the Department of Geriatric and Respiratory Medicine, and Department of Radiology, Tohoku University School of Medicine, Sendai
    Department of Internal Medicine, Furukawa City Hospital, Furukawa, Japan

    ABSTRACT

    PURPOSE: To investigate the efficacy and safety of nitroglycerin plus vinorelbine and cisplatin in patients with previously untreated stage IIIB/IV non–small-cell lung cancer (NSCLC) as the experimental arm for the next phase III trial.

    PATIENTS AND METHODS: One hundred twenty patients with stage IIIB/IV NSCLC were randomly assigned to vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, with transdermally applied nitroglycerin (25 mg/patient daily for 5 days; arm A) or with placebo patch (arm B) every 3 weeks for a maximum of four cycles in a double-blind and controlled trial. Primary efficacy end points were the best confirmed response rate and time to disease progression (TTP).

    RESULTS: The response rate in arm A (72%; 43 of 60 patients) was significantly higher than that for patients in arm B (42%; 25 of 60 patients; P < .001). Median TTP in arm A was longer than that in arm B (327 v 185 days). No severe adverse effect was recognized for either arm. The rate of grade 1 to 2 headache in arm A (30%; 18 of 60 patients) was significantly higher than that in arm B (2%; one of 60 patients; P < .001, 2 test).

    CONCLUSION: Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

    INTRODUCTION

    Low levels of oxygenation due to relative vascular insufficiency have been demonstrated to exist in solid cancers but not in normal tissues,1-4 and hypoxic conditions in solid cancers are associated with resistance to cancer therapy.5-7 Hypoxia-inducible factor-1 (HIF-1) activates the transcription of many genes that code for proteins involved in angiogenesis, cell growth, metastasis, and resistance to chemotherapy.8-12 Hypoxia in solid cancers promotes stabilization of HIF-1,13 and anticancer therapy to inhibit HIF-1 has been reported recently.12,14,15 The administration of nitric oxide (NO) –donating drugs decreased hypoxia-induced resistance to anticancer drugs in cancer cell lines.16 However, the effects of NO and NO-donating drugs on inhibition of HIF-1 activation during hypoxia remains controversial.17-20

    Isosorbide dinitrate and inducible NO synthase gene transfer have various effects on tumor tissue and cells, including augmentation of oxygen pressure in tumor tissue through an increase in blood flow21; cytotoxicity in tumor cells22,23; programmed cell death that is dependent on position in the cell cycle24; and p53 protein activation, apoptosis, and growth inhibition in cancer cells.20,25 In contrast, NO promotes tumor angiogenesis and tumor progression.26,27

    A variety of anticancer drugs have been developed for treatment of lung cancer and have contributed to prolonged survival.28,29 However, even third-generation regimens such as vinorelbine plus cisplatin (VC) result in survival rates of only 26% to 36% at 1 year and in median overall survival of 8 to 9 months among patients with advanced non–small-cell lung cancer (NSCLC) and good performance status (PS).30-32

    In our preliminary survey, the response rate to chemotherapy using VC was significantly higher in patients with lung cancer and angina pectoris treated with nitroglycerin than in patients with lung cancer who did not have angina pectoris and did not use nitroglycerin treatment (unpublished data). However, the beneficial effects of NO-donating drugs on response to chemotherapy and on time to progression (TTP) in patients with lung cancer have not been reported to date.

    PATIENTS AND METHODS

    Patient Characteristics

    A total of 193 patients with inoperable advanced NSCLC were recruited onto this study, and 120 of 193 patients fit the 15 inclusion criteria (Table 1). Grounds for exclusion at enrollment for 73 of 193 recruited patients were as follows: use of vasodilators including antihypertensive drugs in 41 patients; Eastern Cooperative Oncology Group33 PS  2 in 17 patients; brain metastasis in 12 patients; renal, hematologic, or cardiac dysfunction in three patients.

    The 120 eligible patients were randomly assigned to receive VC with or without nitroglycerin during chemotherapy in a double-blind phase II trial at the Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine (Sendai, Japan), and at the Division of Internal Medicine, Furukawa City Hospital (Furukawa, Miyagi Prefecture, Japan). Enrollment took place between April 2001 and February 2003. The random allocation sequence was generated by a random-number table at the coordinating center at the Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine.

    PS was rated using the Eastern Cooperative Oncology Group scale.33 Staging of NSCLC was determined using computed tomography (CT) scans of the brain, chest, and abdomen, positron emission tomography, gallium-67 citrate scintigraphy, and technetium-99m scintigraphy of the bone. Stage was defined using the revised lung cancer staging system of the American Joint Committee on Cancer.34 Participant characteristics are listed in Table 2.

    Chemotherapy Treatment

    Of the 120 patients, 60 were treated with VC (vinorelbine 25 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) every 3 weeks for a maximum of four cycles with transdermally applied nitroglycerin (25 mg/patient daily for 5 days between 3 days before the start of each cycle of chemotherapy and cycle day 2; arm A). Nitroglycerin transdermal patches (5 to 25 mg/patient daily) are widely and safely used in treatment of coronary artery disease and heart failure.35 Therefore, we used 25 mg/patient nitroglycerin transdermal patches daily as the NO donor. The other 60 patients were treated with VC every 3 weeks for a maximum of four cycles with placebo patches (arm B). Nitroglycerin was used only with first-line chemotherapy.

    Change in Chemotherapy Timing and Dose Adjustments

    Drug administration was postponed for a maximum of 2 weeks if there was incomplete hematologic recovery on day 22 (leukocytes < 2,000/mL and/or platelets < 100,000/mL) or there was persistent grade 2 or more nonhematologic toxicity according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 2.0.36 Dosage of anticancer drugs for the subsequent course was reduced to 80% in the event of grade 3 to 4 nonhematologic toxicity (except nausea, vomiting, and headache). Treatment was stopped if the same toxicity occurred with chemotherapy at a reduced dose level. Nonsteroidal anti-inflammatory drugs were used if nitroglycerin-induced headache occurred.

    Estimation of Response to Treatment and Follow-Up Assessments

    To assess nitroglycerin effects on response to chemotherapy, we compared identifiable tumor sizes with a chest CT scan after the finish of the second and fourth cycles of chemotherapy. Response rate was evaluated by two independent radiologists and an independent oncologist according to WHO criteria.37 Patients were categorized as responders when they experienced either a partial response or a complete response. Patients with no change or progressive disease were categorized as nonresponders.

    Once patients came off protocol treatment, they were evaluated by physical examination every 4 weeks and by CBC, biochemical tests, and chest radiograph every 3 months. If necessary, CT scans of the brain, chest, or abdomen were appropriately performed to assess disease progression. CT scans were reviewed by two independent radiologists and an independent oncologist to confirm disease progression.

    Treatment Toxicity

    Toxic effects of anticancer drugs were graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 2.0.36

    Study Design and Sample Size

    The primary efficacy end point was comparison of response rate and TTP between arms A and B. A secondary efficacy end point was overall survival. Efficacy analyses were based on an intent-to-treat analysis.

    We estimated that we needed to enroll 54 patients per arm on the basis of an experimental-treatment group to confer a power of 80% for a two-sided .05-level test to detect an increase in 1-year progression-free probability of 26% (from 26% to 52%) in the pooled nitroglycerin-treated arm.32,38 Actual accrual was 60 eligible patients and 56 assessable patients for both arms A and B (Fig 1). This is the report of an interim analysis; the final analysis is planned for 2 years from the end of accrual. This study was approved by the Tohoku University Ethics Committee and informed consent was obtained from each subject.

    Measurements of Plasma Vascular Endothelial Growth Factor Levels

    To study nitroglycerin effects on the HIF-1 pathway, we measured plasma levels of vascular endothelial growth factor (VEGF), which is regulated by HIF-1.39 Plasma levels of VEGF were measured as previously described40 before and after 3 days of treatment with transdermally applied nitroglycerin patches (arm A) or placebo patches (arm B).

    Statistical Methods

    For statistical analysis, age, sex, performance status, smoking history, cancer cell type, cancer staging, treatment delivery, anticancer drugs dose-intensity, adverse effects due to chemotherapy, and response rate were compared using Pearson's 2 contingency table analysis (or Fisher's exact probability test whenever appropriate) between arms A and B. Age and smoking history (pack-year) between arms A and B, and plasma VEGF levels before and after use of nitroglycerin in arm A and placebo patches in arm B were compared using the Student's t test. Factors associated with response rate such as age, sex, performance status, cancer cell type, cancer staging, and use of nitroglycerin during chemotherapy were calculated with logistic regression analysis. Relative risks (RRs) and 95% CIs were calculated to assess response rate.

    TTP was defined as the time from date of random assignment to date of disease progression. The probability of remaining free of progression or of surviving was estimated using the Kaplan-Meier product-limit method. P values indicated the significance of differences between arms A and B by log-rank test. Overall survival was calculated from the date of random assignment to the date of death or a cutoff date for patients alive at the time of closure of the data set.

    Multivariate analysis by Cox regression analysis was performed to assess the prognostic significance of several variables, including age, sex, performance status, cancer cell type, cancer staging, and use of nitroglycerin combined with anticancer drugs.

    All statistical analyses in this study were carried out using the Stat View program (SAS Institute Inc, Cary, NC). Results of interim significance tests were not considered significant unless the P values were less than .001.

    RESULTS

    Patient Characteristics

    There were no statistically significant differences in baseline characteristics between arms A and B (Table 2).

    Chemotherapy Treatment

    In arm A, 44 (73%) of 60 patients received all four courses of chemotherapy. Of the 44 patients, 17 received chemotherapy at the full prescribed dose, and 10 of 44 received chemotherapy without any modification of dose. Conversely, in arm B, 35 (58%) of 60 patients received all four courses of chemotherapy. Of those 35 patients, 16 received chemotherapy at the full prescribed dose and 12 of 35 received chemotherapy without any modification of dose. The mean number of chemotherapy courses was 3.52 for arm A and 3.27 for arm B. There were no significant differences between arms in dose of anticancer drugs or the number of chemotherapy courses (Table 3).

    Treatment Toxicity

    In first-line chemotherapy, the frequency of adverse effects grade  3 in arm A did not differ from that in arm B (Table 4). 36 The rate of grade 1 (15 of 60 patients) and grade 2 (3 of 60) headache in arm A (30%; 18 of 60) was significantly higher than that in arm B (2%; one of 60; P < .001, 2 test). However, there were no severe headaches of grade  3 in arm A. Conversely, grade 1 hypotension was observed in arm A (5%; three of 60). There was no severe hypotension of grade  3 in arm A during treatment with nitroglycerin.

    There was a high rate of severe neutropenia in arm A (58%; 35 of 60) and arm B (57%; 34 of 60; Table 4). Furthermore, higher frequencies of persistent neutropenia on day 8 were observed in the fourth course in arm A (64%; 28 of 44) and in arm B (63%; 22 of 35). Therefore, the start timing of the fourth course of chemotherapy was postponed for some of the patients in arm A (48%; 21 of 44) and arm B (40%; 14 of 35).

    Response Rate

    Table 5 shows the response rate for arms A and B: the response rate in arm A (72%; 43 of 60 patients) was significantly higher than that in arm B (42%; 25 of 60; odds ratio = 3.5; 95% CI, 1.7 to 7.6; P < .001). Conversely, the rate of no change in arm A (13%; eight of 60) was lower than that in arm B (35%; 21 of 60; odds ratio = 0.29; 95% CI, 0.1 to 0.7; P = .006). The rate of progressive disease in arm A did not differ from that in arm B (Table 5).

    The use of nitroglycerin (RR = 4.3; 95% CI, 1.8 to 10.5; P = .001) and squamous cell carcinoma cell type (RR = 2.6; 95% CI, 1.0 to 6.5; P = .049) were associated positively with response rate in logistic regression analysis (Table 6).

    TTP

    The median follow-up period was 326 days (range, 32 to 1,380 days). Median TTP in arm A was 327 days (range, 32 to 1,151 days) compared with 185 days (range, 32 to 998 days) in arm B; use of nitroglycerin during chemotherapy (hazard ratio [HR] = 2.1; 95% CI, 1.3 to 3.2; P = .002) was associated with prolongation of TTP even after adjustment for age, sex, cancer cell type, and cancer staging in the Cox regression method. High performance status (PS 0; HR = 1.9; 95% CI, 1.4 to 2.7; P < .001) was also associated with prolongation of TTP. Kaplan-Meier analysis showed that progression-free probability in arm A was higher than that in arm B (P = .006; Fig 2).

    Survival

    We confirmed 100 deaths within the total of 120 patients by February 2005. In arm A, we confirmed that 46 of 60 patients had died and that 10 of 60 patients were alive at the end of the follow-up period, with four of 60 patients lost to follow-up. In arm B, we confirmed that 54 of 60 patients had died and that two of 60 patients were alive at the end of the follow-up period, with four of 60 patients lost to follow-up (Fig 1). Median survival time was 413 days (range, 32 to 1,380 days) in arm A, and 289 days (range, 56 to 1,117) in arm B. Treatment with nitroglycerin in arm A (HR = 2.5; 95% CI, 1.6 to 3.9; P < .001) was a significantly good prognostic factor compared with treatment without nitroglycerin even after adjustment for age, sex, cancer cell type, and cancer staging (Table 7). Kaplan-Meier analysis showed that survival probability in arm A was significantly higher than in arm B (P < .001; Fig 3).

    Plasma VEGF Levels

    In arm A patients, plasma VEGF levels after 3 days of treatment with nitroglycerin patches were significantly lower than levels before treatment (mean ± SE, 293 ± 50 v 205 ± 28 pg/mL; n = 6; P = .03). In arm B patients, plasma VEGF levels after 3 days of use of placebo patches did not differ from levels before use (286 ± 47 v 290 ± 48 pg/mL; n = 6; P = .40).

    DISCUSSION

    This randomized phase II trial was designed to evaluate the safety and efficacy of nitroglycerin combined with VC regimen in patients with stage IIIB/IV NSCLC. We demonstrated that treatment with nitroglycerin improved response rate, TTP, and survival time in patients with advanced NSCLC without the appearance of major adverse effects. The response rate in arm B (42%) is consistent with rates given in previous reports.41-43 Furthermore, the response rate in arm A of our study (72%) was more than two times higher than that achieved in patients treated with VC alone in previous reports.41,42 Median TTP and overall survival in arm A were longer than those in arm B (1.8 and 1.4 times, respectively). These findings suggest that use of nitroglycerin during chemotherapy may have beneficial effects on chemosensitivity in patients with NSCLC.

    Although VC is a well-tolerated regimen,41-43 we observed a high rate of severe neutropenia, especially on day 8 in the fourth course in both arm A (58%) and arm B (57%) in the present study. Therefore, we partially postponed the start timing of the fourth course of chemotherapy in both arms. A larger randomized trial is needed to study the toxicity profile in arm A.

    Additional clinical benefit beyond four courses of VC therapy for patients with advanced NSCLC had not been reported at the start of our study. Smith et al44 reported no evidence for additional clinical benefit by continuing mitomycin plus vinblastine and cisplatin beyond three courses in patients with NSCLC. Therefore, in our study, treatment for each arm was to be administered for a maximum of four courses. Additional study is needed to clarify whether there is additional clinical benefit beyond four courses of arm A treatment in patients with NSCLC.

    In this study, there were higher rates of adenocarcinoma and of stage IV patients in arm B compared with arm A, although there were no statistically significant differences between the two arms in univariate analysis. Conversely, histological difference and staging of lung cancer were not associated significantly with response to chemotherapy in multivariate analysis with logistic regression analysis. These findings suggest that high rates of adenocarcinoma and stage IV patients in arm B might not contribute to the poorer response rate for that arm, although the possibility of contribution could not be ruled out.

    The effects of NO donors on HIFs and tumor growth without the use of anticancer drugs are controversial.17-20,26,27 However, NO-donating drugs such as nitroglycerin might reduce resistance to chemotherapy via improvement of hypoxic conditions,10,13,16,21,45-51 reduced HIF-1 stabilization,17-19 direct effects of NO on cancer cells,22-24,52,53 increase in activated p53 protein,20,25,54-56 and via an increase in drug delivery in tumor tissue. In this study, plasma levels of VEGF, an HIF-regulated protein,39,57 after treatment with nitroglycerin for 3 days were lower than levels before nitroglycerin treatment. These findings suggest that reduced levels of plasma VEGF might be associated with mechanisms regarding an increase in response rate in patients treated with nitroglycerin. However, the number of patients whose plasma VEGF levels were measured was very small (n = 6 in each arm), and other HIF-regulated proteins including transforming growth factor alpha and thromobspondin-157 were not examined in this study. Therefore, it is still uncertain what mechanisms contribute to an increase in response rate in patients with NSCLC treated with nitroglycerin. Additional studies are needed to make clear the effects of nitroglycerin.

    In summary, this is the first report demonstrating that combinational treatment with nitroglycerin during chemotherapy may enhance the response rate to VC, elongate the TTP, and improve overall survival in patients with advanced stage IIIB/IV NSCLC without major adverse effects in a randomized phase II trial. VC combined with nitroglycerin and VC alone are feasible and have acceptable toxicity profiles. To validate these provocative results, a prospective randomized phase III trial to evaluate nitroglycerin plus VC is underway in patients with stage IIIB/IV NSCLC.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Hiroyasu Yasuda, Akio Kanda

    Financial support: Hiroyasu Yasuda, Mutsuo Yamaya, Katsutoshi Nakayama

    Administrative support: Hiroyasu Yasuda, Takahiko Sasaki, Akio Kanda

    Provision of study materials or patients: Hiroyasu Yasuda, Katsutoshi Nakayama

    Collection and assembly of data: Hiroyasu Yasuda, Katsutoshi Nakayama, Takahiko Sasaki, Satoru Ebihara, Akio Kanda, Masanori Asada, Daisuke Inoue, Tomoko Suzuki, Tatsuma Okazaki, Hidenori Takahashi, Motoki Yoshida, Kota Ishizawa, Shinsuke Yamanda, Naoki Tomita, Miyako Yamasaki, Akiko Kikuchi, Hiroshi Kubo

    Data analysis and interpretation: Hiroyasu Yasuda, Mutsuo Yamaya, Katsutoshi Nakayama, Akio Kanda, Naoki Tomita, Hidetada Sasaki

    Manuscript writing: Hiroyasu Yasuda, Mutsuo Yamaya, Katsutoshi Nakayama

    Final approval of manuscript: Hiroyasu Yasuda, Mutsuo Yamaya, Katsutoshi Nakayama, Takahiko Sasaki, Satoru Ebihara, Akio Kanda, Masanori Asada, Daisuke Inoue, Tomoko Suzuki, Hidenori Takahashi, Motoki Yoshida, Tomohiro Kaneta, Kota Ishizawa, Shinsuke Yamanda, Naoki Tomita, Miyako Yamasaki, Akiko Kikuchi, Hiroshi Kubo, Hidetada Sasaki

    Acknowledgment

    We thank Grant Crittenden for corrections to the English text.

    NOTES

    Supported in part by a Grant-In-Aid for Scientific Research from the Ministry of Education, Science and Culture (Grant No. 17790524) of the Japanese government (H.Y); a Grant-In-Aid for Scientific Research from the Ministry of Education, Science and Culture (Grant No. 16590732), and the Ministry of Welfare and Labor of the Japanese government (M.Y.); and the Japanese Foundation for Aging and Health (K.Y.).

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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