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Outcomes for Elderly, Advanced-Stage Non–Small-Cell Lung Cancer Patients Treated With Bevacizumab in Combination With Carboplatin and Paclitaxel: Analysis of Eastern Cooperative Oncology Group Trial 4599

Suresh S. Ramalingam, Suzanne E. Dahlberg, Corey J. Langer, Robert Gray, Chandra P. Belani, Julie R. Brahmer, Alan B. Sandler, Joan H. Schiller, David H. Johnson

From the Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh; Fox Chase Cancer Center, Philadelphia, PA; Dana-Farber Cancer Institute, Boston, MA; The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Vanderbilt-Ingram Cancer Center, Nashville, TN; and The University of Texas Southwestern Medical Center, Dallas, TX

Corresponding author: Suresh S. Ramalingam, MD, Emory Winship Cancer Institute, 1365 Clifton Rd, Room C-5090, Atlanta, GA 30322; e-mail: suresh.ramalingam{at}emory.edu

	ABSTRACT

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Purpose Fit elderly patients with advanced non–small-cell lung cancer (NSCLC) benefit from platinum-based, two-drug chemotherapy. Bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) improves survival for advanced, nonsquamous NSCLC, as evidenced in Eastern Cooperative Oncology Group (ECOG) 4599. We conducted a subset analysis of ECOG 4599 to determine the outcome for elderly patients.

Patients and Methods ECOG 4599 randomly assigned patients with advanced nonsquamous NSCLC to PC or to PCB. We analyzed outcome in patients who were at least 70 years of age at the time of study entry. Patient characteristics, efficacy, and toxicity data were compared between PC and PCB for the elderly. Outcomes for elderly and younger patients (< 70 years) treated with PCB were also compared.

Results Among elderly patients (n = 224; 26%), there was a trend towards higher response rate (29% v 17%; P = .067) and progression-free survival (5.9 v 4.9 months; P = .063) with PCB compared with PC, although overall survival (PCB = 11.3 months; PC = 12.1 months; P = .4) was similar. Grade 3 to 5 toxicities occurred in 87% of elderly patients with PCB versus 61% with PC (P < .001), with seven treatment-related deaths in the PCB arm compared with two with PC. Elderly patients had higher incidence of grade 3 to 5 neutropenia, bleeding, and proteinuria with PCB compared with younger patients.

Conclusion In elderly NSCLC patients, PCB was associated with a higher degree of toxicity, but no obvious improvement in survival compared with PC. Data from this unplanned, retrospective analysis justify prospective evaluation of the therapeutic index of PCB regimen in elderly patients.

	INTRODUCTION

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Lung cancer is the leading cause of cancer-related deaths in the United States. An estimated 213,000 new cases of lung cancer will be diagnosed in the year 2007.¹ Non–small-cell lung cancer (NSCLC) accounts for more than 85% of all cases of lung cancer.² Approximately 40% of patients with NSCLC present with advanced-stage disease at the time of diagnosis.¹ The standard treatment for these patients is systemic chemotherapy, which improves both quality of life (QOL) and survival.³ Until recently, platinum or non–platinum based, two-drug regimens were considered the standard of care for advanced NSCLC patients with good performance status (Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0 or 1).

Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF), an important mediator of new blood vessel formation (neoangiogenesis).⁴ Because neoangiogenesis is a critical event for progression of cancer, VEGF-targeted therapies have become an important modality for the treatment of cancer.⁵ A large randomized study conducted by ECOG (ECOG 4599) demonstrated a survival advantage for patients with advanced nonsquamous NSCLC treated with the regimen of bevacizumab, carboplatin and paclitaxel (PCB) versus carboplatin and paclitaxel alone (PC).⁶ The regimen of PCB was associated with a higher incidence of toxicities including neutropenia, hemorrhage, hypertension, and proteinuria, and an increased incidence of treatment-related deaths (TRDs). The results of ECOG 4599 constituted the basis for the US Food and Drug Administration (FDA) approval of the PCB regimen for patients with nonsquamous NSCLC.

On the basis of data from the Surveillance, Epidemiology, and End Results (SEER) database, nearly 50% of all cases of lung cancer occur in the elderly subpopulation (age 70 years). The aging process is associated with several important physiological changes including decrease in renal function, compromised immune responses, and lower marrow regenerative capacity. These have a direct influence on the tolerability of systemic therapy by elderly patients.⁷ Furthermore, the presence of comorbid illness, which is more frequent in elderly patients, has an impact on treatment outcomes. For elderly NSCLC patients, both qualitative and quantitative benefits have been demonstrated with single-agent chemotherapy.⁸ Two-drug combinations appear to have superior efficacy over monotherapy in elderly patients, although the benefit occurs at the expense of added toxicities.⁹ Although prospective elderly-specific randomized clinical trials have not yet been conducted to assess the role of combination regimens versus single agents in this group, retrospective analyses of multiple clinical trials have established the safety and efficacy of platinum-based regimens.^10-13 In ECOG 1594, which compared four different platinum-based doublets, therapeutic benefit was similar in elderly patients and their younger counterparts, with no excess clinical toxicity, although the incidence of myelosuppression was more frequent in elderly patients.¹⁰ Therefore, combination regimens are routinely employed in the United States for elderly NSCLC patients with a good PS. However, as newer treatment options emerge, it is important to evaluate their therapeutic index in the elderly. Therefore we conducted a subset analysis of ECOG 4599 to evaluate the outcomes for elderly patients, comparing results with PCB versus PC, and among those receiving PCB, comparing outcome between patients younger than 70 and 70 years or older.

	PATIENTS AND METHODS

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ECOG 4599 was a large phase III study conducted to determine whether the addition of bevacizumab to standard chemotherapy would result in improved survival for patients with previously untreated advanced nonsquamous NSCLC. Patients (N = 878) were randomly assigned to treatment with carboplatin (area under the curve = 6 mg/mL x min, day 1) and paclitaxel (200 mg/m², day 1) with or without bevacizumab (15 mg/kg, day 1; PCB v PC). Treatment cycles were repeated every 3 weeks and reassessed every 6 weeks. Patients who had stable disease or a response after six cycles in the experimental arm received bevacizumab alone until progression or unacceptable toxicity. Patient cross-over was not allowed. Eligibility criteria included stage IIIB (with pleural or pericardial effusion) or IV NSCLC; ECOG PS of 0 or 1; adequate bone marrow, hepatic, and renal function; and patient willingness to sign informed consent. The study excluded patients with predominant squamous histology, history of major hemoptysis, brain metastasis, recent history of bleeding or thrombotic events, uncontrolled hypertension, and ongoing therapeutic anticoagulation. Patients with measurable and nonmeasurable disease were allowed. All responses were determined using Response Evaluation Criteria in Solid Tumors (RECIST), and toxicity was graded by the National Cancer Institute Common Terminology Criteria, version 2.0. The primary end point of the study was overall survival (OS). The study was carried out in accordance with the Declaration of Helsinki, current FDA Good Clinical Practices, and local institutional ethical and legal requirements.

Elderly Subset Analysis
The objectives of this analysis were to compare the toxicity and efficacy between PC and PCB for the subset of elderly patients enrolled onto ECOG 4599; and to compare the safety and efficacy data between the elderly and younger (age < 70 years) patients. Elderly patients were defined as those at least 70 years of age at the time of study entry.

Statistical Methods
Fisher's exact test was used to examine differences in characteristics between age groups ( 70 v < 70 years) and between treatments (PC v PCB). Response rate, time to progression, OS, incidence of grade 3 to 5 toxicity, and duration of treatment were examined for both age groups in the PC and PCB arms. Progression-free survival (PFS) was defined as the time from random assignment to disease progression or to death without progression. OS was defined as the time from random assignment to death resulting from any cause. Patients without documented progression or death were excluded at the date of the last evaluation. PFS, OS, and duration of response were estimated using the Kaplan-Meier method. Univariate analyses of differences in time-to-event end points were conducted with log-rank tests. Multiple regression was conducted using the Cox proportional hazards models to adjust for the effects of baseline characteristics (stratified on disease measurability, disease stage, prior radiotherapy, and prior weight loss). Adjustments were not made for multiple comparisons, all P values were two sided, and CIs were at the 95% level.

	RESULTS

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Of 878 patients enrolled onto the study, 850 were included in the primary analysis. The details on ineligible patients have been reported previously. Elderly patients accounted for 26% of the study cohort (n = 224), of whom 113 were randomly assigned to the PC arm. Forty-four percent of the elderly were at least 75 years of age and four (1.6%) were 80 years or older. Among patients older than 75 years of age (n = 98), 40 were treated with PC and 58 with PCB. Baseline characteristics for both the elderly and the younger group are described in Table 1. The median age was 74 years for the elderly subgroup (59 years for the younger group). There was a higher proportion of females among the younger group (48%) than in the elderly group (38%, P = .005). There were no major differences in the distribution of histologic subtypes between the PC and PCB arms for both the elderly and younger patients. Although there were a slightly higher proportion of patients with ECOG PS 1 among the elderly, this difference was not statistically significant. More than 85% of the patients were white in both the younger and the elderly groups. Less than 10% of the patients had received prior radiotherapy, and there was no imbalance between the treatment arms. Except for a slightly higher proportion of females (41% v 34%) and those with ECOG PS 1(70% v 60%) in the PCB arm, there were no major imbalances between PCB and PC among the elderly patients.

There was no major difference in the incidence of anemia between the two treatments for the elderly patients (PC, 1.7%; PCB, 0). Neutropenia, fever with grade 3 or 4 neutropenia, and thrombocytopenia were all higher with PCB than PC in the elderly patient population (Table 2). Salient differences in nonhematologic toxicities for elderly patients between PC and PCB are outlined in Table 3. Hemorrhagic events were noted in 7.9% of the elderly patients in the PCB arm compared with 1.7% with PC. Epistaxis (grade 3, 1.8%), hemoptysis (grade 3, 0.9%; grade 5, 1.8%), hematemesis (grade 5, 0.9%), and GI bleeding (grade 3, 2.6%; grade 4, 0.9%) accounted for the hemorrhagic events among elderly receiving PCB. Among metabolic abnormalities, hyponatremia was noted in 5.2% and 2.6% in elderly patients receiving PCB and PC, respectively.

The salient differences in toxicities between the younger and the elderly patients on the PCB arm are outlined in Table 4. In the PC arm, significant differences between the elderly and younger patients were observed for anorexia (elderly, 0.9%; younger patients, 4.9%; P = .05), nausea (elderly, 0; younger, 7.7%; P .001), and vomiting (elderly, 0.9%; younger, 5.9%; P = .03).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Kaplan-Meier curves for (A) overall survival for elderly (PC v PCB), (B) PFS for elderly (PC v PCB), (C) combined overall survival by age groups (PC + PCB), and (D) combined PFS by age groups (PC + PCB). PC, paclitaxel and carboplatin; PCB, bevacizumab, paclitaxel, and carboplatin; PFS, progression-free survival. HR, hazard ratio.

	DISCUSSION

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Elderly NSCLC patients with a good PS are considered candidates for platinum-based combination chemotherapy.¹⁴ With the addition of bevacizumab to chemotherapy, a higher incidence of certain hematologic and nonhematologic toxicities was observed. This necessitated a careful evaluation of both the safety and efficacy data for elderly patients who participated in ECOG 4599. The proportion of elderly patients (age 70 years) enrolled onto ECOG 4599 (26%) is the highest recorded among all ECOG phase III studies for advanced NSCLC. The two previous phase III studies (ECOG 5592 and 1594) had 15% and 20% of patients of age 70 years or older, respectively.^15,16 Although this trend is encouraging, it is clear that elderly patients continue to be underrepresented in clinical trials. It is also noteworthy that the 80 years and older age group accounted for a meager 1.6% of the study population, whereas approximately 11% of all lung cancer patients belong to this age group.¹⁷ Therefore, the applicability of the findings of our analysis to this very elderly subgroup is limited, and it is conceivable that octogenarians might be at an even higher risk of adverse events with three-drug combinations.

This subset analysis demonstrates that elderly patients experienced a higher degree of toxicity with PCB compared with PC, although there were no differences in OS between the two regimens. However, there was a superior response rate and a trend toward improved PFS with PCB. We also noted that elderly patients experienced more toxicity with PCB compared with younger patients. The higher incidence of TRDs with PCB compared with PC in elderly patients is concerning. Among the 15 TRDs recorded in the PCB arm, the incidence in the elderly was 6.3% compared with 2.6% in the younger cohort. This difference was borderline significant. Put another way, 47% of the treatment deaths in the PCB arm occurred in the elderly even though the elderly constituted only 27% of the enrollees in that arm of the study.

Limited reports on studies that utilized bevacizumab-based combinations in other tumor types have yielded mixed results regarding the toxicity profile in elderly patients. In a retrospective chart review of patients with metastatic colorectal cancer who received bevacizumab-based regimens, a trend toward higher incidence of arterial thrombosis and hypertension was noted in the elderly (> 74 years).¹⁸ Another report based on a large community-based colorectal cancer registry noted no increase in the incidence of GI perforation, bleeding/wound healing complications or arterial thromboembolic events between patients in the less than and more than 65 years age groups.¹⁹

To our knowledge, this is the first report on the safety and efficacy (therapeutic index) of a three-drug chemotherapy-targeted agent combination in elderly NSCLC patients. These findings are particularly relevant because most of the ongoing efforts to improve the efficacy of combination chemotherapy for patients with advanced NSCLC involve the addition of a molecularly targeted drug to combination chemotherapy. On the basis of the current analysis, it would be prudent to stratify patients by age in future randomized clinical trials with three-drug combinations (chemotherapy + targeted agent) for NSCLC. Whether 65 or 70 years should be used as the appropriate cutoff continues to be debated. European studies have used 70 years, whereas the North American studies have utilized either 65 or 70 years as the landmark.^9,20,21

The findings are limited by the retrospective, post hoc nature of this analysis. Some or all of the differences could result from potential imbalances in baseline prognostic variables. For instance, higher numbers of patients of age more than 75 years were randomly assigned to PCB compared with PC (58 v 40 patients). This could have accounted for the increased toxicities noted with PCB in the elderly patients. Differences in poststudy therapy between the two treatment arms could have also contributed to the lack of survival advantage with the addition of bevacizumab in elderly patients. Complete data are not available on poststudy therapy administered to patients on ECOG 4599. Imbalances in the distribution of comorbid illness could also be a contributory factor; multiple studies have established this as an important determinant of outcome.^22-24 In addition, baseline QOL and instrumental activities of daily living (IADL) have been reported to influence outcomes for elderly patients with cancer.²⁵ Our analysis did not take these into consideration because the necessary information was unavailable, an issue that needs to be remedied in future trials.

At the very least, these data warrant prospective evaluation of the safety and efficacy of bevacizumab-based regimens in elderly NSCLC patients with careful documentation of baseline QOL, IADL, and comorbid illnesses. A recently reported European study evaluated two different doses of bevacizumab (7.5 mg/kg and 15 mg/kg) in combination with cisplatin and gemcitabine for advanced nonsquamous NSCLC.²⁶ Though the two treatment arms were not powered for direct comparison, they both demonstrated improvements in PFS over chemotherapy alone. No major differences in toxicity were noted between the two doses of bevacizumab. Subset analysis of this study to evaluate the outcome for elderly patients could provide additional information regarding the therapeutic index of bevacizumab-based therapy and also help ascertain the appropriate dose of bevacizumab, particularly in those who are most vulnerable to the toxicities of therapy. If a dose-related reduction in toxicity is noted in elderly patients, then the lower dose could be considered for the treatment of elderly patients.

Another novel approach primed for study in elderly patients is the combination of targeted agents. A recent phase II study for patients with recurrent NSCLC demonstrated promising response and survival results for the combination of bevacizumab and erlotinib.²⁷ Because erlotinib is active as monotherapy for elderly NSCLC patients in the front-line setting,²⁸ the combination of bevacizumab with erlotinib may be a novel alternative approach to bevacizumab-based chemotherapy regimens. Other novel combinations of targeted agents that are currently under evaluation may also be considered in this setting.

In summary, our data provide important information regarding optimal utilization of bevacizumab in elderly patients with NSCLC. It is necessary to exercise caution as we integrate novel agents into standard therapy for elderly patients. Elderly-specific prospective studies are critical to establish the safety of combinations of novel agents for treatment of advanced NSCLC.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.

Employment or Leadership Position: None Consultant or Advisory Role: Suresh S. Ramalingam, Genentech (C); Corey J. Langer, Genentech (C); Julie R. Brahmer, Genentech (C); Alan B. Sandler, Genentech (C); Joan H. Schiller, Bayer, Genentech, AstraZeneca, Pfizer, Merck, Celgene (C) Stock Ownership: None Honoraria: Suresh S. Ramalingam, Genentech; Corey J. Langer, Genentech; Alan B. Sandler, Genentech Research Funding: Corey J. Langer, Genentech; Robert Gray, Genentech; Julie R. Brahmer, Pfizer; Alan B. Sandler, Genentech Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Suresh S. Ramalingam, Corey J. Langer, Chandra P. Belani, Julie R. Brahmer, Alan B. Sandler, Joan H. Schiller, David H. Johnson

Administrative support: Suresh S. Ramalingam

Collection and assembly of data: Suresh S. Ramalingam, Suzanne E. Dahlberg, Robert Gray

Data analysis and interpretation: Suresh S. Ramalingam, Suzanne E. Dahlberg, Corey J. Langer, Robert Gray, Chandra P. Belani, Julie R. Brahmer, Alan B. Sandler, Joan H. Schiller, David H. Johnson

Manuscript writing: Suresh S. Ramalingam, Suzanne E. Dahlberg, Corey J. Langer, Robert Gray, Chandra P. Belani, Julie R. Brahmer, Alan B. Sandler, Joan H. Schiller, David H. Johnson

Final approval of manuscript: Suresh S. Ramalingam, Suzanne E. Dahlberg, Corey J. Langer, Robert Gray, Chandra P. Belani, Julie R. Brahmer, Alan B. Sandler, Joan H. Schiller, David H. Johnson

	NOTES

 
Presented as a poster at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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

	REFERENCES

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Submitted June 20, 2007; accepted September 6, 2007.

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