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Feasibility study of adjuvant chemotherapy with gemcitabine and split-dose cisplatin for completely resected non-small-cell lung cancer
Lung Cancer 68 (2010) 78–83
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Feasibility study of adjuvant chemotherapy with gemcitabine and split-dose cisplatin for completely resected non-small-cell lung cancer Kazuhito Funai a,b,∗ , Kazuya Takamochi b , Toru Itaya b , Takahiro Mochizuki b , Toru Nakamura c , Futoru Toyoda c , Kim Yong-Il d , Kazuyoshi Sasaki a , Shigeru Momiki a , Tsuyoshi Takahashi e , Hiroshi Neyatani e , Kazuya Suzuki b a
Division of Thoracic Surgery, Hamamatsu Medical Center, Hamamatsu, Japan First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan c Division of General Thoracic Surgery, Hamamatsu, Japan d Palliative Medicine, Seirei Hamamatsu General Hospital, Hamamatsu, Japan e Division of Cardiac and Thoracic Surgery, Fujieda Municipal General Hospital, Fujieda Japan b
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Article history: Received 31 March 2009 Received in revised form 25 May 2009 Accepted 26 May 2009 Keywords: Adjuvant chemotherapy Chemotherapy compliance Gemcitabine Non-small-cell lung cancer Split-dose cisplatin Treatment compliance
a b s t r a c t Introduction: Recent clinical trials have shown significant survival benefits from postoperative adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC). However, due to the comparatively low compliance in recent clinical trials, this study investigated the feasibility of adjuvant chemotherapy with gemcitabine plus split-dose cisplatin for completely resected NSCLC. Methods: Gemcitabine at a dose of 1000 mg m−2 and cisplatin at 40 mg m−2 were given intravenously on days 1 and 8 every 4 weeks for a maximum of four cycles. According to Simon’s minimax two-stage design, if the regimen was judged to be safe and tolerable in five or more of the seven patients in the first stage, then enrollment would increase to a total of 20 patients. The feasibility of this regimen was proven if four cycles of chemotherapy were completed in more than 14 patients. The primary endpoint was the compliance to this regimen in the adjuvant setting, while the secondary endpoints were safety and toxicity. Results: The regimen was judged to be safe and tolerable in the first stage, and therefore 21 patients were accrued as planned. Twenty patients (95%) received four cycles of chemotherapy; therefore chemotherapy compliance in the four cycles was 95%. The relative dose intensity was 97% for both gemcitabine and cisplatin. Grade 3/4 toxicities of neutropenia occurred in 33% and thrombocytopenia in 20%. Nonhematological adverse effects were extremely rare. Conclusion: Adjuvant chemotherapy with gemcitabine and split-dose cisplatin showed a favorable feasibility and acceptable toxicity in Japanese NSCLC patients. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Surgery is the most effective therapeutic modality for curing cancer, but the postoperative survival of patients who undergo a complete resection for NSCLC remains unsatisfactory, with a 5year survival ranging from only 30 to 60% [1,2]. Distant metastases usually lead to death, even if a complete resection is performed. Therefore, some effective adjuvant chemotherapy should be administered to reduce the risk of recurrence and improve survival.
∗ Corresponding author at: Division of Thoracic Surgery, Hamamatsu Medical Center, 328, Tomitsuka, Naka, Hamamatsu, Shizuoka 432-8580, Japan. Tel.: +81 53 453 7111; fax: +81 53 451 2768. E-mail address: [email protected] (K. Funai). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.05.018
In 1995, the NSCLC meta-analysis demonstrated a 5% survival benefit at 5 years with cisplatin-based adjuvant chemotherapy in resected NSCLC in comparison to surgery alone (P = 0.08) [3]. This finding prompted the planning of additional randomized trials, and several recent randomized trials and meta-analyses have shown a benefit of adjuvant cisplatin-based chemotherapy on the overall survival in patients with NSCLC [4–9]. In 2008, a Lung Adjuvant Cisplatin Evaluation (LACE) metaanalysis showed the effect of vinorelbine plus cisplatin to be marginally better than the effect of other platinum-doublet combinations [7]. However, the superiority of vinorelbine should be interpreted with caution because the total administered dose of cisplatin was significantly higher in the patients treated with vinorelbine and it was impossible to separate the effect of cisplatin dose from that of the companion drug. Although the completion rate of the planned four cycles of vinorelbine plus cisplatin was
K. Funai et al. / Lung Cancer 68 (2010) 78–83
low (about 50% in JBR.10 [5] and ANITA [6]), vinorelbine associated with a high dose of cisplatin is considered to be the most promising drug combination at this time. If a less toxic cisplatin-based combination regimen can be established with a high completion rate, then a higher survival benefit may be expected. Gemcitabine is a novel nucleoside analogue exercising a wide spectrum of anti-tumoral activity, and in combination with cisplatin has shown activity in NSCLC. The interactions between gemcitabine and cisplatin have been investigated in both in vitro and in vivo studies, and have shown both synergistic and additive effects [10,11]. Therefore, gemcitabine plus cisplatin is one of the most widely used platinum-based combination regimens. Le Chevalier et al. reported that a significant survival benefit of gemcitabine–platinum regimens was shown in their meta-analysis of the first line chemotherapies for locally advanced and metastatic NSCLC patients [12]. Therefore, gemcitabine plus cisplatin may also be effective for NSCLC patients in an adjuvant setting. Moreover, several clinical trials have suggested that a weekly administration of cisplatin might increase its activity with a mild toxicity [13–16]. Splitting the doses of cisplatin over days 1 and 8 increases its activity and reduces the occurrence of emesis and nephrotoxicity [17]. Splitdose cisplatin in combination with gemcitabine showed a good activity with favorable toxicity profiles in patients with ovarian cancer [18], breast cancer [19], and bladder cancer [20]. For advanced NSCLC patients, the first line use of gemcitabine and split-dose cisplatin is active and has been shown to be very well tolerated in several studies [17,21,22]. The Four-Arm Cooperative Study (FACS) in Japan compared the efficacy and toxicity of three platinum-based combination regimens (paclitaxel plus carboplatin, gemcitabine plus cisplatin, and vinorelbine plus cisplatin) with irinotecan plus cisplatin as the reference arm [23]. No statistically significant differences were found in the response rate or overall survival, but gemcitabine plus cisplatin was the most tolerable regimen. Only in the gemcitabine plus cisplatin arm was no treatment-related death observed. From the results of this study, cisplatin at 80 mg m−2 administered on day 1 plus gemcitabine at 1000 mg m−2 administered on days 1 and 8 is effective and commonly used for stage IIIB/IV NSCLC in Japanese patients. Although a significant survival benefit and favorable safety of adjuvant UFT were shown in Japanese patients with stage I lung adenocarcinoma [24], there is little convincing evidence that adjuvant chemotherapy using the platinum-doublet improves the outcome of NSCLC. Due to comparatively low compliance in recent clinical trials in Europe and North America, it is questionable whether Japanese can receive adjuvant platinum-doublet chemotherapy safely as planned. This study investigated the feasibility and toxicity of a gemcitabine and split-dose cisplatin regimen similar to the FACS study for Japanese patients with complete resected stages IB–IIIA NSCLC in an adjuvant setting. 2. Methods 2.1. Study design This trial was an open-labelled, multicenter prospective twostage feasibility study of combination chemotherapy with a regimen of gemcitabine plus split-dose cisplatin in an adjuvant setting for complete resected stages IB–IIIA NSCLC (Fig. 1). The primary endpoint was chemotherapy compliance in all four cycles with gemcitabine and split-dose cisplatin, while the secondary endpoints were safety and toxicity. Fifteen patients had to be accrued for a statistical power of 80% and an alpha-error of 5%, with a threshold feasibility level of 55% (similar to the completion rate of platinum-doublet in the recent
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Fig. 1. A schematic overview of a multicenter prospective two-stage feasibility study of combination chemotherapy with gemcitabine plus split-dose cisplatin in regimen in an adjuvant setting for complete resected stages IB–IIIA NSCLC.
trials) and an expectation feasibility level of 85% (the same as the chemotherapy compliance in the CALGB trial) using Simon’s minimax two-stage design [25]. Assuming several drop-out cases, 20 patients were planned to be accrued for this study. The feasibility of this regimen was evaluated according to Simons’s minimax two-stage design; in other words, feasibility was proven if four cycles of chemotherapy were completed in more than 14 patients. In brief, gemcitabine 1000 mg m−2 and cisplatin 40 mg m−2 were given intravenously on days 1 and 8 every 4 weeks for a maximum of four cycles as level 1. If the regimen was judged to be safe and tolerable in five or more of the seven patients in the first stage, then the enrollment would thus be increased to a total of 20 patients. If less than five tolerable cases were recorded, then the trial would be changed to a lower dose level chemotherapy (level 2). In level 2, the dose of the cisplatin would be reduced to 35 mg m−2 , and the treatment schedule would be similar to that of level 1. The safety and tolerability then would be determined based on the first seven patients. If more than five of the first seven patients received four
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Table 1 Patient characteristics. Characteristics
Number (n = 21)
Median age (range) Gender (male/female)
61 (45–76) 14/7
Pathological stage (%) IB IIA IIB IIIA
10 (48) 2 (10) 4 (19) 5 (24)
Histologic features (%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Adenosquamous carcinoma
11 (52) 5 (24) 4 (19) 1 (5)
ECOG performance status (0/1)
19/2
cycles of adjuvant chemotherapy, then an additional 13 patients would be accrued for a total of 20 patients. If less than five tolerable cases were recorded in the first seven patients of level 2, then this trial would be terminated because of an unacceptable feasibility (Fig. 1). The institutional review board at all the institutions approved this protocol, and all patients provided their written informed consent before recruitment into the study. 2.2. Eligibility criteria Eligible patients had pathologically documented NSCLC in stage IB, II or IIIA. They underwent a complete surgical resection consisting of a segmentectomy, lobectomy or bi-lobectomy with mediastinal lymph node dissection. Other inclusion criterion was an age range of 20–80 years; no history of a previous operation, chemotherapy or radiotherapy; and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients with a history of concurrent malignancy disease (apart from adequately treated carcinoma in situ) or other previous history of malignancy within the last 5 years were excluded. Additional eligibility criteria included adequate bone marrow functions (i.e., white blood cell count, 4000–12,000 mm−3 ; neutrophil count, ≥2000 mm−3 ; platelets, ≥100,000 mm−3 ; hemoglobin, ≥9.5 g dL−1 ), adequate liver and renal function (i.e., creatinine ≤1.5 mg dL−1 ; total bilirubin <1.5 mg dL−1 ; hepatic enzymes <2.5 times the upper normal limit), adequate respiratory function (i.e., a partial pressure of oxygen (PaO2 ) ≥60 torr or oxygen saturation by pulse oximetry (SpO2 ) ≥90%). All eligible patients received adjuvant chemotherapy within 12 weeks after surgery. 2.3. Treatment schedule Gemcitabine 1000 mg m−2 and cisplatin 40 mg m−2 were given intravenously on days 1 and 8 every 4 weeks for a maximum of four
cycles. The dose of gemcitabine (1000 mg m−2 ; days 1 and 8) was the same as in the FACS trial. The dose of cisplatin was the same as in the FACS trial (80 mg m−2 ), however, cisplatin was administered separately (40 mg m−2 ; days 1 and 8) in the current regimen. Patients were premedicated with 5-hydroxytryptamine-3 receptor antagonists and 16 mg dexamethasone. Complete blood cell counts were measured before the beginning of the next course. If the neutrophil count was less than 1500 mm−3 , white blood cell count was less than 2000 mm−3 , platelets were less than 100,000 mm−3 , hemoglobin was less than 9.5 g dL−1 , or there was a grade 3 nonhematological toxic effect, the next course would be postponed. If these conditions were not resolved within 4 weeks, the patient was withdrawn. Cisplatin was reduced to 35 mg m−2 for febrile leucocytopenia, grade 4 neutropenia greater than or equal to 5 days, grade 4 thrombocytopenia, and grade 3 nonhematological toxic effects. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0). 3. Results Six tolerable cases were recorded among the first seven patients, therefore the enrollment was increased to 20 patients. Because the 20th patient had been enrolled from two hospitals at the same time, the study enrolled 21 patients. Between January 2007 and June 2008, 21 patients were enrolled in this study. The patient characteristics are shown in Table 1. The median age was 61 years (range, 45–76). Fourteen patients (67%) were men, and 19 patients had ECOG PS 0. Adenocarcinoma was observed in 11 cases (52%). None of the patients received either induction or postoperative radiotherapy. A total of 82 cycles of chemotherapy were delivered for 21 patients. Ninety-five percent (20 of 21) received all four cycles of adjuvant chemotherapy. Therefore, because 14 or more patients had received all four cycles of adjuvant chemotherapy, this regimen could therefore be proven to be feasible. Chemotherapy compliance in the four cycles was 95%. Among those given four cycles, 85% (17 of 20) received full-dose chemotherapy, and 15% (3 of 20) required a dose reduction at some point. The reasons for the dose reduction were febrile neutropenia (n = 2), and grade 3 fever (n = 1). All three patients who underwent a dose reduction completed the four cycle of therapy; one patient had cycle 4, and two patients had cycles 2, 3 and 4 dose reduced. Eighty-one percent (17 of 21) received four cycles of chemotherapy at a full dose. Although one patient dropped out due to her daughter’s illness during the second cycle, no case was withdrawn as a result of toxicity. The median dose of gemcitabine received was 8000 mg m−2 (100% of the planned dose) with a mean cumulative dose received of 7770 mg m−2 . The median dose of cisplatin received was 320 mg m−2 (100% of the planned dose) with a mean cumulative dose of 309 mg m−2 . The dose intensity was 498 mg m−2 per week
Table 2 Chemotherapy compliance. Characteristics
CDDP (n = 21)
GEM (n = 21)
Patients who completed cycles (%) Cycle 1 Cycle 2 Cycle 3 Cycle 4
21 (100) 21 (100) 20 (95) 20 (95)
21 (100) 21 (100) 20 (95) 20 (95)
Planned dose (mg m−2 ) Median dose (mg m−2 ) Mean Cumulative dose (mg m−2 ) Dose intensity (mg m−2 per week) Relative dose intensity (%)
320 320 (160–320) 309 (160–320) 19.8 (18.1–20) 97 (50–100)
8000 8000 (4000–8000) 7770 (4000–8000) 498 (475–500) 97 (50–100)
Date represent the number of patients (%) or the median (range) unless stated otherwise.
for gemcitabine (99% of planned dose) and 19.8 mg m−2 per week for cisplatin (99% of planned dose). The relative dose intensity was 97% for both gemcitabine and cisplatin (Table 2). Grade 3/4 leucocytopenia and neutropenia were observed in 14% and 33% of the patients, respectively (Table 3). Of these patients, grade 4 leucocytopenia was not observed, and grade 4 neutropenia was found in three cases (14%). Grade 3/4 thrombocytopenia was observed in four cases (20%), but no patients developed significant bleeding associated with thrombocytopenia. Grade 3 decreased hemoglobin was observed in three cases (14%) and only two patients had febrile neutropenia (10%). Severe nonhematological toxic effects from chemotherapy were uncommon. Grade 3 fever was reported by only one patient (5%).
Data from recent randomized trials shows a survival benefit associated with the use of postoperative platinum-based chemotherapy. A British Medical Research Council meta-analysis of cisplatin-based chemotherapy after surgery for stage I through stage III NSCLC showed a 13% reduction in the risk of death and an absolute improvement in survival of 5% at 5 years, but in comparison to surgery alone, the difference was not statistically significant (P = 0.08) [3]. Several randomized trials to evaluate the benefits of adjuvant chemotherapy have been performed based on the result of this meta-analysis. More recently, a large international trial of adjuvant chemotherapy that used cisplatin plus either a vinca alkaloid or etoposide (International Adjuvant Lung Cancer Trial [IALT]) reported a 14% reduction in the risk of death and an absolute improvement in survival of 4.1% at 5 years (P < 0.03) [4]. The Cancer and Leukemia Group B (CALGB) protocol 9633 trial, in which another current adjuvant regimen (paclitaxel plus carboplatin) showed a 12% reduction in mortality at 4 years in stage IB NSCLC [26] and an update with extended follow-up (54 vs 34 months) showed that the improvement in survival was no longer significant [9,27]. The National Cancer Institute of Canada JBR.10 trial demonstrated a significant 15% improvement in overall survival for stages IB–II NSCLC treated with vinorelbine plus cisplatin [5]. The adjuvant Navelbine International Trialist Association (ANITA) trial reported a significant 5.4% survival advantage at 5 years for adjuvant vinorelbine plus cisplatin in patients with resected stages IB–IIIA NSCLC in comparison to surgery alone [6]. Therefore, according to recent advances in postoperative adjuvant chemotherapy, a vinorelbine plus cisplatin regimen improved overall survival in patients with stages II–IIIA NSCLC. However, the completion rate of planned full dose of adjuvant therapy with
Table 4 Chemotherapy compliance and toxicity on recent platinum-doublet adjuvant trials [5,6,23].
4. Discussion
73 85 35 33 275 304 – 309
0 0 0 0 0 0 0 – – 0
400 400 – 320
1 (5%) 0 0 0 0 0 0 – 0 0
45/48* 50 57 81
0 3 (14%) 0 0 0 1 (5%) 0 0 1 (5%) 0
48 CDDP 49 VNR 50 86 95
1 (5%) 7 (33%) 2 (10%) 4 (19%) 6 (29%) 1 (5%) 1 (5%) 6 (29%) 1 (5%) 2 (10%)
4 4 4 4
Nonhematologic toxicity Fever Nausea Vomiting Constipation Fatigue Mucositis-oral cavity Neuropathy Alopecia Hiccoughs Light headedness
CDDP/VNR CDDP/VNR CBDCA/PTX CDDP/GEM
0 3 (14%) 2 (10%) 0 0
JBR.10 (n = 242) ANITA (n = 407) CALGB (n = 344) Present study (n = 21)
3 (14%) 4 (19%) 2 (10%) 3 (14%) 2 (10%)
Grade 3/4 neutropenia (%)
7 (34%) 6 (29%) 2 (10%) 5 (24%) –
Cumulative dose of CDDP (mg m−2 )
5 (23%) 3 (14%) 5 (23%) 8 (38%) –
Planned dose of CDDP (mg m−2 )
Hematologic toxicities Leucocytopenia Neutropenia Thrombocytopenia Anemia Febrile neutropenia
Completed cycle 4 at full dose
Grade 4
Chemotherapy compliance (%)
Grade 3
No. of cycles
Grade 2
Chemotherapy
Grade 1
Trial
Characteristics (n = 21)
Treatment-related death (%)
Table 3 Worst adverse event by NCI grading (NCI-CTC version 3).
JBR.10, National Cancer Institute of Canada Clinical Trial Group trial JBR.10; ANITA, Adjuvant Navelbine International Trialist Association 01; CALGB, Cancer and Leukemia Group B; CDDP, Cisplatin; VNR, Vinorelbine; CBDCA, Carboplatin; PTX, Paclitaxel; GEM, Gemcitabine. * Percent randomized (N = 242), 45% of the patients completed four cycles of chemotherapy. Percent treated (N = 231), 48% of the patients completed cycle 4. The cumulative dose is the mean dose.
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0.8 2 0 0
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vinorelbine plus cisplatin was low in the adjuvant setting, only 48% in the JBR.10 and 50% in the ANITA trial. Moreover, some treatmentrelated deaths were observed in these trials, seven patients (2%) in the ANITA, two (0.8%) in the JBR.10, and seven (0.8%) in the IALT. Although no treatment-related death was observed in CALGB9633, this trial did not show a survival benefit [9]. Since the patients who undergo a complete resection for NSCLC have a possibility of a cure without adjuvant chemotherapy, treatment-related death in adjuvant chemotherapy should be avoided. The current study investigated the feasibility and toxicity of gemcitabine and split-dose cisplatin regimen for complete resected NSCLC. Compliance with the chemotherapy protocol was excellent in the current regimen in comparison to cisplatin plus vinorelbine in an adjuvant setting of NSCLC with 95%/95% in 3/4 cycles of completed cases, while compliance was 58%/48% in the JBR.10 and 61%/50% in the ANITA trials (Table 4). Moreover, the compliance of this trial exceeded the CALGB 9633, which investigated adjuvant chemotherapy with the combination of carboplatin and paclitaxel. The compliance in the CALBG 9633 revealed 86% of patients received four cycles of therapy, and 57% received the four cycles at the full dose. High compliance was observed in this study in comparison to previous trials, one of the reasons is that it is likely that patients accrued to a single arm feasibility study when adjuvant therapy is considered to be the standard of care are likely to be more compliant compared to a randomized trial. Moreover, in JBR.10 the most common cause was patient refusal, rather than protocol specified toxicity. There was only one patient in whom the treatment was discontinued because of treatment rejection by the patients (due to her daughter’s illness). These dates suggest that the low frequency of chemotherapy rejection by the patients in this study might have been the reason for the high compliance. The cumulative dose was 7770 mg m−2 for gemcitabine and 309 mg m−2 for cisplatin. The relative dose intensity was 97% for both gemcitabine and cisplatin in the present study. As for the dose of cisplatin, the planned dose and the mean cumulative dose were 400 mg/304 mg in the ANITA and 400 mg/275 mg in the JBR.10 trials [28]. Although the planned dose of cisplatin (320 mg m−2 ) in the current study was less than both the ANITA and the JBR.10 trials (400 mg m−2 ), the mean cumulative dose (309 mg m−2 ) exceeded that of the ANITA (304 mg m−2 ) and the JBR.10 trials (275 mg m−2 ; Table 4). The completion rate of this four cycle chemotherapy regimen was higher than the adjuvant chemotherapy trials previously reported. Split-dose cisplatin may result in low toxicity and good compliance. In fact, comparison to ANITA, grade 3/4 adverse events occurred less frequently in the JBR.10 trial in which cisplatin was administered as a split-dose of 50 mg m−2 given on days 1 and 8. Cisplatin administered as a split-dose might therefore be preferable as an adjuvant therapy. Hematological toxicity was significantly less in comparison to a cisplatin and vinorelbine combination; especially when considering that grade 3/4 neutropenia which was observed in 33% of the participants. In the JBR.10 and the ANITA trials, the rate of grade 3/4 neutropenia was 73% and 85%, respectively. In the CALGB 9633 trial with a carboplatin and paclitaxel combination, the rate of grade 3/4 neutropenia was 35%. There were some treatment-related deaths in adjuvant trials (two [0.8%] in JBR.10, seven [0.8%] in IALT, and seven [2%] in ANITA). However, no treatment-related deaths were observed in the current trial or in the CALGB 9633 trial. Therefore, the current regimen was as safe as carboplatin-based therapy. In conclusion, adjuvant chemotherapy with gemcitabine and split-dose cisplatin showed both a favorable feasibility and acceptable toxicity in Japanese NSCLC patients, and a higher survival benefit may therefore be expected. However, whether the combination used in this regimen is superior to the other regimens still needs to be elucidated in a phase III trial.
Conflict of interest None of the authors have any conflicts of interest associated with this study. Acknowledgments The following institutions participated in the study: Fujinomiya General Hospital, Fujinomiya, Japan, Shimota H and Yajima K; Yaizu City Hospital, Yaizu, Japan, Kobayashi R; Iwata City Hospital, Iwata, Japan, Ohi S and Matsushita K. References [1] Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–7. [2] Goya T, Asamura H, Yoshimura H, Kato H, Shimokata K, Tsuchiya R, et al. Prognosis of 6644 resected non-small cell lung cancers in Japan: a Japanese lung cancer registry study. Lung Cancer 2005;50:227–34. [3] 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 randomised clinical trials. BMJ 1995;311:899–909. [4] Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351–60. [5] Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589–97. [6] Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzales-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719–27. [7] Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552–9. [8] Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of 5 randomized trials including 4584 patients. J Clin Oncol 2006;24:366S [abstr. 7008]. [9] Strauss GM, Herndon 2nd JE, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043–51. [10] Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996;2:521–30. [11] Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis BJ. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995;22:72–9. [12] Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 2005;47:69–80. [13] Vogl SE, Berenzweig M, Camacho F, Greenwald E, Kaplan BH. Efficacy study of intensive cis-platin therapy in advanced non-small cell bronchogenic carcinoma. Cancer 1982;50:24–6. [14] Wilke H, Achterrath W, Schmoll HJ, Gunzer U, Preusser P, Lenaz L. Etoposide and split-dose cisplatin in small-cell lung cancer. Am J Clin Oncol 1988;11:572– 8. [15] Gandara DR, DeGregorio MW, Wold H, Wilbur BJ, Kohler M, Lawrence HJ, et al. High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in non-small-cell lung cancer. J Clin Oncol 1986;4:1787–93. [16] Gandara DR, Wold H, Perez EA, Deisseroth AB, Doroshow J, Meyers F, et al. Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen. J Natl Cancer Inst 1989;81:790–4. [17] Kim JH, Lee DH, Shin HC, Kwon JH, Jung JY, Kim HJ, et al. A phase II study with gemcitabine and split-dose cisplatin in patients with advanced non-small cell lung cancer. Lung Cancer 2006;54:57–62. [18] Nagourney RA, Brewer CA, Radecki S, Kidder WA, Sommers BL, Evans SS, et al. Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol 2003;88:35–9. [19] Nagourney RA, Link JS, Blitzer JB, Forsthoff C, Evans SS. Gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed breast cancer patients. J Clin Oncol 2000;18:2245–9. [20] Hussain SA, Stocken DD, Riley P, Palmer DH, Peake DR, Geh JI, et al. A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer. Br J Cancer 2004;91:844–9.
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Feasibility study of adjuvant chemotherapy with gemcitabine and split-dose cisplatin for completely resected non-small-cell lung cancer Kazuhito Funai a,b,∗ , Kazuya Takamochi b , Toru Itaya b , Takahiro Mochizuki b , Toru Nakamura c , Futoru Toyoda c , Kim Yong-Il d , Kazuyoshi Sasaki a , Shigeru Momiki a , Tsuyoshi Takahashi e , Hiroshi Neyatani e , Kazuya Suzuki b a
Division of Thoracic Surgery, Hamamatsu Medical Center, Hamamatsu, Japan First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan c Division of General Thoracic Surgery, Hamamatsu, Japan d Palliative Medicine, Seirei Hamamatsu General Hospital, Hamamatsu, Japan e Division of Cardiac and Thoracic Surgery, Fujieda Municipal General Hospital, Fujieda Japan b
a r t i c l e
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Article history: Received 31 March 2009 Received in revised form 25 May 2009 Accepted 26 May 2009 Keywords: Adjuvant chemotherapy Chemotherapy compliance Gemcitabine Non-small-cell lung cancer Split-dose cisplatin Treatment compliance
a b s t r a c t Introduction: Recent clinical trials have shown significant survival benefits from postoperative adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC). However, due to the comparatively low compliance in recent clinical trials, this study investigated the feasibility of adjuvant chemotherapy with gemcitabine plus split-dose cisplatin for completely resected NSCLC. Methods: Gemcitabine at a dose of 1000 mg m−2 and cisplatin at 40 mg m−2 were given intravenously on days 1 and 8 every 4 weeks for a maximum of four cycles. According to Simon’s minimax two-stage design, if the regimen was judged to be safe and tolerable in five or more of the seven patients in the first stage, then enrollment would increase to a total of 20 patients. The feasibility of this regimen was proven if four cycles of chemotherapy were completed in more than 14 patients. The primary endpoint was the compliance to this regimen in the adjuvant setting, while the secondary endpoints were safety and toxicity. Results: The regimen was judged to be safe and tolerable in the first stage, and therefore 21 patients were accrued as planned. Twenty patients (95%) received four cycles of chemotherapy; therefore chemotherapy compliance in the four cycles was 95%. The relative dose intensity was 97% for both gemcitabine and cisplatin. Grade 3/4 toxicities of neutropenia occurred in 33% and thrombocytopenia in 20%. Nonhematological adverse effects were extremely rare. Conclusion: Adjuvant chemotherapy with gemcitabine and split-dose cisplatin showed a favorable feasibility and acceptable toxicity in Japanese NSCLC patients. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Surgery is the most effective therapeutic modality for curing cancer, but the postoperative survival of patients who undergo a complete resection for NSCLC remains unsatisfactory, with a 5year survival ranging from only 30 to 60% [1,2]. Distant metastases usually lead to death, even if a complete resection is performed. Therefore, some effective adjuvant chemotherapy should be administered to reduce the risk of recurrence and improve survival.
∗ Corresponding author at: Division of Thoracic Surgery, Hamamatsu Medical Center, 328, Tomitsuka, Naka, Hamamatsu, Shizuoka 432-8580, Japan. Tel.: +81 53 453 7111; fax: +81 53 451 2768. E-mail address: [email protected] (K. Funai). 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.05.018
In 1995, the NSCLC meta-analysis demonstrated a 5% survival benefit at 5 years with cisplatin-based adjuvant chemotherapy in resected NSCLC in comparison to surgery alone (P = 0.08) [3]. This finding prompted the planning of additional randomized trials, and several recent randomized trials and meta-analyses have shown a benefit of adjuvant cisplatin-based chemotherapy on the overall survival in patients with NSCLC [4–9]. In 2008, a Lung Adjuvant Cisplatin Evaluation (LACE) metaanalysis showed the effect of vinorelbine plus cisplatin to be marginally better than the effect of other platinum-doublet combinations [7]. However, the superiority of vinorelbine should be interpreted with caution because the total administered dose of cisplatin was significantly higher in the patients treated with vinorelbine and it was impossible to separate the effect of cisplatin dose from that of the companion drug. Although the completion rate of the planned four cycles of vinorelbine plus cisplatin was
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low (about 50% in JBR.10 [5] and ANITA [6]), vinorelbine associated with a high dose of cisplatin is considered to be the most promising drug combination at this time. If a less toxic cisplatin-based combination regimen can be established with a high completion rate, then a higher survival benefit may be expected. Gemcitabine is a novel nucleoside analogue exercising a wide spectrum of anti-tumoral activity, and in combination with cisplatin has shown activity in NSCLC. The interactions between gemcitabine and cisplatin have been investigated in both in vitro and in vivo studies, and have shown both synergistic and additive effects [10,11]. Therefore, gemcitabine plus cisplatin is one of the most widely used platinum-based combination regimens. Le Chevalier et al. reported that a significant survival benefit of gemcitabine–platinum regimens was shown in their meta-analysis of the first line chemotherapies for locally advanced and metastatic NSCLC patients [12]. Therefore, gemcitabine plus cisplatin may also be effective for NSCLC patients in an adjuvant setting. Moreover, several clinical trials have suggested that a weekly administration of cisplatin might increase its activity with a mild toxicity [13–16]. Splitting the doses of cisplatin over days 1 and 8 increases its activity and reduces the occurrence of emesis and nephrotoxicity [17]. Splitdose cisplatin in combination with gemcitabine showed a good activity with favorable toxicity profiles in patients with ovarian cancer [18], breast cancer [19], and bladder cancer [20]. For advanced NSCLC patients, the first line use of gemcitabine and split-dose cisplatin is active and has been shown to be very well tolerated in several studies [17,21,22]. The Four-Arm Cooperative Study (FACS) in Japan compared the efficacy and toxicity of three platinum-based combination regimens (paclitaxel plus carboplatin, gemcitabine plus cisplatin, and vinorelbine plus cisplatin) with irinotecan plus cisplatin as the reference arm [23]. No statistically significant differences were found in the response rate or overall survival, but gemcitabine plus cisplatin was the most tolerable regimen. Only in the gemcitabine plus cisplatin arm was no treatment-related death observed. From the results of this study, cisplatin at 80 mg m−2 administered on day 1 plus gemcitabine at 1000 mg m−2 administered on days 1 and 8 is effective and commonly used for stage IIIB/IV NSCLC in Japanese patients. Although a significant survival benefit and favorable safety of adjuvant UFT were shown in Japanese patients with stage I lung adenocarcinoma [24], there is little convincing evidence that adjuvant chemotherapy using the platinum-doublet improves the outcome of NSCLC. Due to comparatively low compliance in recent clinical trials in Europe and North America, it is questionable whether Japanese can receive adjuvant platinum-doublet chemotherapy safely as planned. This study investigated the feasibility and toxicity of a gemcitabine and split-dose cisplatin regimen similar to the FACS study for Japanese patients with complete resected stages IB–IIIA NSCLC in an adjuvant setting. 2. Methods 2.1. Study design This trial was an open-labelled, multicenter prospective twostage feasibility study of combination chemotherapy with a regimen of gemcitabine plus split-dose cisplatin in an adjuvant setting for complete resected stages IB–IIIA NSCLC (Fig. 1). The primary endpoint was chemotherapy compliance in all four cycles with gemcitabine and split-dose cisplatin, while the secondary endpoints were safety and toxicity. Fifteen patients had to be accrued for a statistical power of 80% and an alpha-error of 5%, with a threshold feasibility level of 55% (similar to the completion rate of platinum-doublet in the recent
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Fig. 1. A schematic overview of a multicenter prospective two-stage feasibility study of combination chemotherapy with gemcitabine plus split-dose cisplatin in regimen in an adjuvant setting for complete resected stages IB–IIIA NSCLC.
trials) and an expectation feasibility level of 85% (the same as the chemotherapy compliance in the CALGB trial) using Simon’s minimax two-stage design [25]. Assuming several drop-out cases, 20 patients were planned to be accrued for this study. The feasibility of this regimen was evaluated according to Simons’s minimax two-stage design; in other words, feasibility was proven if four cycles of chemotherapy were completed in more than 14 patients. In brief, gemcitabine 1000 mg m−2 and cisplatin 40 mg m−2 were given intravenously on days 1 and 8 every 4 weeks for a maximum of four cycles as level 1. If the regimen was judged to be safe and tolerable in five or more of the seven patients in the first stage, then the enrollment would thus be increased to a total of 20 patients. If less than five tolerable cases were recorded, then the trial would be changed to a lower dose level chemotherapy (level 2). In level 2, the dose of the cisplatin would be reduced to 35 mg m−2 , and the treatment schedule would be similar to that of level 1. The safety and tolerability then would be determined based on the first seven patients. If more than five of the first seven patients received four
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Table 1 Patient characteristics. Characteristics
Number (n = 21)
Median age (range) Gender (male/female)
61 (45–76) 14/7
Pathological stage (%) IB IIA IIB IIIA
10 (48) 2 (10) 4 (19) 5 (24)
Histologic features (%) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Adenosquamous carcinoma
11 (52) 5 (24) 4 (19) 1 (5)
ECOG performance status (0/1)
19/2
cycles of adjuvant chemotherapy, then an additional 13 patients would be accrued for a total of 20 patients. If less than five tolerable cases were recorded in the first seven patients of level 2, then this trial would be terminated because of an unacceptable feasibility (Fig. 1). The institutional review board at all the institutions approved this protocol, and all patients provided their written informed consent before recruitment into the study. 2.2. Eligibility criteria Eligible patients had pathologically documented NSCLC in stage IB, II or IIIA. They underwent a complete surgical resection consisting of a segmentectomy, lobectomy or bi-lobectomy with mediastinal lymph node dissection. Other inclusion criterion was an age range of 20–80 years; no history of a previous operation, chemotherapy or radiotherapy; and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients with a history of concurrent malignancy disease (apart from adequately treated carcinoma in situ) or other previous history of malignancy within the last 5 years were excluded. Additional eligibility criteria included adequate bone marrow functions (i.e., white blood cell count, 4000–12,000 mm−3 ; neutrophil count, ≥2000 mm−3 ; platelets, ≥100,000 mm−3 ; hemoglobin, ≥9.5 g dL−1 ), adequate liver and renal function (i.e., creatinine ≤1.5 mg dL−1 ; total bilirubin <1.5 mg dL−1 ; hepatic enzymes <2.5 times the upper normal limit), adequate respiratory function (i.e., a partial pressure of oxygen (PaO2 ) ≥60 torr or oxygen saturation by pulse oximetry (SpO2 ) ≥90%). All eligible patients received adjuvant chemotherapy within 12 weeks after surgery. 2.3. Treatment schedule Gemcitabine 1000 mg m−2 and cisplatin 40 mg m−2 were given intravenously on days 1 and 8 every 4 weeks for a maximum of four
cycles. The dose of gemcitabine (1000 mg m−2 ; days 1 and 8) was the same as in the FACS trial. The dose of cisplatin was the same as in the FACS trial (80 mg m−2 ), however, cisplatin was administered separately (40 mg m−2 ; days 1 and 8) in the current regimen. Patients were premedicated with 5-hydroxytryptamine-3 receptor antagonists and 16 mg dexamethasone. Complete blood cell counts were measured before the beginning of the next course. If the neutrophil count was less than 1500 mm−3 , white blood cell count was less than 2000 mm−3 , platelets were less than 100,000 mm−3 , hemoglobin was less than 9.5 g dL−1 , or there was a grade 3 nonhematological toxic effect, the next course would be postponed. If these conditions were not resolved within 4 weeks, the patient was withdrawn. Cisplatin was reduced to 35 mg m−2 for febrile leucocytopenia, grade 4 neutropenia greater than or equal to 5 days, grade 4 thrombocytopenia, and grade 3 nonhematological toxic effects. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 3.0). 3. Results Six tolerable cases were recorded among the first seven patients, therefore the enrollment was increased to 20 patients. Because the 20th patient had been enrolled from two hospitals at the same time, the study enrolled 21 patients. Between January 2007 and June 2008, 21 patients were enrolled in this study. The patient characteristics are shown in Table 1. The median age was 61 years (range, 45–76). Fourteen patients (67%) were men, and 19 patients had ECOG PS 0. Adenocarcinoma was observed in 11 cases (52%). None of the patients received either induction or postoperative radiotherapy. A total of 82 cycles of chemotherapy were delivered for 21 patients. Ninety-five percent (20 of 21) received all four cycles of adjuvant chemotherapy. Therefore, because 14 or more patients had received all four cycles of adjuvant chemotherapy, this regimen could therefore be proven to be feasible. Chemotherapy compliance in the four cycles was 95%. Among those given four cycles, 85% (17 of 20) received full-dose chemotherapy, and 15% (3 of 20) required a dose reduction at some point. The reasons for the dose reduction were febrile neutropenia (n = 2), and grade 3 fever (n = 1). All three patients who underwent a dose reduction completed the four cycle of therapy; one patient had cycle 4, and two patients had cycles 2, 3 and 4 dose reduced. Eighty-one percent (17 of 21) received four cycles of chemotherapy at a full dose. Although one patient dropped out due to her daughter’s illness during the second cycle, no case was withdrawn as a result of toxicity. The median dose of gemcitabine received was 8000 mg m−2 (100% of the planned dose) with a mean cumulative dose received of 7770 mg m−2 . The median dose of cisplatin received was 320 mg m−2 (100% of the planned dose) with a mean cumulative dose of 309 mg m−2 . The dose intensity was 498 mg m−2 per week
Table 2 Chemotherapy compliance. Characteristics
CDDP (n = 21)
GEM (n = 21)
Patients who completed cycles (%) Cycle 1 Cycle 2 Cycle 3 Cycle 4
21 (100) 21 (100) 20 (95) 20 (95)
21 (100) 21 (100) 20 (95) 20 (95)
Planned dose (mg m−2 ) Median dose (mg m−2 ) Mean Cumulative dose (mg m−2 ) Dose intensity (mg m−2 per week) Relative dose intensity (%)
320 320 (160–320) 309 (160–320) 19.8 (18.1–20) 97 (50–100)
8000 8000 (4000–8000) 7770 (4000–8000) 498 (475–500) 97 (50–100)
Date represent the number of patients (%) or the median (range) unless stated otherwise.
for gemcitabine (99% of planned dose) and 19.8 mg m−2 per week for cisplatin (99% of planned dose). The relative dose intensity was 97% for both gemcitabine and cisplatin (Table 2). Grade 3/4 leucocytopenia and neutropenia were observed in 14% and 33% of the patients, respectively (Table 3). Of these patients, grade 4 leucocytopenia was not observed, and grade 4 neutropenia was found in three cases (14%). Grade 3/4 thrombocytopenia was observed in four cases (20%), but no patients developed significant bleeding associated with thrombocytopenia. Grade 3 decreased hemoglobin was observed in three cases (14%) and only two patients had febrile neutropenia (10%). Severe nonhematological toxic effects from chemotherapy were uncommon. Grade 3 fever was reported by only one patient (5%).
Data from recent randomized trials shows a survival benefit associated with the use of postoperative platinum-based chemotherapy. A British Medical Research Council meta-analysis of cisplatin-based chemotherapy after surgery for stage I through stage III NSCLC showed a 13% reduction in the risk of death and an absolute improvement in survival of 5% at 5 years, but in comparison to surgery alone, the difference was not statistically significant (P = 0.08) [3]. Several randomized trials to evaluate the benefits of adjuvant chemotherapy have been performed based on the result of this meta-analysis. More recently, a large international trial of adjuvant chemotherapy that used cisplatin plus either a vinca alkaloid or etoposide (International Adjuvant Lung Cancer Trial [IALT]) reported a 14% reduction in the risk of death and an absolute improvement in survival of 4.1% at 5 years (P < 0.03) [4]. The Cancer and Leukemia Group B (CALGB) protocol 9633 trial, in which another current adjuvant regimen (paclitaxel plus carboplatin) showed a 12% reduction in mortality at 4 years in stage IB NSCLC [26] and an update with extended follow-up (54 vs 34 months) showed that the improvement in survival was no longer significant [9,27]. The National Cancer Institute of Canada JBR.10 trial demonstrated a significant 15% improvement in overall survival for stages IB–II NSCLC treated with vinorelbine plus cisplatin [5]. The adjuvant Navelbine International Trialist Association (ANITA) trial reported a significant 5.4% survival advantage at 5 years for adjuvant vinorelbine plus cisplatin in patients with resected stages IB–IIIA NSCLC in comparison to surgery alone [6]. Therefore, according to recent advances in postoperative adjuvant chemotherapy, a vinorelbine plus cisplatin regimen improved overall survival in patients with stages II–IIIA NSCLC. However, the completion rate of planned full dose of adjuvant therapy with
Table 4 Chemotherapy compliance and toxicity on recent platinum-doublet adjuvant trials [5,6,23].
4. Discussion
73 85 35 33 275 304 – 309
0 0 0 0 0 0 0 – – 0
400 400 – 320
1 (5%) 0 0 0 0 0 0 – 0 0
45/48* 50 57 81
0 3 (14%) 0 0 0 1 (5%) 0 0 1 (5%) 0
48 CDDP 49 VNR 50 86 95
1 (5%) 7 (33%) 2 (10%) 4 (19%) 6 (29%) 1 (5%) 1 (5%) 6 (29%) 1 (5%) 2 (10%)
4 4 4 4
Nonhematologic toxicity Fever Nausea Vomiting Constipation Fatigue Mucositis-oral cavity Neuropathy Alopecia Hiccoughs Light headedness
CDDP/VNR CDDP/VNR CBDCA/PTX CDDP/GEM
0 3 (14%) 2 (10%) 0 0
JBR.10 (n = 242) ANITA (n = 407) CALGB (n = 344) Present study (n = 21)
3 (14%) 4 (19%) 2 (10%) 3 (14%) 2 (10%)
Grade 3/4 neutropenia (%)
7 (34%) 6 (29%) 2 (10%) 5 (24%) –
Cumulative dose of CDDP (mg m−2 )
5 (23%) 3 (14%) 5 (23%) 8 (38%) –
Planned dose of CDDP (mg m−2 )
Hematologic toxicities Leucocytopenia Neutropenia Thrombocytopenia Anemia Febrile neutropenia
Completed cycle 4 at full dose
Grade 4
Chemotherapy compliance (%)
Grade 3
No. of cycles
Grade 2
Chemotherapy
Grade 1
Trial
Characteristics (n = 21)
Treatment-related death (%)
Table 3 Worst adverse event by NCI grading (NCI-CTC version 3).
JBR.10, National Cancer Institute of Canada Clinical Trial Group trial JBR.10; ANITA, Adjuvant Navelbine International Trialist Association 01; CALGB, Cancer and Leukemia Group B; CDDP, Cisplatin; VNR, Vinorelbine; CBDCA, Carboplatin; PTX, Paclitaxel; GEM, Gemcitabine. * Percent randomized (N = 242), 45% of the patients completed four cycles of chemotherapy. Percent treated (N = 231), 48% of the patients completed cycle 4. The cumulative dose is the mean dose.
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0.8 2 0 0
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vinorelbine plus cisplatin was low in the adjuvant setting, only 48% in the JBR.10 and 50% in the ANITA trial. Moreover, some treatmentrelated deaths were observed in these trials, seven patients (2%) in the ANITA, two (0.8%) in the JBR.10, and seven (0.8%) in the IALT. Although no treatment-related death was observed in CALGB9633, this trial did not show a survival benefit [9]. Since the patients who undergo a complete resection for NSCLC have a possibility of a cure without adjuvant chemotherapy, treatment-related death in adjuvant chemotherapy should be avoided. The current study investigated the feasibility and toxicity of gemcitabine and split-dose cisplatin regimen for complete resected NSCLC. Compliance with the chemotherapy protocol was excellent in the current regimen in comparison to cisplatin plus vinorelbine in an adjuvant setting of NSCLC with 95%/95% in 3/4 cycles of completed cases, while compliance was 58%/48% in the JBR.10 and 61%/50% in the ANITA trials (Table 4). Moreover, the compliance of this trial exceeded the CALGB 9633, which investigated adjuvant chemotherapy with the combination of carboplatin and paclitaxel. The compliance in the CALBG 9633 revealed 86% of patients received four cycles of therapy, and 57% received the four cycles at the full dose. High compliance was observed in this study in comparison to previous trials, one of the reasons is that it is likely that patients accrued to a single arm feasibility study when adjuvant therapy is considered to be the standard of care are likely to be more compliant compared to a randomized trial. Moreover, in JBR.10 the most common cause was patient refusal, rather than protocol specified toxicity. There was only one patient in whom the treatment was discontinued because of treatment rejection by the patients (due to her daughter’s illness). These dates suggest that the low frequency of chemotherapy rejection by the patients in this study might have been the reason for the high compliance. The cumulative dose was 7770 mg m−2 for gemcitabine and 309 mg m−2 for cisplatin. The relative dose intensity was 97% for both gemcitabine and cisplatin in the present study. As for the dose of cisplatin, the planned dose and the mean cumulative dose were 400 mg/304 mg in the ANITA and 400 mg/275 mg in the JBR.10 trials [28]. Although the planned dose of cisplatin (320 mg m−2 ) in the current study was less than both the ANITA and the JBR.10 trials (400 mg m−2 ), the mean cumulative dose (309 mg m−2 ) exceeded that of the ANITA (304 mg m−2 ) and the JBR.10 trials (275 mg m−2 ; Table 4). The completion rate of this four cycle chemotherapy regimen was higher than the adjuvant chemotherapy trials previously reported. Split-dose cisplatin may result in low toxicity and good compliance. In fact, comparison to ANITA, grade 3/4 adverse events occurred less frequently in the JBR.10 trial in which cisplatin was administered as a split-dose of 50 mg m−2 given on days 1 and 8. Cisplatin administered as a split-dose might therefore be preferable as an adjuvant therapy. Hematological toxicity was significantly less in comparison to a cisplatin and vinorelbine combination; especially when considering that grade 3/4 neutropenia which was observed in 33% of the participants. In the JBR.10 and the ANITA trials, the rate of grade 3/4 neutropenia was 73% and 85%, respectively. In the CALGB 9633 trial with a carboplatin and paclitaxel combination, the rate of grade 3/4 neutropenia was 35%. There were some treatment-related deaths in adjuvant trials (two [0.8%] in JBR.10, seven [0.8%] in IALT, and seven [2%] in ANITA). However, no treatment-related deaths were observed in the current trial or in the CALGB 9633 trial. Therefore, the current regimen was as safe as carboplatin-based therapy. In conclusion, adjuvant chemotherapy with gemcitabine and split-dose cisplatin showed both a favorable feasibility and acceptable toxicity in Japanese NSCLC patients, and a higher survival benefit may therefore be expected. However, whether the combination used in this regimen is superior to the other regimens still needs to be elucidated in a phase III trial.
Conflict of interest None of the authors have any conflicts of interest associated with this study. Acknowledgments The following institutions participated in the study: Fujinomiya General Hospital, Fujinomiya, Japan, Shimota H and Yajima K; Yaizu City Hospital, Yaizu, Japan, Kobayashi R; Iwata City Hospital, Iwata, Japan, Ohi S and Matsushita K. References [1] Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111:1710–7. [2] Goya T, Asamura H, Yoshimura H, Kato H, Shimokata K, Tsuchiya R, et al. Prognosis of 6644 resected non-small cell lung cancers in Japan: a Japanese lung cancer registry study. Lung Cancer 2005;50:227–34. [3] 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 randomised clinical trials. BMJ 1995;311:899–909. [4] Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004;350:351–60. [5] Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589–97. [6] Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzales-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006;7:719–27. [7] Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552–9. [8] Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung Adjuvant Cisplatin Evaluation (LACE): a pooled analysis of 5 randomized trials including 4584 patients. J Clin Oncol 2006;24:366S [abstr. 7008]. [9] Strauss GM, Herndon 2nd JE, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043–51. [10] Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996;2:521–30. [11] Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis BJ. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol 1995;22:72–9. [12] Le Chevalier T, Scagliotti G, Natale R, Danson S, Rosell R, Stahel R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 2005;47:69–80. [13] Vogl SE, Berenzweig M, Camacho F, Greenwald E, Kaplan BH. Efficacy study of intensive cis-platin therapy in advanced non-small cell bronchogenic carcinoma. Cancer 1982;50:24–6. [14] Wilke H, Achterrath W, Schmoll HJ, Gunzer U, Preusser P, Lenaz L. Etoposide and split-dose cisplatin in small-cell lung cancer. Am J Clin Oncol 1988;11:572– 8. [15] Gandara DR, DeGregorio MW, Wold H, Wilbur BJ, Kohler M, Lawrence HJ, et al. High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in non-small-cell lung cancer. J Clin Oncol 1986;4:1787–93. [16] Gandara DR, Wold H, Perez EA, Deisseroth AB, Doroshow J, Meyers F, et al. Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen. J Natl Cancer Inst 1989;81:790–4. [17] Kim JH, Lee DH, Shin HC, Kwon JH, Jung JY, Kim HJ, et al. A phase II study with gemcitabine and split-dose cisplatin in patients with advanced non-small cell lung cancer. Lung Cancer 2006;54:57–62. [18] Nagourney RA, Brewer CA, Radecki S, Kidder WA, Sommers BL, Evans SS, et al. Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol Oncol 2003;88:35–9. [19] Nagourney RA, Link JS, Blitzer JB, Forsthoff C, Evans SS. Gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed breast cancer patients. J Clin Oncol 2000;18:2245–9. [20] Hussain SA, Stocken DD, Riley P, Palmer DH, Peake DR, Geh JI, et al. A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer. Br J Cancer 2004;91:844–9.
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