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Second-line weekly paclitaxel in resistant or relapsed non-small cell lung cancer treated with docetaxel and carboplatin: A multi-center phase II study
Lung Cancer 69 (2010) 319–322
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Second-line weekly paclitaxel in resistant or relapsed non-small cell lung cancer treated with docetaxel and carboplatin: A multi-center phase II study夽 Motoshi Ichikawa a , Ryujiro Suzuki b , Kensuke Kataoka c , Yasunobu Noda b , Joe Shindoh d , Syuichi Matsumoto e , Yoshimasa Tanikawa a , Kiyoshi Suzuki f , Kenji Baba g , Yuichiro Shindo h , Masashi Kondo h , Kazuyoshi Imaizumi h , Hiroaki Kume h , Yoshinori Hasegawa h , Kenzo Takagi i , Hiroyuki Taniguchi c,∗ a
Department of Respiratory Medicine and Allergy, Toyota Kosei Hospital, 500-1 Ibohara Josui-cho, Toyota, Aichi 470-0396, Japan Department of Respiratory Medicine, Toyohashi Municipal Hospital, 50 Hachiken-nishi Aotake-cho, Toyohashi, Aichi 441-8570, Japan c Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwake-cho, Seto, Aichi 489-8642, Japan d Department of Respiratory Medicine, Ogaki Municipal Hospital, 4-86 Minami-no-kawa-cho, Ogaki, Gifu 503-8502, Japan e Department of Respiratory Medicine and Allergy, Komaki Municipal Hospital, 1-20 Joubushin, Komaki, Aichi 485-8520, Japan f Department of Respiratory Medicine, Meijo Hospital, 1-3-1 San-no-maru, Naka-ku, Nagoya, Aichi 460-0001, Japan g Department of Respiratory Medicine, Aichi Medical University, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan h Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan i Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya, Aichi 461-8763, Japan b
a r t i c l e
i n f o
Article history: Received 22 June 2009 Received in revised form 10 September 2009 Accepted 5 November 2009 Keywords: Non-small cell lung cancer Chemotherapy Second-line treatment Paclitaxel Cross-resistance
a b s t r a c t We conducted a phase II trial to evaluate the safety and efficacy of weekly paclitaxel in patients with resistant or relapsed non-small cell lung cancer (NSCLC) treated with docetaxel and carboplatin. Thirtytwo NSCLC patients at a median age of 58.0 years (range 33–75) were enrolled. The Eastern Cooperative Oncology Group performance status scores (0/1/2) were 18/9/5, respectively. The majority of patients had adenocarcinoma (84%) and stage IV disease (81%). The response rate for the first-line chemotherapy was 28%. Paclitaxel was administered at a dose of 80 mg/m2 as an intravenous infusion 60 min weekly for 6 consecutive weeks of an 8-week cycle. All patients were assessable for response and toxicity. The median number of cycles administered was two (range 1–8), and the overall response rate was 15.6%. The median survival time (MST) was 10.6 months (95% CI = 8.2–12.5), while the 1-year survival rate was 37.5%, and the median progression-free survival was 4.9 months (95% CI = 3.0–7.1). Hematological toxicities (grade 3 or 4) were observed in 15 patients (46.9%) with leukopenia, and in 4 (12.5%) with anemia. Non-hematological toxicity was generally mild, though grade 3 anorexia was observed in 3 patients (9.3%). No treatmentrelated deaths were observed. In conclusion, second-line weekly paclitaxel is effective in NSCLC patients treated with docetaxel plus carboplatin and is associated with a tolerable toxicity profile. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is currently the most common cancer worldwide (12.3% of all new cases), with an estimated 1.2 million new cases and 1.1 million deaths (17.8% of all cancer deaths) throughout the world in 2000 [1]. Above all, non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. Among all deaths in Japan from malignant neoplasms, lung cancer is the most common among males, and ranks third among females. For
夽 This study was presented in part at the Annual Meeting of the American Society of Clinical Oncology, 2002 (Abstract No 1299). ∗ Corresponding author. Tel.: +81 561 82 5101; fax: +81 561 82 9139. E-mail address: [email protected] (H. Taniguchi). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.11.021
chemotherapy-naive patients with a good performance status (PS) and stage IIIb or IV disease, platinum-based chemotherapy offers a modest survival advantage over the best supportive care (BSC) alone in NSCLC [2–4]. Despite these advantages, because first-line therapy is not curative, patients will ultimately experience disease progression and/or disease-related complications. During disease progression, many patients may be suitable candidates for secondline treatment. Docetaxel is a widely recognized chemotherapy agent for the second-line treatment of advanced NSCLC. Two randomized phase III studies have clearly demonstrated that second-line treatment with docetaxel conferred a statistically significant survival advantage, improved quality of life, and clinical benefits over either the best supportive care [5] or monotherapy with either vinorelbine or ifosfamide [6]. On the other hand, paclitaxel has shown no proven
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clinical benefit in a second-line setting especially in docetaxelresistant cases. However, a lack of complete cross-resistance has been observed between docetaxel and paclitaxel in preclinical and clinical studies [7]. Preclinical data have suggested that the duration of exposure is an important factor in the cytotoxic activity of paclitaxel [8], and that it may be more effective when administered at frequent intervals, such as on a weekly schedule. A phase I/II study has suggested that paclitaxel can be given as a brief weekly infusion in pre-treated patients with solid tumors and acceptable toxicity [9]. The objective of this study was to evaluate the safety and efficacy of a weekly low-dose paclitaxel regimens in patients with resistant or relapsed NSCLC treated with docetaxel and carboplatin. 2. Patients and methods
Table 1 Patient characteristics (N = 32). Characteristics
No. of patients
Gender (male/female) Median age (range, years) ECOG performance status 0/1/2 Histological subtype (%) Adenocarcinoma Squamous cell carcinoma Stage (%) IIIB IV Response to previous chemotherapy (%) PR SD PD
20/12 58.0 (33–75) 18/9/5 27 (84) 5 (16) 6 (19) 26 (81) 9 (28) 15 (47) 8 (25)
Abbreviation: ECOG, The Eastern Cooperative Oncology Group.
2.1. Eligibility Patients with histologic or cytologic confirmation of NSCLC with stage IIIb or IV disease not amenable to curative therapy were assessed for eligibility. Eligible patients met the following criteria: resistant or relapsed NSCLC treated with docetaxel and carboplatin; measurable disease; an Eastern Cooperative Oncology Group (ECOG) PS of 0–2; and adequate bone marrow reserve (defined as an absolute white blood cell count of ≥2,000/L, hemoglobin ≥ 10.0 g/dL and platelet count ≥ 100,000/L); adequate hepatic and renal function (defined as serum creatinine level and BUN ≤ at the upper limit of normal and AST and ALT ≤ 2 times that limit). Patients with a history of a second or third cancer, or uncontrolled pleural effusions were ineligible, while those with brain metastases were not. All patients provided written informed consent before treatment.
of the trial was established according to Simon’s two-stage minimax design [10]. To conclude that the therapy was effective, at least 1 of 13 patients had to achieve this end-point to proceed to the second stage, in which at least 4 of 27 patients overall had to achieve it. A response rate of 5% was deemed ineffective, whereas a rate of 15% was considered effective. This design yielded a ˛ = 0.05 with 80% power. At the first stage, we counted 3 PR out of 13 response assessments. In accordance with the study design, we proceeded to the next stage. Response and survival rates were both calculated on an intent-to-treat basis. The rates of overall survival and time to progression were measured from the date of entry into the trial to either the time of death or up to the date of the last followup clinical assessment. Survival curves were constructed using the Kaplan–Meier method. 3. Results
2.2. Treatment schedule, toxicity and response evaluations Paclitaxel was administered at a dose of 80 mg/m2 as a 60-min intravenous infusion weekly for 6 consecutive weeks of an 8-week cycle. Premedication included ranitidine (50 mg) intravenously and diphenhydramine (50 mg) orally administered 30 min before treatment. Dexamethasone (24 mg) was given intravenously on the prior evening and the morning of chemotherapy. A reduction in the dose of dexamethasone was allowed after the first paclitaxel administration, as long as patients exhibited no signs of hypersensitivity reaction. The dose of paclitaxel for subsequent cycles was reduced to 70 mg/m2 (first step) and 60 mg/m2 (second step) in case of a plunge in leukocytes below 1,000/L or neutrophils below 500/L for at least 3 days, based on the National Cancer Institute Common Toxicity Criteria (CTC) for grade 4 thrombocytopenia, and febrile neutropenia, or CTC grade 3 or 4 non-hematological toxicity. The treatment was continued, barring disease progression, unacceptable toxicity (non-recovered neutrophils above 2,000/L or continuous CTC grade 3 neuropathy), or until the patient or the investigator requested that the therapy be discontinued. Patients who received at least one cycle (8 weeks) of chemotherapy were assessed for their response according to the WHO criteria for reporting results of cancer treatment. Patients were assessed every week for toxicity until discontinuation of the treatment. For the toxicity assessment, the National Cancer Institute Common Toxicity Criteria (CTC, version 2.0) were used. 2.3. Statistical methods This study was designed as a phase II trial. The primary objective of the study was to determine the overall response rate. Sample size
3.1. Patient characteristics From October 1999 until November 2001, a total of 32 patients were enrolled among 7 participation centers. Baseline characteristics are summarized in Table 1. The disease stage of patients was evaluated at the time of entry to this study, with stage IV diseases numbering 26 (81%). All the patients had been previously treated with docetaxel (60 mg/m2 ) and carboplatin (area under the concentration time curve 6) as a first-line chemotherapy, during which no patient received additional thoracic radiotherapy. 3.2. Efficacy Overall response data are summarized in Table 2. Thirty-two patients were evaluated for response. The median number of cycles per patient was 2 (range 1–8). There were 5 PR, for an overall Table 2 Summary of tumor response. Number of patients Median number of cycles Response Complete response (%) Partial response (%) Stable disease (%) Progressive disease (%) Overall response rate (%) (95% CI) Disease control rate (%) (95% CI) Median survival (months) (95% CI) 1-Year survival (%) (95% CI) Median time to progression (months) (95% CI) Abbreviation: CI, confidence interval.
32 2 0 5 (15.6) 16 (50.0) 11 (34.4) 15.6 (2.3–28.9) 65.6 (48.2–83.0) 10.6 (8.2–12.5) 37.5 (19.8–55.2) 4.9 (3.0–7.1)
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Table 4 Non-hematological toxicities. Toxicities
No. of patients (%) Grade 1
Neuropathy Anorexia Nausea/vomiting Diarrhea Alopecia Hepatotoxicity Nephrotoxicity Hypersensitivity reaction
Fig. 1. Kaplan–Meier survival curves.
3.3. Toxicity All patients were assessable for toxicity. The hematological toxicities are summarized in Table 3. The severest toxicities were neutropenia and leucopenia, with neutropenia CTC grade 3 or 4 occurring in 13 patients (40.6%). No febrile neutropenia was observed. Granulocyte stimulating factors were used for four patients. No patient received platelets, red blood cell transfusions or erythropoietin. The non-hematological toxicities were relatively mild, and are summarized in Table 4. Frequent non-hematological toxicities were anorexia, alopecia and neuropathy, the severest of which was anorexia. CTC grade 3 anorexia occurred in three Table 3 Hematological toxicities.
Leukopenia Neutropenia Anemia Thrombocytopenia Neutropenic fever
Grade 2 1 (3.1) 4 (12.5) 1 (3.1) – 6 (18.8) – – –
Grade 3
Grade 4
– 3 (9.3) – – – – – –
– – – – – – – –
patients (9.3%). CTC grade 4 non-hematological toxicities were not observed. No treatment-related deaths were observed.
response rate of 15.6% (95% CI = 2.3–28.9%), and 16 SD, for a disease control rate (DCR) of 65.6% (95% CI = 48.2–83.0%). PD was observed in 11 patients. Among five responders, the responses to previous chemotherapy were one PR, three SD and one PD. Furthermore, in 16 SD, those responses were 5 PR, 8 SD and 3 PD. In contrasts, four patients improved following treatment (1PR and 3SD) out of 8 who had been PD in the first-line chemotherapy. Median overall survival was 10.6 months (95% CI = 8.2–12.5), with a 1-year survival rate of 37.5% (95% CI = 19.8–55.2), and median time to progression was 4.9 months (95% CI = 3.0–7.1). We analyzed the influence of histology on the outcome of our patient population. The majority of patients (27) had adenocarcinoma (84%), and five had squamous cell carcinoma (16%). Median overall survival in patients with adenocarcinoma was 10.3 months (95% CI = 7.7–13.0), while in those with squamous cell histology it was 10.8 months (95% CI = 1.9–19.7). These data suggest that the effect on survival of second-line weekly paclitaxel did not differ according to histology (log-rank test, p = 0.827). In addition, we performed a sub-analysis of responses to weekly paclitaxel according to the outcome of firstline treatment. Median overall survival rates in patients with PR, SD and PD as a first-line chemotherapy were, respectively, 17.4 months (95% CI = 10.4–24.4), 9.5 months (95% CI = 5.7–13.3) and 9.9 months (95% CI = 4.8–13.0) after the second-line weekly paclitaxel (logrank test, p = 0.077). Survival curves (by the Kaplan–Meier method) according to the outcome of first-line treatment in addition to the total overall survival are shown in Fig. 1.
Toxicities
6 (18.8) 11 (34.3) 1 (3.1) – 10 (31.3) 1 (3.1) – –
No. of patients (%) Grade 1
Grade 2
Grade 3
Grade 4
2 (6.3) 4 (12.5) 8 (25.0) 3 (9.4) –
9 (28.1) 9 (28.1) 10 (31.3) 2 (6.3) –
13 (40.6) 8 (25.0) 3 (9.4) – –
2 (6.3) 5 (15.6) 1 (3.1) – –
4. Discussion Second-line chemotherapy provides pre-treated NSCLC patients with a clear survival advantage. While docetaxel 75 mg/m2 is the present standard second-line chemotherapy, pemetrexed, erlotinib and oral topotecan recently emerged as alternatives with similar efficacy and an eventual best safety profile [11–13]. Infact, 2003 ASCO Guidelines established docetaxel as the gold standard for second-line therapy in patients with locally advanced or metastatic NSCLC at a reasonable performance status, and who were previously treated with platinum-based chemotherapy [14]. Other single agents of second-line chemotherapy for NSCLC studied in several phase II trials are gemcitabine and weekly paclitaxel. In trials, second-line gemcitabine achieved 6.2–20% response rates, 3.9–8.9 months median survivals and a 37–45% 1year survival [15–18]. Several studies have reported on second-line weekly paclitaxel. Most of the patients pre-treated with platinumbased combination chemotherapy as first-line chemotherapy achieved 6–38% response rates, 8.0–13.6 months median survivals and a 18–53% 1-year survival [19–22]. However, combination chemotherapy in a second-line setting is not currently recommended, because it is not more effective but is, in fact, more associated with toxicity than single-agent chemotherapy [23–25]. In this multi-center phase II study of 32 patients pre-treated with carboplatin plus docetaxel, we showed that paclitaxel, as a single agent, is active as a second-line chemotherapy. Socinski et al., who reported on second-line weekly paclitaxel in patients who failed first-line chemotherapy treated with carboplatin plus paclitaxel, showed an overall response rate of 8%, with a median survival of 5.2 months, and a 1-year survival rate of 20% [26]. All our patients were treated with carboplatin plus docetaxel as the first-line chemotherapy, and the response rate (15.6% of patients achieved partial responses), median survival time (10.6 months) and 1-year survival (37.5%) were comparable to those reported in previous second-line chemotherapy for NSCLC. One recent strategy has focused on the importance of histology for the outcome of NSCLC patients dependent on the choice of a chemotherapeutic agent [27]. This prompted us to perform a subanalysis of the influence of histology on the outcome of our study. Our data suggested that the effect on the survival of second-line weekly paclitaxel did not differ histologically. We performed a further sub-analysis of responses to weekly paclitaxel according to the outcome of first-line treatment. Although the responder group as a first-line chemotherapy tended to survive longer, further study will be required. The two taxanes share a mechanism of action with those structural main parts, but differ in several other aspects, e.g., one difference is that in tubulin polymer generation, docetaxel seems to be twice as active in the inhibition of depolymerization [28]. Although in vitro docetaxel has been reported to be more potent
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in various cell lines and investigational models, Hanauske et al. compared the anti-proliferative action of docetaxel with paclitaxel against a variety of freshly explanted human tumor specimens, and found that cross-resistance between the two agents was incomplete [29]. In addition, Valero et al. reported the absence of cross-resistance to docetaxel in patients with paclitaxel-resistant metastatic breast cancer [30]. Verweij et al. also suggested that prolonged exposure to paclitaxel was better than a brief exposure, though no such tendency was seen in docetaxel, indicating it to be a schedule-independent drug [31]. Thus, we speculated that weekly paclitaxel might be effective for patients unresponsive to docetaxel. However, there has been no prospective study of paclitaxel administration for patients with docetaxel-resistant solid tumors, including NSCLC. In our study, out of 8 patients who had been classified PD under previous treatment, 4 improved following treatment (1PR and 3SD). This finding indicates that weekly paclitaxel is partially active in patients with docetaxel-resistant NSCLC, while further indicating a partial cross-resistance between paclitaxel and docetaxel. Hematological toxicity was commonly observed in our patients. Neutropenia CTC grade 3 or 4 occurred in 13 patients (40.6%), though febrile neutropenia was not observed. No patient received platelets or red blood cell transfusion, and non-hematological toxicities were relatively mild. Hematological and non-hematological toxicities in this study were similar to or less than those previously reported [5,6,11,13]. In conclusion, second-line weekly paclitaxel is well tolerated and appears to be effective in NSCLC patients treated with docetaxel plus carboplatin. Conflict of interest statement The authors indicate that no financial conflict of interest exists with any commercial entity whose products are described in this manuscript. References [1] Parkin DM, Bray FI, Devessa SS. Cancer burden for the year 2000, the global picture. Eur J Cancer 2001;37:4–66. [2] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer, a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899–909. [3] Grilli R, Oxyman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer, how much benefit is enough? J Clin Oncol 1993;11:1866–72. [4] Cullen MH, Billingham LJ, Woodroffe CM, Chetyawardana AD, Gower NH, Joshi R, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-smallcell lung cancer, effects on survival and quality of life. J Clin Oncol 1999;17: 3188–94. [5] Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2000;18:2095–103. [6] Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinumcontaining chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–62. [7] Von Hoff DD. The taxoids, same roots, different drugs. Semin Oncol 1997;24:3–10.
[8] Lopes NM, Adams EG, Pitts TW, Bluyan BK. Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 1993;32:235–42. [9] Löffler TM, Freund W, Lipke J, Hausamen TU. Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors, results of a phase I/II trial. Semin Oncol 1996;23:32–4. [10] Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10. [11] Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589–97. [12] Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32. [13] Ramlau R, Gervais R, Krzakowski M, von Pawel J, Kaukel E, Abratt RP, et al. Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol 2006;24:2800– 7. [14] Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline, update 2003. J Clin Oncol 2004;22:330–53. [15] Crino L, Mosconi AM, Scagliotti G, Selvaggi G, Novello S, Rinaldi M, et al. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer, a phase II trial. J Clin Oncol 1999;17:2081–5. [16] Sculier JP, Lafitte JJ, Berghmans T, Thiriaux J, Lecomte J, Efremidis A, et al. A phase II trial testing gemcitabine as second-line chemotherapy for non-small cell lung cancer. The European Lung Cancer Working Party. Lung Cancer 2000;29:67– 73. [17] Gridelli C, Perrone F, Gallo C, Rossi A, Barletta E, Barzelloni ML, et al. Single-agent gemcitabine as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC), a phase II trial. Anticancer Res 1999;19:4535–8. [18] Cho KH, Song YB, Choi IS, Cho EH, Choi JW, Ahn YM, et al. A phase II study of single-agent gemcitabine as a second-line treatment in advanced non-small cell lung cancer. Jpn J Clin Oncol 2006;36:50–4. [19] Ceresoli GL, Gregorc V, Cordio S, Bencardino KB, Schipani S, Cozzarini C, et al. Phase II study of weekly paclitaxel as second-line therapy in patients with advanced non-small cell lung cancer. Lung Cancer 2004;44:231–9. [20] Buccheri G, Ferrigno D, Cuneo Lung Cancer Study Group. Second-line weekly paclitaxel in patients with inoperable non-small cell lung cancer who fail combination chemotherapy with cisplatin. Lung Cancer 2004;45:227–36. [21] Juan O, Albert A, Ordono F, Casany R, Caranana V, Campos JM, et al. Low-dose weekly paclitaxel as second-line treatment for advanced non-small cell lung cancer, a phase II study. Jpn J Clin Oncol 2002;32:449–54. [22] Yasuda K, Igishi T, Kawasaki Y, Kato K, Matsumoto S, Katayama S, et al. Phase II study of weekly paclitaxel in patients with non-small cell lung cancer who have failed previous treatments. Oncology 2004;66:347–52. [23] Barlesi F, Jacot W, Astoul P, Pujol JL. Second-line treatment for advanced nonsmall cell lung cancer, a systematic review. Lung Cancer 2006;51:159–72. [24] Bedano PM, Hanna NH. Salvage therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol 2006;1:582–7. [25] Noble J, Ellis PM, Mackay JA, Evans WK, et al. Second-line or subsequent systemic therapy for recurrent or progressive non-small cell lung cancer, a systematic review and practice guideline. J Thorac Oncol 2006;1:1042–58. [26] Socinski MA, Schell MJ, Bakri K, Peterman A, Lee JH, Unger P, et al. Second-line, low-dose, weekly paclitaxel in patients with stage IIIB/IV nonsmall cell lung carcinoma who fail first-line chemotherapy with carboplatin plus paclitaxel. Cancer 2002;95:1265–73. [27] Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients with advanced-stage non-smallcell lung cancer. J Clin Oncol 2008;26:3543–51. [28] Ringel I, Horwitz SB. Studies with RP 56976 (taxotere). a semisynthetic analogue of taxol. J Natl Cancer Inst 1991;83:288–91. [29] Hanauske AR, Degen D, Hilsenbeck SG, Bissery MC, Von Hoff DD. Effects of taxotere and taxol on in vitro colony formation of freshly explanted human tumor cells. Anticancer Drugs 1992;3:121–4. [30] Valero V, Jones SE, Von Hoff DD, Booser DJ, Mennel RG, Ravdin PM, et al. A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol 1998;16:3362–8. [31] Verweij J, Clavel M, Chevalier B. Paclitaxel (Taxol) and docetaxel (Taxotere), not simply two of a kind. Ann Oncol 1994;5:495–505.
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Second-line weekly paclitaxel in resistant or relapsed non-small cell lung cancer treated with docetaxel and carboplatin: A multi-center phase II study夽 Motoshi Ichikawa a , Ryujiro Suzuki b , Kensuke Kataoka c , Yasunobu Noda b , Joe Shindoh d , Syuichi Matsumoto e , Yoshimasa Tanikawa a , Kiyoshi Suzuki f , Kenji Baba g , Yuichiro Shindo h , Masashi Kondo h , Kazuyoshi Imaizumi h , Hiroaki Kume h , Yoshinori Hasegawa h , Kenzo Takagi i , Hiroyuki Taniguchi c,∗ a
Department of Respiratory Medicine and Allergy, Toyota Kosei Hospital, 500-1 Ibohara Josui-cho, Toyota, Aichi 470-0396, Japan Department of Respiratory Medicine, Toyohashi Municipal Hospital, 50 Hachiken-nishi Aotake-cho, Toyohashi, Aichi 441-8570, Japan c Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwake-cho, Seto, Aichi 489-8642, Japan d Department of Respiratory Medicine, Ogaki Municipal Hospital, 4-86 Minami-no-kawa-cho, Ogaki, Gifu 503-8502, Japan e Department of Respiratory Medicine and Allergy, Komaki Municipal Hospital, 1-20 Joubushin, Komaki, Aichi 485-8520, Japan f Department of Respiratory Medicine, Meijo Hospital, 1-3-1 San-no-maru, Naka-ku, Nagoya, Aichi 460-0001, Japan g Department of Respiratory Medicine, Aichi Medical University, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan h Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan i Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya, Aichi 461-8763, Japan b
a r t i c l e
i n f o
Article history: Received 22 June 2009 Received in revised form 10 September 2009 Accepted 5 November 2009 Keywords: Non-small cell lung cancer Chemotherapy Second-line treatment Paclitaxel Cross-resistance
a b s t r a c t We conducted a phase II trial to evaluate the safety and efficacy of weekly paclitaxel in patients with resistant or relapsed non-small cell lung cancer (NSCLC) treated with docetaxel and carboplatin. Thirtytwo NSCLC patients at a median age of 58.0 years (range 33–75) were enrolled. The Eastern Cooperative Oncology Group performance status scores (0/1/2) were 18/9/5, respectively. The majority of patients had adenocarcinoma (84%) and stage IV disease (81%). The response rate for the first-line chemotherapy was 28%. Paclitaxel was administered at a dose of 80 mg/m2 as an intravenous infusion 60 min weekly for 6 consecutive weeks of an 8-week cycle. All patients were assessable for response and toxicity. The median number of cycles administered was two (range 1–8), and the overall response rate was 15.6%. The median survival time (MST) was 10.6 months (95% CI = 8.2–12.5), while the 1-year survival rate was 37.5%, and the median progression-free survival was 4.9 months (95% CI = 3.0–7.1). Hematological toxicities (grade 3 or 4) were observed in 15 patients (46.9%) with leukopenia, and in 4 (12.5%) with anemia. Non-hematological toxicity was generally mild, though grade 3 anorexia was observed in 3 patients (9.3%). No treatmentrelated deaths were observed. In conclusion, second-line weekly paclitaxel is effective in NSCLC patients treated with docetaxel plus carboplatin and is associated with a tolerable toxicity profile. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is currently the most common cancer worldwide (12.3% of all new cases), with an estimated 1.2 million new cases and 1.1 million deaths (17.8% of all cancer deaths) throughout the world in 2000 [1]. Above all, non-small cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. Among all deaths in Japan from malignant neoplasms, lung cancer is the most common among males, and ranks third among females. For
夽 This study was presented in part at the Annual Meeting of the American Society of Clinical Oncology, 2002 (Abstract No 1299). ∗ Corresponding author. Tel.: +81 561 82 5101; fax: +81 561 82 9139. E-mail address: [email protected] (H. Taniguchi). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.11.021
chemotherapy-naive patients with a good performance status (PS) and stage IIIb or IV disease, platinum-based chemotherapy offers a modest survival advantage over the best supportive care (BSC) alone in NSCLC [2–4]. Despite these advantages, because first-line therapy is not curative, patients will ultimately experience disease progression and/or disease-related complications. During disease progression, many patients may be suitable candidates for secondline treatment. Docetaxel is a widely recognized chemotherapy agent for the second-line treatment of advanced NSCLC. Two randomized phase III studies have clearly demonstrated that second-line treatment with docetaxel conferred a statistically significant survival advantage, improved quality of life, and clinical benefits over either the best supportive care [5] or monotherapy with either vinorelbine or ifosfamide [6]. On the other hand, paclitaxel has shown no proven
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clinical benefit in a second-line setting especially in docetaxelresistant cases. However, a lack of complete cross-resistance has been observed between docetaxel and paclitaxel in preclinical and clinical studies [7]. Preclinical data have suggested that the duration of exposure is an important factor in the cytotoxic activity of paclitaxel [8], and that it may be more effective when administered at frequent intervals, such as on a weekly schedule. A phase I/II study has suggested that paclitaxel can be given as a brief weekly infusion in pre-treated patients with solid tumors and acceptable toxicity [9]. The objective of this study was to evaluate the safety and efficacy of a weekly low-dose paclitaxel regimens in patients with resistant or relapsed NSCLC treated with docetaxel and carboplatin. 2. Patients and methods
Table 1 Patient characteristics (N = 32). Characteristics
No. of patients
Gender (male/female) Median age (range, years) ECOG performance status 0/1/2 Histological subtype (%) Adenocarcinoma Squamous cell carcinoma Stage (%) IIIB IV Response to previous chemotherapy (%) PR SD PD
20/12 58.0 (33–75) 18/9/5 27 (84) 5 (16) 6 (19) 26 (81) 9 (28) 15 (47) 8 (25)
Abbreviation: ECOG, The Eastern Cooperative Oncology Group.
2.1. Eligibility Patients with histologic or cytologic confirmation of NSCLC with stage IIIb or IV disease not amenable to curative therapy were assessed for eligibility. Eligible patients met the following criteria: resistant or relapsed NSCLC treated with docetaxel and carboplatin; measurable disease; an Eastern Cooperative Oncology Group (ECOG) PS of 0–2; and adequate bone marrow reserve (defined as an absolute white blood cell count of ≥2,000/L, hemoglobin ≥ 10.0 g/dL and platelet count ≥ 100,000/L); adequate hepatic and renal function (defined as serum creatinine level and BUN ≤ at the upper limit of normal and AST and ALT ≤ 2 times that limit). Patients with a history of a second or third cancer, or uncontrolled pleural effusions were ineligible, while those with brain metastases were not. All patients provided written informed consent before treatment.
of the trial was established according to Simon’s two-stage minimax design [10]. To conclude that the therapy was effective, at least 1 of 13 patients had to achieve this end-point to proceed to the second stage, in which at least 4 of 27 patients overall had to achieve it. A response rate of 5% was deemed ineffective, whereas a rate of 15% was considered effective. This design yielded a ˛ = 0.05 with 80% power. At the first stage, we counted 3 PR out of 13 response assessments. In accordance with the study design, we proceeded to the next stage. Response and survival rates were both calculated on an intent-to-treat basis. The rates of overall survival and time to progression were measured from the date of entry into the trial to either the time of death or up to the date of the last followup clinical assessment. Survival curves were constructed using the Kaplan–Meier method. 3. Results
2.2. Treatment schedule, toxicity and response evaluations Paclitaxel was administered at a dose of 80 mg/m2 as a 60-min intravenous infusion weekly for 6 consecutive weeks of an 8-week cycle. Premedication included ranitidine (50 mg) intravenously and diphenhydramine (50 mg) orally administered 30 min before treatment. Dexamethasone (24 mg) was given intravenously on the prior evening and the morning of chemotherapy. A reduction in the dose of dexamethasone was allowed after the first paclitaxel administration, as long as patients exhibited no signs of hypersensitivity reaction. The dose of paclitaxel for subsequent cycles was reduced to 70 mg/m2 (first step) and 60 mg/m2 (second step) in case of a plunge in leukocytes below 1,000/L or neutrophils below 500/L for at least 3 days, based on the National Cancer Institute Common Toxicity Criteria (CTC) for grade 4 thrombocytopenia, and febrile neutropenia, or CTC grade 3 or 4 non-hematological toxicity. The treatment was continued, barring disease progression, unacceptable toxicity (non-recovered neutrophils above 2,000/L or continuous CTC grade 3 neuropathy), or until the patient or the investigator requested that the therapy be discontinued. Patients who received at least one cycle (8 weeks) of chemotherapy were assessed for their response according to the WHO criteria for reporting results of cancer treatment. Patients were assessed every week for toxicity until discontinuation of the treatment. For the toxicity assessment, the National Cancer Institute Common Toxicity Criteria (CTC, version 2.0) were used. 2.3. Statistical methods This study was designed as a phase II trial. The primary objective of the study was to determine the overall response rate. Sample size
3.1. Patient characteristics From October 1999 until November 2001, a total of 32 patients were enrolled among 7 participation centers. Baseline characteristics are summarized in Table 1. The disease stage of patients was evaluated at the time of entry to this study, with stage IV diseases numbering 26 (81%). All the patients had been previously treated with docetaxel (60 mg/m2 ) and carboplatin (area under the concentration time curve 6) as a first-line chemotherapy, during which no patient received additional thoracic radiotherapy. 3.2. Efficacy Overall response data are summarized in Table 2. Thirty-two patients were evaluated for response. The median number of cycles per patient was 2 (range 1–8). There were 5 PR, for an overall Table 2 Summary of tumor response. Number of patients Median number of cycles Response Complete response (%) Partial response (%) Stable disease (%) Progressive disease (%) Overall response rate (%) (95% CI) Disease control rate (%) (95% CI) Median survival (months) (95% CI) 1-Year survival (%) (95% CI) Median time to progression (months) (95% CI) Abbreviation: CI, confidence interval.
32 2 0 5 (15.6) 16 (50.0) 11 (34.4) 15.6 (2.3–28.9) 65.6 (48.2–83.0) 10.6 (8.2–12.5) 37.5 (19.8–55.2) 4.9 (3.0–7.1)
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Table 4 Non-hematological toxicities. Toxicities
No. of patients (%) Grade 1
Neuropathy Anorexia Nausea/vomiting Diarrhea Alopecia Hepatotoxicity Nephrotoxicity Hypersensitivity reaction
Fig. 1. Kaplan–Meier survival curves.
3.3. Toxicity All patients were assessable for toxicity. The hematological toxicities are summarized in Table 3. The severest toxicities were neutropenia and leucopenia, with neutropenia CTC grade 3 or 4 occurring in 13 patients (40.6%). No febrile neutropenia was observed. Granulocyte stimulating factors were used for four patients. No patient received platelets, red blood cell transfusions or erythropoietin. The non-hematological toxicities were relatively mild, and are summarized in Table 4. Frequent non-hematological toxicities were anorexia, alopecia and neuropathy, the severest of which was anorexia. CTC grade 3 anorexia occurred in three Table 3 Hematological toxicities.
Leukopenia Neutropenia Anemia Thrombocytopenia Neutropenic fever
Grade 2 1 (3.1) 4 (12.5) 1 (3.1) – 6 (18.8) – – –
Grade 3
Grade 4
– 3 (9.3) – – – – – –
– – – – – – – –
patients (9.3%). CTC grade 4 non-hematological toxicities were not observed. No treatment-related deaths were observed.
response rate of 15.6% (95% CI = 2.3–28.9%), and 16 SD, for a disease control rate (DCR) of 65.6% (95% CI = 48.2–83.0%). PD was observed in 11 patients. Among five responders, the responses to previous chemotherapy were one PR, three SD and one PD. Furthermore, in 16 SD, those responses were 5 PR, 8 SD and 3 PD. In contrasts, four patients improved following treatment (1PR and 3SD) out of 8 who had been PD in the first-line chemotherapy. Median overall survival was 10.6 months (95% CI = 8.2–12.5), with a 1-year survival rate of 37.5% (95% CI = 19.8–55.2), and median time to progression was 4.9 months (95% CI = 3.0–7.1). We analyzed the influence of histology on the outcome of our patient population. The majority of patients (27) had adenocarcinoma (84%), and five had squamous cell carcinoma (16%). Median overall survival in patients with adenocarcinoma was 10.3 months (95% CI = 7.7–13.0), while in those with squamous cell histology it was 10.8 months (95% CI = 1.9–19.7). These data suggest that the effect on survival of second-line weekly paclitaxel did not differ according to histology (log-rank test, p = 0.827). In addition, we performed a sub-analysis of responses to weekly paclitaxel according to the outcome of firstline treatment. Median overall survival rates in patients with PR, SD and PD as a first-line chemotherapy were, respectively, 17.4 months (95% CI = 10.4–24.4), 9.5 months (95% CI = 5.7–13.3) and 9.9 months (95% CI = 4.8–13.0) after the second-line weekly paclitaxel (logrank test, p = 0.077). Survival curves (by the Kaplan–Meier method) according to the outcome of first-line treatment in addition to the total overall survival are shown in Fig. 1.
Toxicities
6 (18.8) 11 (34.3) 1 (3.1) – 10 (31.3) 1 (3.1) – –
No. of patients (%) Grade 1
Grade 2
Grade 3
Grade 4
2 (6.3) 4 (12.5) 8 (25.0) 3 (9.4) –
9 (28.1) 9 (28.1) 10 (31.3) 2 (6.3) –
13 (40.6) 8 (25.0) 3 (9.4) – –
2 (6.3) 5 (15.6) 1 (3.1) – –
4. Discussion Second-line chemotherapy provides pre-treated NSCLC patients with a clear survival advantage. While docetaxel 75 mg/m2 is the present standard second-line chemotherapy, pemetrexed, erlotinib and oral topotecan recently emerged as alternatives with similar efficacy and an eventual best safety profile [11–13]. Infact, 2003 ASCO Guidelines established docetaxel as the gold standard for second-line therapy in patients with locally advanced or metastatic NSCLC at a reasonable performance status, and who were previously treated with platinum-based chemotherapy [14]. Other single agents of second-line chemotherapy for NSCLC studied in several phase II trials are gemcitabine and weekly paclitaxel. In trials, second-line gemcitabine achieved 6.2–20% response rates, 3.9–8.9 months median survivals and a 37–45% 1year survival [15–18]. Several studies have reported on second-line weekly paclitaxel. Most of the patients pre-treated with platinumbased combination chemotherapy as first-line chemotherapy achieved 6–38% response rates, 8.0–13.6 months median survivals and a 18–53% 1-year survival [19–22]. However, combination chemotherapy in a second-line setting is not currently recommended, because it is not more effective but is, in fact, more associated with toxicity than single-agent chemotherapy [23–25]. In this multi-center phase II study of 32 patients pre-treated with carboplatin plus docetaxel, we showed that paclitaxel, as a single agent, is active as a second-line chemotherapy. Socinski et al., who reported on second-line weekly paclitaxel in patients who failed first-line chemotherapy treated with carboplatin plus paclitaxel, showed an overall response rate of 8%, with a median survival of 5.2 months, and a 1-year survival rate of 20% [26]. All our patients were treated with carboplatin plus docetaxel as the first-line chemotherapy, and the response rate (15.6% of patients achieved partial responses), median survival time (10.6 months) and 1-year survival (37.5%) were comparable to those reported in previous second-line chemotherapy for NSCLC. One recent strategy has focused on the importance of histology for the outcome of NSCLC patients dependent on the choice of a chemotherapeutic agent [27]. This prompted us to perform a subanalysis of the influence of histology on the outcome of our study. Our data suggested that the effect on the survival of second-line weekly paclitaxel did not differ histologically. We performed a further sub-analysis of responses to weekly paclitaxel according to the outcome of first-line treatment. Although the responder group as a first-line chemotherapy tended to survive longer, further study will be required. The two taxanes share a mechanism of action with those structural main parts, but differ in several other aspects, e.g., one difference is that in tubulin polymer generation, docetaxel seems to be twice as active in the inhibition of depolymerization [28]. Although in vitro docetaxel has been reported to be more potent
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in various cell lines and investigational models, Hanauske et al. compared the anti-proliferative action of docetaxel with paclitaxel against a variety of freshly explanted human tumor specimens, and found that cross-resistance between the two agents was incomplete [29]. In addition, Valero et al. reported the absence of cross-resistance to docetaxel in patients with paclitaxel-resistant metastatic breast cancer [30]. Verweij et al. also suggested that prolonged exposure to paclitaxel was better than a brief exposure, though no such tendency was seen in docetaxel, indicating it to be a schedule-independent drug [31]. Thus, we speculated that weekly paclitaxel might be effective for patients unresponsive to docetaxel. However, there has been no prospective study of paclitaxel administration for patients with docetaxel-resistant solid tumors, including NSCLC. In our study, out of 8 patients who had been classified PD under previous treatment, 4 improved following treatment (1PR and 3SD). This finding indicates that weekly paclitaxel is partially active in patients with docetaxel-resistant NSCLC, while further indicating a partial cross-resistance between paclitaxel and docetaxel. Hematological toxicity was commonly observed in our patients. Neutropenia CTC grade 3 or 4 occurred in 13 patients (40.6%), though febrile neutropenia was not observed. No patient received platelets or red blood cell transfusion, and non-hematological toxicities were relatively mild. Hematological and non-hematological toxicities in this study were similar to or less than those previously reported [5,6,11,13]. In conclusion, second-line weekly paclitaxel is well tolerated and appears to be effective in NSCLC patients treated with docetaxel plus carboplatin. Conflict of interest statement The authors indicate that no financial conflict of interest exists with any commercial entity whose products are described in this manuscript. References [1] Parkin DM, Bray FI, Devessa SS. Cancer burden for the year 2000, the global picture. Eur J Cancer 2001;37:4–66. [2] Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer, a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med J 1995;311:899–909. [3] Grilli R, Oxyman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer, how much benefit is enough? J Clin Oncol 1993;11:1866–72. [4] Cullen MH, Billingham LJ, Woodroffe CM, Chetyawardana AD, Gower NH, Joshi R, et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-smallcell lung cancer, effects on survival and quality of life. J Clin Oncol 1999;17: 3188–94. [5] Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinumbased chemotherapy. J Clin Oncol 2000;18:2095–103. [6] Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinumcontaining chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 2000;18:2354–62. [7] Von Hoff DD. The taxoids, same roots, different drugs. Semin Oncol 1997;24:3–10.
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