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© 2000 American Society for Clinical Oncology Tirapazamine Plus Cisplatin Versus Cisplatin in Advanced Non–Small-Cell Lung Cancer: A Report of the International CATAPULT I Study GroupFrom the Asklepios Fachkliniken München-Gauting, Gauting, and Hospital Grosshansdorf, Hamburg, Germany; Sanofi Research, Malvern, and University of Pennsylvania Medical Center, Philadelphia, PA; Royal Prince Alfred Hospital, Camperdown, New South Wales, Royal Adelaide Hospital, Adelaide, South Australia, and Monash Medical Centre, Clayton, Victoria, Australia; University Hospital, Malmö, and Sahlgrenska University Hospital, Gothenburg, Sweden; Clatterbridge Centre for Oncology, Merseyside, Churchill Hospital, Oxford, and Glasgow Royal Infirmary, Glasgow, United Kingdom; Sanofi Recherche, Gentilly Cedex, France; The Clarksville Regional Hematology-Oncology Group, Clarksville, TN; Royal Victoria Hospital and Hospital Notre Dame, Montreal, Quebec, Canada; Washington DC Veterans Affairs Medical Center, Washington, DC; and Veterans Affairs Medical Center–West Los Angeles, Los Angeles, CA. Address reprint requests to Joachim von Pawel, MD, Leiter der Abteilung Onkologie, Asklepios-klinik, Robert-Koch-Allee 2, Gauting, Germany D82131.
PURPOSE: A phase III trial, Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non–Small-Cell Lung Tumors (CATAPULT I), was designed to determine the efficacy and safety of tirapazamine plus cisplatin for the treatment of non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated NSCLC were randomized to receive either tirapazamine (390 mg/m2 infused over 2 hours) followed 1 hour later by cisplatin (75 mg/m2 over 1 hour) or 75 mg/m2 of cisplatin alone, every 3 weeks for a maximum of eight cycles.
RESULTS: A total of 446 patients with NSCLC (17% with stage IIIB disease and pleural effusions; 83% with stage IV disease) were entered onto the study. Karnofsky performance status (KPS) was CONCLUSION: The CATAPULT I study shows that tirapazamine enhances the activity of cisplatin in patients with advanced NSCLC and confirms that hypoxia is an exploitable therapeutic target in human malignancies.
THE MAJORITY OF THE approximately 129,000 patients diagnosed with non–small-cell lung cancer (NSCLC) in the United States in 1998 received chemotherapy.1 Even for elderly patients with advanced NSCLC, chemotherapy provides a measurable but modest survival benefit over best supportive care.2 Cisplatin monotherapy, used since the mid-1970s to treat NSCLC, yields response rates of approximately 9% to 17%, depending on dose, the characteristics of the patient population, and the definition of response (eg, requirement of confirmation).3-6 To improve response rates, cisplatin has been combined with other chemotherapeutic agents, such as etoposide, paclitaxel, gemcitabine, and vinorelbine. These combinations have resulted in response rates of 14% to 40% and median survival between 6 and 9 months.4-8 Combination chemotherapy may also be associated with life-threatening toxicities, leading to dose reductions and treatment delays, which may compromise the therapeutic benefit.4,5,9 In addition, long-term toxicity, such as peripheral neuropathy, ototoxicity, and nephrotoxicity associated with cisplatin, remains a concern.6,7 Resistance to chemotherapy may be associated with tumor hypoxia.10 NSCLC and other solid tumors have long been recognized to include significant areas of profound hypoxia.11,12 Innovative therapies specifically designed to target hypoxic cells may enhance treatment results in NSCLC. Tirapazamine (1,2,4-benzotriazin-3-amine 1,4-dioxide; Sanofi Research, Malvern, PA) is a cytotoxic agent with high selective toxicity toward hypoxic cells.13,14 In preclinical in vitro and in vivo models, tirapazamine has been shown to display significant schedule-dependent synergy with cisplatin.15-17 NSCLC tumors, because of their high degree of hypoxia, are a particularly promising target for the evaluation of the combination therapy of tirapazamine plus cisplatin. Single-agent tirapazamine had little antitumor activity in a phase I clinical trial.18 However, a response rate of 29.2% was observed in 41 patients with advanced NSCLC when escalating doses of tirapazamine were added to cisplatin (75 mg/m2 every 3 weeks).19 Preliminary data from phase II clinical trials in patients with advanced NSCLC treated with tirapazamine plus cisplatin also demonstrated improved response rates and survival compared with historical results for cisplatin monotherapy.19-21 An integrated analysis of phase I/II trial results involving 132 patients with advanced NSCLC found remarkable consistency across trials, with the rate of confirmed objective response of 25%, median survival of 38.9 weeks, and 1-year survival of 37.5% in patients who received tirapazamine plus cisplatin.22 This comparative phase III trial (called Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non–Small-Cell Lung Tumors [CATAPULT I]) was conducted to evaluate the efficacy and safety of the combination of tirapazamine plus cisplatin versus cisplatin monotherapy in patients with advanced NSCLC.
Study Design This international, multicenter, randomized, controlled, phase III study, conducted at 47 sites, compared the efficacy and safety of tirapazamine plus cisplatin with cisplatin monotherapy for the treatment of patients with previously untreated advanced NSCLC. Patients entering the study were stratified by disease stage (IIIB and IV), tumor assessability (measurable and evaluable tumors), and Karnofsky performance status (KPS; 60% and 70% to 100%).
Patient Selection The study protocol was reviewed and approved by the institutional review board at each study site. This study was conducted according to the Declaration of Helsinki and in agreement with national, local, and institutional guidelines. Written informed consent was obtained from all patients.
Treatment
The doses of both tirapazamine and cisplatin could be delayed or reduced in response to toxicity. Dose reduction or treatment delay of cisplatin in either arm of the study was guided by serum creatinine levels and the presence of cisplatin-induced peripheral neuropathy
Study Objectives
Assessment Patients received complete physical examinations before each cycle of therapy, including determination of KPS and vital signs. In addition, hearing (audiograms), color vision (standard pseudoisochromatic plates: red/green, blue/yellow), and visual acuity (Early Treatment Diabetic Retinopathy Study Test) were assessed at baseline and before cycles 3, 5, and 7. All patients were evaluated for tumor response at the beginning of alternate cycles. Adverse events were recorded as mild to severe using a modified National Cancer Institute four-point toxicity scale, including a special scale for muscle cramps, and grouped by body systems. Information such as day of onset, resolution, and potential for cumulative toxicity was also collected and analyzed. Adverse events attributed to cisplatin or tirapazamine were of special interest and analyzed in depth.
Statistical Analysis
Demographics A total of 446 patients with advanced NSCLC were randomized, 223 to receive tirapazamine plus cisplatin and 223 to receive cisplatin alone; 438 were evaluable for safety and 437 for efficacy. Two patients did not have NSCLC on examination and eight did not receive treatment. One of the patients without NSCLC received one cycle of treatment and was included in the safety analysis. The two treatment arms were well balanced for demographic and prognostic characteristics (Table 1). Overall, this was a high-risk population, characterized by a greater than 80% proportion of stage IV disease. All but eight patients with stage IIIB disease had pleural effusion, as per protocol-defined eligibility. Almost 10% of patients entered the study with a compromised performance status (KPS = 60%) and nearly 14% had a history of brain metastases.
Patients received a total of 815 cycles of tirapazamine plus cisplatin and 823 cycles of cisplatin monotherapy. The mean total cumulative dose of cisplatin was comparable in both treatment arms: 505.7 mg for patients who received tirapazamine plus cisplatin versus 495.3 mg for patients who received cisplatin monotherapy. Fifty-two percent of patients who received tirapazamine plus cisplatin and 53% of patients who received cisplatin monotherapy completed at least four cycles of therapy. Treatment delays were observed in less than 10% of cycles 2 through 8 for both treatment arms. The dose-intensity of cisplatin was similar in both treatment arms. Cisplatin dose reduction occurred in 2% of cycles for cisplatin monotherapy, giving a mean dose-intensity of 24.0 mg/m2/wk (range, 16.7 to 29.0 mg/m2/wk). For tirapazamine plus cisplatin, the dose of cisplatin was reduced in 5% of cycles, giving a mean dose-intensity of 23.3 mg/m2/wk (range, 0 to 26.2 mg/m2/wk). The dose of tirapazamine was reduced in 12% of cycles, and the doses of both tirapazamine and cisplatin were reduced in less than 3% of cycles.
Efficacy
Both the maximal response rate (27.5% v 13.7%) and the rate of confirmed responses (20.2% v 6.9%) were significantly higher for tirapazamine plus cisplatin versus cisplatin alone (P = .001) (Table 3). The median time to progression, 12.9 weeks for patients who received tirapazamine plus cisplatin compared with 11.6 weeks for patients who received cisplatin monotherapy, was significantly longer (P = .0076) (Fig 2).
Changes in KPS, analyzed by three distinct statistical methods, showed no significant differences between the two treatment arms (area under the curve, P = .410; rank order at 24 weeks, P = .96; data not shown). The time to first occurrence of a  10% decrease in KPS is shown in Fig 3 (log-rank test, P = .358). The addition of tirapazamine to cisplatin did not compromise overall performance status compared with the cisplatin monotherapy group.
Safety The number of patients reporting adverse events was similar between treatment arms (P = .317). Few patients had grade 3 or 4 toxicities (Table 4). Fifty-eight patients who received tirapazamine plus cisplatin reported grade 4 adverse events, compared with 45 patients who received cisplatin monotherapy. The incidence and severity of cisplatin-associated adverse events or cumulative toxicity, such as nephrotoxicity, peripheral neuropathy, tinnitus, or chronic ototoxicity, were not changed by coadministration of tirapazamine. Adverse events, such as neutropenia or other hematologic toxicities, were notably absent in both treatment arms of this study. No clinically important differences were observed between treatment arms (Table 5).
The most frequently reported adverse events (all grades), nausea and vomiting, occurred significantly more often in patients who received tirapazamine plus cisplatin (P = .001). Nausea occurred in 189 (86.3%) of 219 patients and vomiting in 179 (81.7%) of 219 patients who received tirapazamine plus cisplatin. The median time to onset in this treatment arm was less than 1 day for both adverse events, with median duration of 3 days. Nausea occurred in 68.5% (150 of 219) and vomiting in 45.7% (100 of 219) of patients who received cisplatin monotherapy, with both a median time to onset and median duration of 3 days. The added toxicity from tirapazamine was acute in nature. Most of these adverse events were mild to moderate. Other adverse events reported by patients who received tirapazamine plus cisplatin included diarrhea, intermittent muscle cramping, abnormal vision, acute, transient hearing loss, fatigue, and rash. Diarrhea, observed in 59.4% (130 of 219) of patients who received tirapazamine plus cisplatin, was acute and transient, generally beginning less than 1 day after therapy. Approximately 75% of cases resolved within 1 day. In contrast, only 11.4% (25 of 219) of patients who received cisplatin monotherapy experienced diarrhea (P = .001). Muscle cramping was mostly associated with tirapazamine plus cisplatin, occurring in 49.3% (108 of 219) of patients compared with 3.7% (eight of 219) of patients who received cisplatin monotherapy (P = .001). This adverse event was characterized by rapid onset (median time to onset, 1 day) and rapid resolution (median, 1 day). Intermittent muscle cramping occurred more often during cycles 1 and 2, with no evidence of cumulative toxicity. Only 45% of patients who experienced muscle cramping in cycle 1 reported a recurrence in later cycles. Special monitoring was provided to detect adverse events involving hearing and vision. Two distinct patterns of hearing loss were observed in this trial. Ototoxicity (hearing loss at high frequencies and tinnitus) attributed to cisplatin was persistent and characterized by delayed onset after the start of treatment. There was no excess of this type of ototoxicity in the tirapazamine-plus-cisplatin group. An additional pattern of hearing loss attributed to tirapazamine was characterized by rapid onset (median, 1 day) and short duration (median, 1 day). This acute and reversible hearing loss was across all frequencies, showed no evidence of being cumulative, did not predispose to cisplatin-induced chronic ototoxicities, and typically did not reoccur after the first cycle. Quantitative measurements of visual acuity and color vision at 2-month intervals did not reveal differences between the treatment arms. This monitoring was motivated by the preclinical findings of a retinal lesion in dogs exposed to tirapazamine. Fifty abnormal vision adverse events (22.8%) were reported by patients who received tirapazamine plus cisplatin, compared with 21 (9.6%) by patients who received cisplatin monotherapy (P = .001). Blurred vision, decreased visual acuity, visual disturbance, and flickering in the eye, the most common abnormal vision adverse events, occurred in both treatment arms. All other reported events occurred in one patient each. These events had a median time to onset of 2 days and a median duration of 7.5 days. Approximately 80% of abnormal vision adverse events in both treatment arms resolved by the end of the study. No evidence of late-onset cumulative toxicity was observed. No correlation could be established between these symptoms and abnormalities in objective testing of visual acuity or color perception. The number of early-onset toxicities associated with tirapazamine plus cisplatin did not seem to have a negative impact on treatment delivery or KPS. There was no clinically significant difference in the incidence of potentially life-threatening events between tirapazamine plus cisplatin and cisplatin monotherapy. Overall, more deaths were reported during the study for patients who received cisplatin monotherapy than for patients who received tirapazamine plus cisplatin (33 of 219 [15%] v 20 of 219 [9%]). No treatment-related deaths were associated with tirapazamine administration. Two deaths from renal failure, one in each treatment arm, were attributed to cisplatin.
Hypoxia is one of the most common manifestations of the abnormal biologic context of tumors, including NSCLC.12 The presence of tumor hypoxia can profoundly influence the success of radio- or chemotherapeutic regimens for cancer treatment,23 and it has been proposed that therapies specifically designed to target hypoxic tumor cells may enhance treatment results.24 In preclinical models, tirapazamine shows significant synergy with cisplatin, largely through a cellular interaction between the two drugs that is dependent on hypoxia.25 In CATAPULT I, the increased efficacy of tirapazamine plus cisplatin was quantified by significant increases in response rate, time to progression, and survival compared with cisplatin monotherapy, thus establishing that tirapazamine is an enhancer of cisplatin activity in NSCLC. In addition, because the activity of tirapazamine depends on the presence of hypoxia, these results confirm that hypoxia is a clinically meaningful mechanism of cisplatin resistance in NSCLC. When the results of CATAPULT I are compared with other clinical trials examining chemotherapeutic regimens in patients with previously untreated stage IIIB or IV NSCLC, study-specific details and differences in study populations with prognostic implications must be considered. Cisplatin monotherapy has served as the comparator arm in three contemporary phase III trials. The values for response rate and survival for cisplatin monotherapy in the CATAPULT I trial are consistent with other reported values, despite differences in patient populations, ie, inclusion of subjects with brain metastases and a KPS of 60 at baseline.4-6 All in all, the international scope of CATAPULT I, the inclusion of higher-risk patients, and the consistent values for cisplatin monotherapy give credence to the robustness of results observed for the tirapazamine-plus-cisplatin treatment group. Overall survival and response rates for tirapazamine plus cisplatin are consistent with the results observed in three phase II trials as well as with the integrated analyses of those trials.19-22 Furthermore, the observed efficacy is comparable to currently available therapies, making tirapazamine plus cisplatin a viable option for treatment of NSCLC.4-8 Another observation from CATAPULT I is that while tirapazamine enhanced the efficacy of cisplatin against NSCLC, it did not change the frequency, severity, or chronology of cisplatin-associated damage to normal tissues, such as nephrotoxicity, ototoxicity, or peripheral nephropathy, and did not compromise cisplatin-dose delivery. We interpret this finding as further evidence for the selective action of tirapazamine in hypoxic (tumoral) tissues. Tirapazamine-related adverse events are generally associated with treatment administration and are self-limiting. Acute nausea, vomiting, and diarrhea can be controlled by an oral regimen of a 5-hydroxytryptamine-3 antagonist, dexamethasone, and diphenoxylate-atropine given immediately before tirapazamine infusion. For delayed nausea and vomiting, an oral regimen of metoclopramide and dexamethasone initiated 16 to 18 hours after the administration of tirapazamine and continued twice a day for 3 days may be effective. As noted, muscle cramping, which occurred more frequently in the combination arm, was short-term, self-limiting, and exhibited both rapid onset and rapid resolution. No patients suffered any long-term consequences. The mechanism responsible for the muscle cramping remains unknown. There was no evidence that any tirapazamine-associated toxicity was cumulative in nature, with the possible exception of asthenia/fatigue. No additional myelosuppression was observed. No additional life-threatening toxicity and no toxic deaths were reported. Overall, the additional toxicities of tirapazamine did not compromise the delivery of cisplatin and were not associated with a compromise in performance status. Combinations of cisplatin plus etoposide, vinorelbine, gemcitabine, or paclitaxel for the treatment of advanced NSCLC are associated with significant hematologic toxicity, which may be treatment-limiting.4-8 In contrast, fewer than 25% of patients who received tirapazamine plus cisplatin reported hematologic toxicity of any grade; only 6% of patients reported grade 3/4 toxicity. The absence of hematologic toxicity allows tirapazamine plus cisplatin to serve as the foundation of triple-drug combinations. The initial results from phase I trials have shown that when paclitaxel or vinorelbine is added to a regimen of tirapazamine plus cisplatin, full doses of all three chemotherapeutic agents may be administered with manageable toxicity.26,27 Phase II trials to evaluate the efficacy of these triple combinations have been initiated. Future studies may address the role of tirapazamine in combined-modality regimens or include oral tirapazamine.28 In conclusion, the results of CATAPULT I have established that tirapazamine enhances the efficacy of cisplatin for the treatment of NSCLC, providing significant increases in response rate, time to progression, and survival. While enhancing cisplatin efficacy, tirapazamine does not worsen anticipated cisplatin-induced normal tissue toxicities. It is not associated with myelosuppression at the recommended dose and schedule. The findings from CATAPULT I also confirm that hypoxia is an exploitable therapeutic target in human malignancies.
Members of the International CATAPULT I Study Group—In the United States: Alex Chang, MD, Interlakes Oncology and Hematology PC, Rochester, NY; John Eckhardt, MD, St John’s Mercy Medical Center, St Louis, MO; Peter Eisenberg, MD, Marin Oncology Associates, Greenbrae, CA; John Feigert, MD, Arlington-Fairfax Hematology-Oncology, Arlington, VA; Andrew A. Hertler, MD, Rockwood Clinic P.S., Spokane, WA; Robert Kratzke, MD, Hematology/Oncology, Minneapolis, MN; Alan M. Keller, MD, Warren Cancer Research Foundation/Cancer Care Associates, Tulsa, OK; Kelly Pendergrass, MD, Kansas City Internal Medicine, Kansas City, MO; Keith Skubitz, MD, University of Minnesota Hospital and Clinics, Masonic Cancer Center, Minneapolis, MN; Basel Yanes, MD, Medical Oncology and Hematology, Dayton, OH; James T. Lin, MD, University of Texas Medical Branch, Division of Hematology/Oncology, Galveston, TX; Robert Nickelson, MD, Louisiana State University Medical Center/Shreveport, Shreveport, LA; Thomas Campbell, MD, Sidney Kimmel Cancer Center, San Diego, CA; Brian Pruitt, MD, Don & Sybill Harrington Cancer Center, Amarillo, TX; and Jeffrey K. Giguere, MD, Hematology and Oncology Associates, Greenville, SC. In Canada: John Wilson, MD, Humber Memorial Hospital, Weston, Ontario; Saleem Malik, MD, Thunder Bay Regional Cancer Centre, Thunder Bay, Ontario; Catalin Mihalcioui, MD, Winnipeg Clinic, Winnipeg, Manitoba; and S-C Tang, MD, Dr H. Bliss Murphy Cancer Centre, Health Sciences Centre, St John’s, Newfoundland. In Australia: David Grimes, MD, Royal Brisbane Hospital, Herston, Queensland; John Zalcberg, MD, Austin/Repatriation Medical Centre, Heidelberg, Victoria; Michael Millward, MD, Peter MacCallum Cancer Institute, East Melbourne, Victoria; Michael Green, MD, Royal Melbourne Hospital, Parkville, Victoria; and Russell Basser, MD, Western Hospital, Footscray, Victoria. In Europe: Alison Jones, MD, Royal Free Hospital, London, United Kingdom; Nick Stuart, MD, Ysbyty Gwynedd, Bangor, United Kingdom; Roger Henrikson, MD, Department of Oncology, Umea Center, University Hospital, Umea, Sweden; Ola Brodin, MD, Department of Oncology, Uppsala Center, Academic Hospital, Uppsala, Sweden; Rolf Lewensohn, MD, Karolinska Hospital Center, Radiumhemmet Clinic of General Oncology, Stockholm, Sweden; M. Radermecker, MD, Universite de Liege, Service de Pneumologie, Institut de Pathologie, Domaine Universitaire, Liege, Belgium; and J. Lorenz, MD, Kreiskrankenhaus Luedenscheid, Akas Lehrkrankenhaus der Universitat Bonn, Luedenscheid, Germany.
Supported by Sanofi Pharmaceuticals Inc, New York, NY.
1. Landis SH, Murray T, Bolden S, et al: Cancer statistics, 1998. CA Cancer J Clin 48:6-29, 1998[Abstract] 2. Perrone F, Rossi A, Ianniello GP, et al: Vinorelbine (VNR) plus best supportive care (BSC) vs BSC in the treatment of advanced non-small cell lung cancer (NSCLC) elderly patients (PTS): Results of a phase III randomized trial. Oncol 17:455a, 1998 (abstr 1752) 3. Fossella FV, Lee JS, Hong WK: Management strategies for recurrent non-small cell lung cancer. Oncol 24:455-462, 1997 4. Sandler A, Nemunaitis J, Dehnam C, et al: Phase III study of cisplatin (C) with or without gemcitabine (G) in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:454a, 1998 (abstr 1747) 5. Wozniak AJ, Crowley JJ, Balcerzak SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: A Southwest Oncology Group study. J Clin Oncol 16:2459-2465, 1998[Abstract] 6. Gatzemeier U, von Pawel J, Gottfried M, et al: Phase III comparative study of high-dose cisplatin (HD-CIS) versus a combination of paclitaxel (TAX) and cisplatin (CIS) in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:454a, 1998 (abstr 1748) 7. Belani CP, Natale RB, Lee JS, et al: Randomized phase III trial comparing cisplatin/etoposide versus carboplatin/paclitaxel in advanced and metastatic non-small cell lung cancer (NSCLC). Clin Oncol 17:455a, 1998 (abstr 1751) 8. Crino L, Conte P, DeMarinus F, et al: A randomised trial of gemcitabine cisplatin (GP) versus mitomycin, ifosamide and cisplatin (MIC) in advanced non-small cell lung cancer (NSCLC): A multicenter phase III study. Proc Am Soc Clin Oncol 17:455a, 1998 (abstr 1750) 9. Klastersky J, Sculier JP, Lacroix H, et al: A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small cell lung cancer: European Organization for Research and Treatment of Cancer protocol 07861. Oncol 8:1556-1562, 1990 10. Grau C, Overgaard J: Effect of cancer chemotherapy on the hypoxic fraction of a solid tumor measured using a local tumor control assay. Radiother Oncol 13:301-309, 1988[Medline] 11. Thomlinson RH, Gray LH: The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9:539-549, 1955[Medline] 12. Vaupel PW, Hockel M: Oxygenation status of human tumors, in Vaupel PW, Kelleher DK, Gunderoth M (eds): Tumor Oxygenation. Stuttgart, Germany,Gustav Fischer Verlag, 1995, pp 219-232 13. Zeman EM, Brown JM, Lemmon MJ, et al: SR-4233: A new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys 12:1239-1242, 1986[Medline] 14. Brown JM: SR 4233 (Tirapazamine): A new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer 67:1163-1170, 1993[Medline]
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Brown JM, Giaccia AJ: The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Res 58:1408-1416, 1998 24. Kennedy KA: Hypoxic cells as specific drug targets for chemotherapy. Des 2:181-194, 1987 25. Brown JM, Wang LH: Tirapazamine: Laboratory data relevant to clinical activity. Anticancer Drug Des 13:529-539, 1998[Medline] 26. Gatineau M, Rixe O, Fizazi K, et al: Phase I study of tirapazamine-cisplatin-vinorelbine in patients with inoperable non small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:485a, 1998 (abstr 1865) 27. Ng K, Treat J, O’Dwyer P, et al: A phase I trial of the addition of paclitaxel to tirapazamine (TPZ) and cisplatin in patients with advanced non-small cell lung cancer. Oncol 17:496a, 1998 (abstr 1910) 28. Curran WJ, Movsas B, Hancock S, et al: Phase I trial of oral TirazoneTM (tirapazamine, TPZ) shows good bioavailability and tolerance. Proc Am Soc Clin Oncol 17:208a, 1998 (abstr 802) Submitted March 5, 1999; accepted November 16, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test with significance at the two-sided .05 level. Survival and time-to-event variables were calculated using Kaplan-Meier product-limit estimates and compared between treatment arms using the log-rank test. 
