eve re e mes is (3). Of the 38 co mbinatio n c he mothe rapy with low-dose pac litaxe l and evaluable patients , 14 had PR and the res po ns e rate was cis platin in patie nts with advanced no n-s mall cell lung 36.8%. Amo ng partial res po nde rs , 6 patie nts rece ived cance r. additio nal c hes t radiatio n. The median duration of re- Materials and Methods : Che mothe rapy-naive patie nts s po ns e was 47.9 wee ks and the median overall s urvival with unres ectable, patho logically prove n no n-s mall ce ll was 54.0 weeks . Of the total 176 co urs es , 14 we re de layed, lung cance r we re e lig ible fo r inc lus io n in the s tudy. 22 required dose reduction, and g rade 3∼ 4 neutrope nia Patients rece ived pac litaxe l (145 mg/m2 iv 3 ho ur D1) and occ urred in 5.6% of co urs es . Only o ne e pisode of ne u- cis platin (60 mg/m2 iv D1) eve ry 3 wee ks . tro pe nic feve r deve loped and the re we re no treatme nt- Results : Fo rty-two patie nts we re e nrolled betwee n re lated mo rtalities . Other toxic ities we re ge ne rally mild. Fe bruary 2000 and Fe bruary 2001. The median age was Conclusion: The combination c he mothe rapy with low- 53.5 years . Patie nts with ade nocarc ino ma numbered 29, dos e paclitaxe l and cis platin was effective and to le rable squamo us ce ll carc inoma 7, large ce ll carc inoma 3, and in patie nts with advanced non-s mall ce ll lung cance r. undiffe re ntiated carc ino ma 3. Seve ntee n patie nts had (Cancer Research and Treatment 2001;33:469 473) stage IIIB, 19 had stage IV dis ease and the re maining 6 dis played rec urred dis eas e afte r previo us s urg ical resec- Key Words : No n-s mall ce ll lung cance r, Che motherapy, tio n. Four patie nts te rminated treatme nt early becaus e of Pac litaxel, Cis platin NSCLC has been modest, emphasizing the need for continued INTRODUCTION efforts to improve systemic therapy for this disease. Paclitaxel (Taxol ) is the first available compound of a new class of antitumor agents, the taxanes, which act by inducing Despite great efforts in terms of clinical investigation over the polymerization of tubulin both in vitro and in vivo (4,5). the past decades, the treatment options for patients with Several phase II studies of single-agent paclitaxel have been metastatic (stage IV) or locally advanced (stage IIIB) non-small performed in chemotherapy-naive patients with NSCLC stage cell lung cancer (NSCLC) remain limited. Survival rates for IIIB and IV (6∼ 8). These studies, in which paclitaxel has been patients with NSCLC stage IIIB or IV have remained un- administered at doses ranging from 200 to 250 mg/m2 every changed and poor (1). Although the current 5-year survival 21 days, as either a 24-hour infusion or a 3-hour infusion, rates of 4% to 8% for patients with stage IIIB disease and less indicate that paclitaxel is active in NSCLC. than 1% for those with stage IV disease are disappointing (2), Since paclitaxel exerts its cytostatic effect via a mechanism there have been some encouraging advancements in the treat- different from that of cisplatin, and because paclitaxel does not ment of NSCLC. Cisplatin-based chemotherapy in combination share the nephrotoxicity or ototoxicity of cisplatin, it appears with other active drugs has resulted in both a higher response reasonable to combine the two drugs. A clinical phase I trial rate and better survival than combinations without cisplatin (3). evaluating paclitaxel (24 hour infusion) combined with cisplatin Overall, however, the therapeutic impact of cisplatin on has been performed and demonstrated that there was less toxicity when paclitaxel was administered before cisplatin (4). Correspondence: Dae Seog Heo, Department of Internal Medicine, In addition, a synergistic interaction between paclitaxel and Seoul National University College of Medicine, 28 Yeongeon- cisplatin has been reported from in vitro studies (5). von Pawel dong, Jongno-gu, Seoul 110-744, Korea. (Tel) 82-2-760-2857, et al also performed a phase II clinical study of paclitaxel/ (Fax) 82-2-742-6689, (E-mail) [email protected] cisplatin and reported a major response rate of 42% and 1-year This work was supported by KOSEF through SRC-MTRC. survival rate of 33% (9). Received September 5, 2001, Accepted November 15, 2001 Based on this data, major clinical oncology study groups 469 470 Cancer Research and Treatment 2001;33(6) compared the combination of paclitaxel and cisplatin with the minutes, followed by 2 hours of posthydration. A standard old standard regimens: cisplatin and etoposide, cisplatin and antiemetic regimen with 5HT3-antagonists was also admin- teniposide, and high-dose cisplatin. They reported improved istered. The treatment was repeated every 21 days provided clinical response or superior survival for the combination of there was recovery from toxicity and no evidence of disease paclitaxel and cisplatin, which is now recognized as the progression. standard regimen. However, the incidence of hematologic and History and physical examination, complete blood count, and non-hematologic toxicities was high (10∼ 12). Grade 3/4 serum chemistries were performed before each treatment cycle. neutropenia developed in about 40∼ 55% of patients and grade Disease response was evaluated with a chest X-ray before each 3/4 neuropathy in 9∼ 23% of patients. cycle and with a chest computed tomographic (CT) scan every In order to reduce the toxicity and maintain the efficacy, 2∼ 3 cycles. Patients with complete or partial response received researchers have explored a variety of doses and varying two further cycles; patients with stable disease received a schedules for the administration of paclitaxel. Hsu et al re- maximum of six cycles. Treatment was discontinued if the ported a response rate of 50.0% and minimal hematologic and disease progressed. Toxicity and tumor responses were defined non-hematologic toxicities using the combination of cisplatin according to WHO criteria (14). Survival estimates were and a low-dose (135 mg/m2), 3-hour infusion of paclitaxel (13). calculated by the Kaplan-Meier method. Our study also tested the possibility of a combination of cisplatin and low-dose paclitaxel to reduce the toxicity and RESULTS maintain the efficacy. MATERIALS AND METHODS Between February 2000 and February 2001, 42 patients were entered into the trial. The characteristics of the 42 enrolled patients are listed in Table 1. There were 27 men and 15 Patients with histologically or cytologically proven, mea- women, with a median age of 53.5 years (age range, 32 to 65) surable or evaluable NSCLC stage IIIB or IV were candidates and a median ECOG performance status of 1 (range, 0 to 2). for this study. Those who presented recurrent disease after 17 patients had stage IIIB, and 19 had stage IV disease. Six surgical resection were also included. Patients were allowed to patients presented with recurred disease with distant metastasis have had previous radiation, provided it had been completed after surgical resection (lobectomy: 4 and pneumonectomy: 2). ≥ 4 weeks before study entry, however patients whose only The predominant histology was adenocarcinoma (69.0%). measurable lesion was within a radiated field were ineligible. 23.8% of the patients had lost more than 5% of their usual Patients who had taken previous chemotherapy were excluded. body weight during the 6 months before entry into the study. Eligibility criteria further required an ECOG performance status The lung was the most frequent distant metastatic site of 0, 1, or 2 and adequate hematologic (granulocyte count≥ (10/42=23.8%) followed by bone (7/42=16.7%). Seven patients 1,500/μL, platelet count≥ 100,000/μL), hepatic (bilirubin≤ 1.25 upper normal limit), and renal (serum creatinine≤ 1.25 upper normal limit) functions. Patients had to be at least 18 years of age and should have a life expectancy of at least 12 Table 1. Patient characteristics weeks. Additionally, patients could not have any coexistent medical problem of sufficient severity to prevent full com- Sex pliance with the study and should have no previous history of Male 27 (64.3%) malignant disease, with the exception of skin cancer or car- Female 15 (35.7%) cinoma-in-situ of the cervix. All patients gave written informed Age (years) consent before the start of chemotherapy. Patients were ineli- Median 53.5 gible if they had any of the following: a history of atrial or Range 32∼ 65 ventricular arrhythmia, severe congestive heart failure, or ECOG performance status myocardial infarction; preexisting motor and sensory neuro- 0 6 (14.3%) pathy of World Health Organization (WHO) grade ≥ 2; active 1 29 (69.0%) bacterial, viral, or fungal infection; or serious underlying med- 2 7 (16.7%) ical conditions that would impair their ability to receive pro- Weight loss during last 6 months 10 (23.8%) tocol treatment, including prior allergic reactions to Cremo- more than 5% phor-containing drugs.
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