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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9097-9104 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.3771 Phase III Trial of Paclitaxel Plus Carboplatin With or Without Tirapazamine in Advanced Non–Small-Cell Lung Cancer: Southwest Oncology Group Trial S0003From the University of Kansas Medical Center, Kansas City, KS; Southwest Oncology Group Statistical Center, Seattle, WA; University of California, Davis, Sacramento, CA; Wake Forest University School of Medicine, Winston-Salem, NC; and Louisiana State University, Shreveport, LA. Address reprint requests to Bonnie Granados, Southwest Oncology Group (SWOG-S0003), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: bgranados{at}swog.org
PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m2 in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine. RESULTS: Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003). CONCLUSION: The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.
Lung cancer is the leading cause of cancer deaths in the United States for both men and women. In 2005, it is estimated that 172,600 new patients will be diagnosed, and 163,400 patients will die from their disease.[1] Eighty-five percent of patients with lung cancer have non–small-cell lung cancer (NSCLC), and unfortunately, 50% of these patients present with incurable stage IIIB or IV disease. The overall 5-year survival rate for this subset of patients is 5%, and median survival time is typically 6 to 9 months after standard platinum-based doublet therapy. Clearly, more effective treatment regimens are desperately needed. Despite relatively modest response rates, the platinum compounds cisplatin and carboplatin have consistently demonstrated a positive impact on survival in NSCLC. Recent studies have demonstrated improved survival, quality of life, and symptom control for patients who received platinum-based chemotherapy when compared with best supportive care.[2-4] Platinum-based combination chemotherapy has also been demonstrated to be superior to single-agent therapy.[5] Similarly, platinum-containing combination regimens have resulted in improved survival in the adjuvant therapy of early-stage NSCLC and in combined-modality therapy of stage III disease.[6,7] Over the last 10 years, sequential phase III clinical trials of the Southwest Oncology Group (SWOG) have evaluated new therapeutic approaches to platinum-based therapy for advanced-stage disease. SWOG 9308 compared the combination of vinorelbine and cisplatin with cisplatin alone in patients with advanced and metastatic NSCLC. There was a statistically significant advantage with regard to response rate, progression-free survival, and overall survival for the cisplatin and vinorelbine arm. The 1-year survival rate was 20% for cisplatin alone and 36% for the combination arm. However, there was more hematologic toxicity on the cisplatin and vinorelbine arm of the study. Other toxicities, such as renal insufficiency, ototoxicity, nausea and vomiting, and neuropathy, were similar.[5] This is the first SWOG study to demonstrate a significant advantage of combination therapy compared with cisplatin alone. SWOG 9509 compared the combination of vinorelbine and cisplatin with a combination of paclitaxel and carboplatin in advanced NSCLC. The two regimens were similar in terms of response rates, survival, and quality-of-life issues; however, on the basis of differences in tolerability of the two regimens, the SWOG chose paclitaxel and carboplatin to be the comparator in future phase III trials.[8] Tirapazamine is the prototype of a new class of antineoplastic agents with preferential activity toward hypoxic cells.[9] Preclinical studies in hypoxic tumor models have demonstrated synergistic or additive effects for tirapazamine when evaluated with platinum compounds and taxanes.[10-14] A phase II trial reported by Treat et al[15] demonstrated that tirapazamine at a dose of 260 mg/m2 can be safely added to cisplatin with a response rate of 23%, median survival time of 37 weeks, and 1-year survival rate of 32%. Subsequently, a phase III trial (Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors [CATAPULT] I) demonstrated a survival benefit for the combination of tirapazamine (390 mg/m2) and cisplatin (75 mg/m2) compared with cisplatin alone in patients with advanced NSCLC.[16] Despite using a higher dose of tirapazamine, the combination arm of CATAPULT I demonstrated a 27.5% response rate, median survival time of 34.6 weeks, and a 33% 1-year survival rates; these results are almost identical to those observed in the phase II trial by Treat et al.[15] The toxicity of the tirapazamine plus cisplatin combination was comparable to the toxicity of cisplatin alone, with the exception of acute, transient hearing loss, incremental increase of nausea and vomiting, diarrhea, skin rashes, and muscle cramping. Transient hearing loss has not been reported with a tirapazamine dose of 260 mg/m2 probably because of lower peak plasma concentrations.[17] CATAPULT II, a randomized phase III trial comparing cisplatin and etoposide versus cisplatin and tirapazamine (390 mg/m2), was designed to assess whether tirapazamine could effectively replace a standard chemotherapeutic agent in NSCLC.[18] Unfortunately, this trial failed to demonstrate improvement in both time to progression and overall survival with the substitution of tirapazamine for etoposide. This was, in part, a result of early patient drop out on the tirapazamine arm related to toxicities observed at the 390 mg/m2 dose level. In view of these conflicting results, further preclinical studies were conducted to determine the efficacy of tirapazamine in combination with carboplatin (to avoid overlapping toxicities with cisplatin, such as hearing loss and vomiting) and with newer chemotherapeutic agents such as paclitaxel. An in vivo study in mice examined the interaction between tirapazamine with paclitaxel and carboplatin in two- and three-way combination studies using the MV-522 human lung carcinoma xenograft model. Although tirapazamine as a single agent was ineffective against this human lung tumor model, a substantial increase in tumor growth inhibition was seen in animals treated with the triplet regimen (tirapazamine, paclitaxel, and carboplatin) compared with animals treated with the chemotherapeutic agents alone or in combination. The addition of tirapazamine resulted in a 50% complete response rate, whereas there were no complete responses seen in any regimen that did not contain tirapazamine. Time to tumor doubling was also significantly improved with the addition of tirapazamine. Tirapazamine did not increase the toxicity of paclitaxel, carboplatin, or their combination.[19] To evaluate the clinical relevance of these observations, a National Cancer Institute–sponsored phase I evaluation of paclitaxel, carboplatin, and tirapazamine found that the maximally tolerated dose level of this combination was well tolerated and active at a paclitaxel dose of 225 mg/m2 over 3 hours, carboplatin area under the curve of 6, and tirapazamine dose of 330 mg/m2. Importantly, hearing loss was not problematic at this dose level. The common grade 3 toxicities observed in chemotherapy-naïve patients treated at this recommended dose level included neutropenia, nausea, dehydration, infection, hypotension, rash, and myalgia. The only grade 4 toxicity observed was neutropenia.[20] In this phase I trial, one patient with previously treated NSCLC achieved a complete response lasting nearly 2 years. Therefore, we designed a phase III trial to determine whether the addition of tirapazamine to the combination of paclitaxel and carboplatin offers an advantage in terms of response, survival, and toxicity. Secondary objectives were to compare the toxicity profiles of the two regimens. The paclitaxel and carboplatin dose and schedule were identical to the prior SWOG trial of this combination (S9509).[8] In an attempt to avoid early drop out on the tirapazamine arm, as occurred in the CATAPULT II trial, we incorporated a dose-escalation strategy for tirapazamine starting at 260 mg/m2 and escalating to 330 mg/m2. Other secondary objectives included the collection of archival tissue samples and serum obtained at baseline and at 4 months to evaluate for potential changes in levels of methylated DNA shed from tumor into serum related to treatment. The pretreatment tissue specimen will be used to confirm that a particular gene is methylated in the tumor. In addition, the serum levels of the proteins plasminogen activator inhibitor, vascular endothelial growth factor, insulin-like growth factor–binding protein, and osteopontin will be measured. The genes encoding these proteins have been demonstrated to be upregulated in hypoxic tumor models.[21-23] Serum levels of these proteins will be correlated with the two treatment arms and patient response data. We have received 475 specimens from 230 patients; however, the analysis of these specimens is ongoing, and the results will be presented in a subsequent publication.
Patients All patients entered onto this study had histologically or cytologically confirmed NSCLC (categorized as squamous cell, large cell, adenocarcinoma, or NSCLC not otherwise specified) with stage IV (no brain metastases) or selected stage IIIB disease (positive pleural effusion or multiple ipsilateral lung nodules) by the International Staging System (lung cancer). Other eligibility criteria included the following: measurable or assessable disease; performance status of 0 or 1; neutrophil count  1,500/µL; platelet count the institutional lower limits of normal; hemoglobin 9 mg/dL; serum creatinine less than the institutional upper limit of normal and a calculated or measured creatinine clearance 50 mL/min; bilirubin, AST or ALT, and alkaline phosphatase levels  2x the institutional upper limits of normal or 4x the institutional upper limits of normal if the patient had liver metastases. Patients were excluded if they had grade 2 or higher peripheral neuropathy or prior chemotherapy or biologic therapy. All patients provided written informed consent in accordance with institutional and federal regulations. Stratification at the time of registration was by weight loss (< 5% v 5%), disease stage (IIIB v IV), and lactate dehydrogenase level (normal v abnormal). Patients were also requested to allow submission of serum collected at baseline and at 4 months after starting treatment as well as archival tissue specimens to be used in the proposed translational correlative studies.
Treatment Schedule
Dose Modification
Pretreatment and Follow-Up Studies
Response and Toxicity Criteria
Statistical Considerations
Patient Characteristics Three hundred ninety-seven patients were accrued between November 2000 and November 2002. As a result of rapid accrual, an interim analysis was performed after the accrual of approximately 350 patients, and in November 2002, this analysis determined that the primary objective was not achievable even with full patient accrual ([Table 1]). Therefore, in November 2002, the data monitoring committee recommended the trial to be closed. The remaining patients were accrued between the interim analysis and the trial's eventual closure. Thirty patients (7.5%) were ineligible; nine patients did not have stage IIIB or IV disease, nine patients had insufficient documentation of required staging studies, 10 patients did not meet the prestudy requirements, and two patients had incorrect histology. Therefore, 367 patients were eligible (181 patients on arm 1 and 186 patients on arm 2). Patient characteristics are listed in [Table 2]. There were no statistical differences in any of the characteristics listed between the two groups. A large proportion of patients were white males with stage IV disease. There were seven major protocol deviations on arm 1 (six patients never started protocol treatment and one patient only received a small amount of paclitaxel and then stopped treatment because of an allergic reaction) and four deviations in arm 2 (one patient received a life-threatening carboplatin overdose, one patient never started treatment, one patient had a paclitaxel allergic reaction, and patient had omission of carboplatin during cycle 3).
Response and Survival There was no difference in the objective response rate between the two arms in the subset of patients with measurable disease ([Table 3]). The overall response rate was 26% on arm 1 and 35% on arm 2. One patient (1%) on arm 1 and four patients (2%) on arm 2 achieved a complete response. Partial responses were documented in 25% of patients on arm 1 and 33% of patients on arm 2. Progressive disease was the best response in 19% of patients on arm 1 and 23% of patients on arm 2. The median progression-free survival time was 5 months on both arms ([Fig 1]), and median survival was identical at 9 months, as depicted in [Figure 2].
Toxicity One hundred seventy-six patients on arm 1 and 184 patients on arm 2 were assessable for toxicity ([Table 4]). The tirapazamine-containing arm resulted in significantly increased fatigue, neutropenic fever, hypotension, rash, myalgias, abdominal cramping, vomiting, and transient hearing loss. Twenty patients on the tirapazamine arm developed grade 3 febrile neutropenia compared with six patients on arm 2 (P = .004). Grade 3 and 4 peripheral neuropathy and other grade 3 and 4 nonhematologic toxicities were similar between the two arms. Treatment-related death occurred in five patients on arm 1 and seven patients on arm 2 (P = not significant).
Tolerability Almost 50% of patients on arm 1 were unable to have tirapazamine dose escalated as planned. The primary reason for not escalating the dose was toxicity ([Table 5]). Other reasons included failure to follow the protocol and escalation at cycle 3 rather than cycle 2, and, for one patient, drug supply was an issue. Disease progression or death was the most common reason for early discontinuation of treatment; 59 of 177 patients on arm 1 and 61 of 183 patients on arm 2 stopped therapy because of tumor progression or death ([Table 6]).
It is also demonstrated in [Table 6] that a significant number of patients were removed from study early on because of toxicity or refusal, primarily on the tirapazamine arm. [Table 7] demonstrates that patients on the tirapazamine arm received fewer cycles of therapy and that significantly more patients were removed because of toxicity. Overall, 24% of patients on arm 1 completed therapy as planned compared with 37% of patients on arm 2 (P = .003). Only 12% of patients on the tirapazamine arm received all six cycles of tirapazamine at the planned dose levels. The other patients required a dose reduction, never had the dose escalated, or did not complete all six cycles as planned.
Hypoxic tumor cells have been shown to be resistant to radiotherapy and are variably resistant to conventional chemotherapeutic agents.[19] The difference in radiation sensitivity between aerobic and hypoxic conditions, referred to as the oxygen enhancement ratio, is typically in the range of 2.5 to 3 in human tumors. In the absence of oxygen, radiation-induced radicals, which can cause DNA damage, may be reversed by donation of hydrogen from nonprotein sulfhydryls, providing a mechanism for hypoxia-induced radioresistance.[19] Although these observations provided the basis for early studies attempting to improve radioresponsiveness by the use of hyperbaric oxygen or radiosensitizing agents, such as misonidazole, neither approach has achieved general clinical application. In contrast, clinical studies with the novel hypoxic cytotoxin tirapazamine in NSCLC have yielded promising results.[15-18] Unfortunately, in this randomized phase III trial, we found that the addition of tirapazamine to carboplatin and paclitaxel does not result in improved response, time to progression, or survival but significantly increases the toxicity of the carboplatin and paclitaxel regimen. A significant number of patients could not tolerate the planned dose escalation of tirapazamine. Despite the poor tolerance of adding tirapazamine to the carboplatin and paclitaxel regimen, median survival was the same in both groups. The median survival in this trial compares favorably with other published results and the results of SWOG 9509, in which the median survival time was 8 months for both arms.[8] The control arm in the current trial had a slightly improved response rate (35%) and median survival compared with SWOG 9509, in which the response rate for carboplatin and paclitaxel was 23% and the median survival time was 8 months. Interestingly, more patients were able to complete six cycles of therapy with carboplatin and paclitaxel in this trial than in SWOG 9509 (37% v 27%, respectively). The 24% of patients on the tirapazamine arm who were able to complete all six cycles of therapy compares favorably with the 27% of patients who completed all six cycles of carboplatin and paclitaxel in SWOG 9509. This improvement in the percentage of patients completing carboplatin and paclitaxel therapy could be a result of the slightly different patient population in this study compared with the SWOG 9509 study; in this study, we had slightly more women (37% v 31%, respectively) and more patients with less than 5% weight loss (69% v 51%, respectively). Another factor could be that clinicians are becoming more comfortable with the regimen, and thus, there was improved management of associated toxicity with the older regimen compared with the investigational regimen. The poorer tolerance and decreased ability to complete six cycles of carboplatin, paclitaxel, and tirapazamine therapy could have contributed to the inability to demonstrate an improved outcome. Among the factors that contributed to the disappointing results of this phase III trial is the possibility that tirapazamine likely benefits only those patients with a significant population of hypoxic cells. If a reliable marker for tumor hypoxia were available, it would have been desirable to either stratify patients based on these markers or restrict enrollment only to patients with markers suggestive of significant populations of hypoxic cells. Of interest, in a preliminary analysis of specimens obtained from patients enrolled onto this trial, plasma markers of tumor hypoxia suggested that their predictive values for survival were confined to the tirapazamine arm alone.[32,33] Although these biologic data are preliminary, they support further study of this agent in which patients would be stratified based on the presence or absence of abnormal markers of tumor hypoxia. Another potential factor that may have affected the outcome is that the tirapazamine dose we used was two thirds of the dose used in CATAPULT trials I and II, and the dose of tirapazamine may be more important than we believed it to be. It is also possible that the same mechanisms that lead to tumor hypoxia may have contributed to ineffective intratumoral levels of tirapazamine or that the population of hypoxic cells may not always represent a significant mechanism of resistance to chemotherapy. It has been demonstrated that there is significant heterogeneity in tumor oxygenation from tumor to tumor.[34] It may be more beneficial to target hypoxic sensitizing agents in situations in which the disease is more commonly confined locally, such as in head and neck or cervical cancer, and in which there are data that have demonstrated that tumor tissue hypoxia is directly related to prognosis and treatment response.[35-37] In conclusion, the addition of tirapazamine to paclitaxel and carboplatin does not result in improved response rates or survival in advanced NSCLC compared with paclitaxel and carboplatin alone. Paclitaxel plus carboplatin produced fewer life-threatening toxicities and was more tolerable. Continued evaluation of newer agents and treatment strategies is justified.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the Expanded Participation Project, The EMMES Corporation for study participation.
Supported by the following Public Health Service Cooperative Agreement Grant Nos. awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA46441, CA58416, CA46282, CA35261, CA58658, CA35431, CA45807, CA58882, CA35119, CA67663, CA76447, CA12644, CA63844, CA45808, CA35128, CA20319, CA42777, CA16385, CA45377, CA52654, CA67575, CA35192, CA22433, CA46113, CA37981, CA35176, CA11083, CA74647, CA74811, CA14028, CA27057, CA58861, CA45461, CA35090, and CA58686; also supported in part by Sanofi-Synthelabo. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; and the 10th World Conference on Lung Cancer, Vancouver, British Columbia, Canada, August 10-14, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
