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

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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. Fertile patients who were not using Prior chest radiotherapy 7 (16.7%) contraceptives, and pregnant or lactating women were also Stage ineligible. IIIB 17 (40.5%) All patients received premedication with hydrocortisone, IV 19 (45.2%) pheniramine, and famotidine. Hydrocortisone 100 mg, pheni- Relapse after surgery 6 (14.3%) ramine 45.5 mg, and famotidine 20 mg were administered as Cell type an intravenous bolus injection 30 minutes before infusion of Adenocarcinoma 29 (69.0%) paclitaxel. Patients received paclitaxel 145 mg/m2 dissolved in Squamous cell 7 (16.7%) 500 mL 5% glucose and administered by continuous infusion Large cell 3 (7.1%) over 3 hours. After overnight hydration and standard pre- Undifferentiated 3 (7.1%) hydration, patients then received cisplatin 60 mg/m2 over 15 Byung Su Kim, et al：Efficacy of Paclitaxel and Cisplatin 471 had received previous chest radiation (4: postoperative radi- 2) Toxicity ation, 2: obstructive pneumonia, 1: SVC syndrome). Four patients had pericardial effusion and three of these required Of a total of 176 courses, 14 courses were delayed primarily pericardiocentesis. due to insufficient hematologic recovery and 22 courses required a 25% dose reduction. WHO grade 3 or 4 neutropenia 1) Response and survival occurred in 5.6% of courses (Table 3). However, throm- The 42 patients received a total of 176 courses of paclitaxel/ bocytopenia and anemia remained infrequent throughout the cisplatin combination. The median number of cycles adminis- study, with no grade 3 or 4 toxicity. Neutropenic fever occurred tered was 4.5 (range, one to twelve). Fourteen patients (33.3%) in only one patient and there was no treatment-related received the planned maximum of six courses due to favorable mortality. Nonhematologic toxicity, including nausea/vomiting responses; three patients (7.1%) received seven courses, and and neuropathy, was generally mild. WHO grade 3 or 4 nausea/ one patient received twelve courses. Four patients were not evaluable for response, 1 because of hypersensitivity reaction and 3 due to severe emesis. Objective antitumor responses are Table 2. Clinical response to combination chemotherapy with listed in Table 2. The objective response rate for the 38 paclitaxel and cisplatin assessable patients was 36.8%, with no complete responses and 14 partial responses. Six of 14 patients who had attained Complete response 0 (0.0%) partial response received additional chest radiation. Their data Partial response 14 (36.8%) was not included in the calculation of median response Stable disease 2 (5.3%) duration, which was 47.9 weeks (Fig. 1). With a minimum Progressive disease 22 (57.9%) follow-up duration of 5.3 months, the median overall survival Response duration Median: 47.9 weeks time was 54.0 weeks and the 1-year survival rate was 50.4% 1-year: 17.3% (Fig. 2). Overall survival Madian: 54.0 weeks 1-year: 50.4%

Fig. 1. Duration of response in patients with partial response Fig. 2. Survival of overall patients (n=42) (n=14)

Table 3. Hematologic toxicity

WHO grade (% of total courses) 0 1 2 3 4

Leukopenia 74.4 20.5 4.5 0.6 0.0 Neutropenia 67.0 16.5 10.8 4.5 1.1 Anemia 77.3 17.6 5.1 0.0 0.0 Thrombocytopenia 98.3 1.7 0.0 0.0 0.0 Neutropenic fever 1 patients RBC, platelet transfusion No Prophylactic G-CSF No 472 Cancer Research and Treatment 2001;33(6)

Table 4. Nonhematologic toxicity has been well established. Paclitaxel has been evaluated in the treatment of patients with advanced NSCLC in several phase Grade≥ 3 Peripheral neuropathy 3 (7.1%) II trials. In these trials, it has yielded response rates greater than Grade≥ 3 Emesis 5 (11.9%) 20% and it has been associated with notable 1-year survival Grade≥ 2 Hepatotoxicity 2 (4.8%) rates (6∼ 8). Preclinical studies that evaluated paclitaxel-based Grade≥ 2 Arthralgia 1 (2.4%) combination regimens have shown a synergistic antineoplastic Grade≥ 2 Nephrotoxicity 0 (0.0%) effect for the paclitaxel/cisplatin combination (5). In addition, Grade≥ 2 Hypersensitivity 2 (4.8%) clinical phase I studies evaluating paclitaxel/cisplatin have shown the feasibility and modest efficacy of the combination (4,15,16). EORTC performed a phase II clinical study of paclitaxel/cisplatin and reported a major response rate of 42% and 1-year survival rate of 33% (9). vomiting occurred in 11.9% of patients and only 3 patients Large-scale phase III studies conducted by ECOG demon- suffered from grade 3 neuropathy (Table 4). Grade 3 alopecia strated improved survival as compared to the etoposide/ occurred in 19 patients. The cases of oral mucositis and diar- paclitaxel combination (11), whereas two other studies per- rhea were confined to patients with grade 2 or lower toxicity. formed by EORTC showed an improved response rate and Three patients refused to receive further treatment because of progression free survival but failed to suggest an improved grade 4 emesis, although no patients refused chemotherapy due overall survival as compared to teniposide/paclitaxel in com- to neuropathy. Hypersensitivity reaction occurred in two pa- bination or a high-dose cisplatin regimen (10,12). This is tients: one terminated treatment, while the other received a 24- explained by the fact that more patients are eligible to receive hour infusion of paclitaxel and subsequently exhibited no fur- the 2n d line chemotherapy including taxanes. ther hypersensitivity reaction. The response rate of 36.8% and the 1-year survival rate of 3) Salvage treatment 50.4% experienced in this study compare favorably with results obtained using other regimens in advanced NSCLC (17∼ 19). Many patients received salvage chemotherapy or radiation The other Korean study of paclitaxel/cisplatin in advanced after they failed in the paclitaxel/cisplatin combination. Ten NSCLC reported a response rate of 58%, a median response patients received salvage chest radiation and five patients duration of 21 weeks and a median overall survival of 28 received brain radiation. Various chemotherapy regimens were weeks, which is better than our study in terms of response rate, performed and the most frequently used agent was vinorelbine although the response duration and survival are shorter. Other (18 patients) followed by gemcitabine (11 patients) then clinical studies performed recently in Korea in the field of ifosfamide (9 patients) and docetaxel (5 patients). Two patients advanced NSCLC have primarily been concerned with the received intrathecal methotrexate due to leptomeningeal carci- vinorelbine and platinum-compound combination and have nomatosis. reported outcomes similar to those of our study (20∼ 22). In addition, the toxicities of this regimen were modest and for the DISCUSSION most part, easily managed. The most common hematologic toxicity was grade 3 or 4 neutropenia, which developed in 5.6% of the treatment courses. Neutropenic fever occurred in one NSCLC continues to be a major health problem in developed patient and there were no treatment-related deaths. Neuro- countries. Although the incidence in males generally seems to toxicity occurred, but was mostly WHO grade 1 or 2, even with be leveling off, the incidence in females continues to increase the 3-hour paclitaxel infusion. (1). At the time of diagnosis, the majority of patients will be diagnosed with metastatic (stage IV) or locally advanced (stage CONCLUSIONS III) disease. Thoracic radiotherapy, generally considered as the standard therapy for inoperable, locally advanced disease, has a limited impact on survival, and most patients will develop The results of our study suggest that the low-dose paclitaxel/ distant metastatic disease. Consequently, most patients diag- cisplatin combination was effective for treating advanced nosed with NSCLC are potential candidates for chemotherapy NSCLC with reduced toxicity. A new study comparing pac- trial. litaxel and other new chemotherapeutic agents such as vino- Among the agents considered active in the treatment of relbine or gemcitabine is required to optimize the treatment of advanced NSCLC, cisplatin has been reported to produce a NSCLC. response rate of up to 20%. Moreover, cisplatin-based combination regimens have demonstrated some improvement in REFERENCES survival when compared with non-platinum-containing regimens (3). However, there is a definite need for more effective chemotherapy to treat NSCLC. 1. Ginsberg R, Vokes E, Rosenzweig K. Non-Small Cell Lung Cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Paclitaxel has been shown to have a unique mechanism of Cancer: Principles and Practice of Oncology. 6th ed. Philadel- antitumor action; it promotes microtubule assembly and phia: Lippingcott, 2001:925-951. stabilization. The safety profile, as well as the anticancer 2. Ihde DC. Chemotherapy of lung cancer. N Engl J Med 1992; activity, of paclitaxel in patients with advanced malignancies 327:1434-1441. Byung Su Kim, et al：Efficacy of Paclitaxel and Cisplatin 473

3. Donnadieu N, Paesmans M, Sculier JP. Chemotherapy of non- study of paclitaxel and cisplatin chemotherapy for advanced small cell lung cancer according to disease extent: A meta- non-small-cell lung cancer in Chinese patients. Am J Clin analysis of the literature. Lung Cancer 1991;7:243-252. Oncol 1998;21(5):487-490. 4. Rowinsky EK, Gilbert MR, McGuire WP, Noe DA, Grochow 14. World Health Organization. Handbook for Reporting Results LB, Forastiere AA, Ettinger DS, Lubejko BG, Clark B, Sar- of Cancer Treatment. Offset publication 48. Geneva: World torius SE, et al. Sequences of taxol and cisplatin: a phase I Healeth Organization, 1979. and pharmacologic study. J Clin Oncol 1991;9:1692-1703. 15. Rowinsky EK, Chaudhry V, Forastiere AA, Sartorius SE, Et- 5. Jekunen AP, Christen RD, Shalinsky DR, Howell SB. Syner- tinger DS, Grochow LB, Lubejko BG, Cornblath DR, Done- gistic interaction between cisplatin and taxol in human ovarian hower RC. Phase I and pharmacologic study of paclitaxel and carcinoma cells in vitro. Br J Cancer 1994;69:299-306. cisplatin with granulocyte colony-stimulating factor: neuro- 6. Chang AY, Kim K, Glick J, Anderson T, Karp D, Johnson muscular toxicity is dose-limiting. J Clin Oncol 1993;11:2010- D. Phase II study of taxol, merbarone, and piroxantrone in 2020. stage IV non-small-cell lung cancer: The Eastern Cooperative 16. Klastersky J, Sculier JP. Dose-finding study of paclitaxel Oncology Group Results. J Natl Cancer Inst 1993;85:388-394. (Taxol) plus cisplatin in patients with non-small cell lung 7. Murphy WK, Fossella FV, Winn RJ, Shin DM, Hynes HE, cancer. European Lung Cancer Working Party. Lung Cancer Gross HM, Davilla E, Leimert J, Dhingra H, Raber MN, et 1995;12(Suppl 2):117-125. al. Phase II study of taxol in patients with untreated advanced 17. Le Chevalier T, Pujol JL, Douillard JY, Alberola V, Monnier non-small-cell lung cancer. J Natl Cancer Inst 1993;85:384- A, Riviere A, Lianes P, Chomy P, Cigolari S, Besson F, et 388. al. A three-arm trial of vinorelbine (Navelbine) plus cisplatin, 8. Gatzemeier U, Heckmayer M, Neuhauss R, Schluter I, von vindesine plus cisplatin, and single-agent vinorelbine in the Pawel J, Wagner H, Dreps A. Chemotherapy of advanced ino- treatment of non-small cell lung cancer: an expanded analysis. perable non-small cell lung cancer with paclitaxel: a phase II Semin Oncol 1994;21(5 Suppl 10):28-33. trial. Semin Oncol 1995;22(6 Suppl 15):24-28. 18. Dhingra HM, Valdivieso M, Carr DT, Chiuten DF, Farha P, 9. von Pawel J, Wagner H, Niederle N, Heider A, Koschel G, Murphy WK, Spitzer G, Umsawasdi T. Randomized trial of Hecker D, Hanske M. Phase II study of paclitaxel and cisplatin three combinations of cisplatin with vindesine and/or VP-16- in patients with non-small cell lung cancer. Semin Oncol 1996; 213 in the treatment of advanced non-small-cell lung cancer. 23(6 Suppl 16):47-50. J Clin Oncol 1985;3:176-183. 10. Giaccone G, Splinter TA, Debruyne C, Kho GS, Lianes P, van 19. Klastersky J, Sculier JP, Ravez P, Libert P, Michel J, Van- Zandwijk N, Pennucci MC, Scagliotti G, van Meerbeeck J, van dermoten G, Rocmans P, Bonduelle Y, Mairesse M, Michiels Hoesel Q, Curran D, Sahmoud T, Postmus PE. Randomized T, et al. A randomized study comparing a high and a standard study of paclitaxel-cisplatin versus cisplatin-teniposide in pa- dose of cisplatin in combination with etoposide in the treat- tients with advanced non-small-cell lung cancer. The European ment of advanced non-small-cell lung carcinoma. J Clin Oncol Organization for Research and Treatment of Cancer Lung 1986;4:1780-1786 Cancer Cooperative Group. J Clin Oncol 1998;16:2133-2141. 20. Lee YW, Ryoo BY, Kim TY, Kim BS, Park YH, Hong HJ, 11. Bonomi P, Kim K, Fairclough D, Cella D, Kugler J, Rowinsky Kwag JY, Lee SW, Kang YK. The effect of combination E, Jiroutek M, Johnson D. Comparison of survival and quality chemotherapy with vinorelbine, carboplatin, and ifosfamide in of life in advanced non-small-cell lung cancer patients treated patients with advanced non-small cell lung cancer. J Korean with two dose levels of paclitaxel combined with cisplatin Cancer Assoc 1999;31:1227-1235. versus etoposide with cisplatin: results of an Eastern Coop- 21. Chang HM, Lee JA, Ahn JS, Woo IS, Park YI, Son JW, Lee erative Oncology Group trial. J Clin Oncol 2000;18:623-631. SJ, Jung KS, Park YS. Efficacy of combination chemotherapy 12. Gatzemeier U, von Pawel J, Gottfried M, ten Velde GP, with vinorelbine, ifosfamide and cisplatin in patients with Mattson K, DeMarinis F, Harper P, Salvati F, Robinet G, advanced non-small cell lung cancer. J Korean Cancer Assoc Lucenti A, Bogaerts J, Gallant G. Phase III comparative study 2000;32:612-618. of high-dose cisplatin versus a combination of paclitaxel and 22. Kim JL, Kim BS, Na BJ, So MJ, Lee JH, Chung OY, Lee cisplatin in patients with advanced non-small-cell lung cancer. GL, Roh YH. A phase 2 study with vinorelbine and carbo- J Clin Oncol 2000;18:3390-3399. platin in patients with advanced non-small cell lung cancer. 13. Hsu JW, Hsu JY, Chiang CD. Preliminary result of phase II J Korean Cancer Assoc 2000;32:690-698.