|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2006.08.9995 on January 16 2007 © 2007 American Society of Clinical Oncology.
Mind Your Elders: Therapeutic Implications of Epidermal Growth Factor Receptor Inhibition in Older Patients With Advanced Non–Small-Cell Lung Cancer
Thoracic Oncology, Fox Chase Cancer Center, Philadelphia, PA Elderly patients with advanced non–small-cell lung cancer (NSCLC) constitute a special therapeutic challenge. Historically, they have been underrepresented in clinical trials, often out of bias or misperception rather than true ineligibility. In addition, the elderly are more likely to have logistical challenges or comorbidities, including renal and hepatic dysfunction, as well as cardiopulmonary disorders and impaired marrow reserve, which limit their opportunities to participate in clinical trials.1,2 "Minding our elders" in this context has two distinct meanings1: taking care of older individuals to the best of our ability2; listening and appreciating the unique insights and expectations of older patients, particularly when it comes to their care and prognosis. The optimal approach toward elderly patients with NSCLC combines both concepts. The automatic initiation of standard platinum-based therapy in the elderly may not necessarily be appropriate, particularly in individuals with significant comorbidities or in fit patients who have therapeutic expectations that differ from their younger counterparts. The frequent failure to apply standard therapy—or any therapy at all to the elderly—is equally inappropriate, particularly if older patients are medically fit and willing to accept toxicities of treatment. Advanced age does not automatically connote compromised performance status or inability to tolerate appropriate therapy. While most US medical oncologists will administer platinum-based combinations to younger individuals with advanced NSCLC, the therapeutic paradigms employed in older individuals are divergent, even in clinicians who share the same practice. In this issue of the Journal of Clinical Oncology, Jackman et al3 have succinctly summarized the results of a Boston-based consortium trial evaluating the role of erlotinib in treatment-naïve, otherwise fit elderly individuals with advanced NSCLC. This is the first elderly-specific trial to specifically assess the role of epidermal growth factor receptor tyrosine kinase inhibition (EGFR TKI) in NSCLC; and it remains one of the relatively few trials to evaluate EGFR TKI in treatment-naïve patients. Based on a landmark phase III trial in the second- and third-line setting in advanced NSCLC, in which erlotinib yielded a greater than 40% improvement in 1-year survival compared with placebo control, this agent is the first EGFR inhibitor to be approved in solid tumor oncology.4 The therapeutic advantage of erlotinib was realized despite the "unselected" nature of the patients enrolled onto that trial, none of whom were picked on the basis of EGFR expression or absence or presence of EGFR mutation. Despite a response rate of only 10% with single-agent erlotinib, Jackman et al3 noted a median progression-free survival rate of 3.5 months and, more impressively, a median overall survival of nearly 11 months. The latter is encouraging in this setting, particularly for a single agent that does not yield the toxicity typically seen with chemotherapy. The study met its primary end point: median survival exceeded a pre-established target of 37 weeks. In addition, the 1- and 2-year survival rates rival results observed in E4599, which established a therapeutic advantage for bevacizumab in combination with chemotherapy compared with standard chemotherapy alone in a more tightly defined population.5 Treatment with erlotinib, as summarized by Jackman et al, was reasonably well-tolerated, although there was one putative treatment-related death from interstitial lung disease.3 The authors properly conclude that this approach needs to be investigated further, ideally in a more targeted population. Based on the results available, these conclusions are unimpeachable. However, before we embrace the empiric use of EGFR TKI prematurely, it is probably best to temper our enthusiasm. In a broader population of patients with good performance status and advanced NSCLC treated with standard platinum doublets, the median survival in cooperative group trials typically ranges between 8 and 10 months,6-9 not much less than that observed in this effort. In addition, some degree of inherent selection bias is likely. It is quite possible that the patients enrolled on the Jackman et al trial were in better shape and more functional than age-equivalent patients who rejected treatment, received standard chemotherapy instead, or were treated elsewhere. In addition, 90% were performance status (PS) 0 to 1, and 50% were women. In advanced NSCLC trials, women typically fare better than men, and the higher-than-usual percentage seen in this study may have a favorably influenced outcome.10 We have very little data regarding baseline comorbidities, quality of life (QoL), and instrumental activities of daily living (IADL), although analyses of the latter are promised. Gridelli et al23,28 have shown that baseline QoL and IADL correlate strongly with prognosis in elderly NSCLC patients treated with chemotherapy.11,12 Others have demonstrated a correlation between comorbidity,13,14 based on the Charlson comorbidity scale, and therapeutic outcome.15 While it is hazardous to extrapolate observations in a PS 2 population to an elderly population, it is difficult to reconcile the results enumerated by Jackman et al3 with the implications of a recent, randomized phase II trial reported by Lilenbaum et al16 in which single-agent erlotinib in treatment-naïve PS 2 patients, appeared potentially inferior to a paclitaxel/carboplatin combination: erlotinib in the Lilenbaum effort yielded a median survival of 6.57 months, while conventional carboplatin and paclitaxel yielded a median survival of 9.66 months.16 Although fewer than 50% of enrollees in the Jackman trial received second- and third-line treatments after experiencing failure with erlotinib, it is conceivable that salvage therapy may have had a beneficial effect on survival. For instance, vinorelbine, which was administered subsequently to nearly 26% of the patients on this trial, demonstrated a clear-cut advantage compared with best supportive care (BSC) in the Elderly Lung Vinorelbine Italian Study (ELVIS) trial11 with a marked improvement in 1-year survival (32% v 14%). Both paclitaxel and gemcitabine in combination with carboplatin have yielded 2-month improvements in survival versus the constituent, nonplatinum single agent.9,17 Pemetrexed, which was given to three individuals after progression on erlotinib,18 has shown de facto therapeutic equivalence to docetaxel, which in turn, in a landmark phase III trial, demonstrated a clear-cut survival advantage compared with BSC in the salvage setting.19 In this vein, it would be helpful to know if outcome in those receiving second-line treatment was superior to that observed in patients who did not receive second-line treatment. It also raises the question of whether initial treatment with erlotinib acts as a "primer," potentially enhancing the efficacy of subsequent cytotoxic therapy. Baselga et al20 have suggested that asynchronous therapy may offer the optimal strategy for integration of chemotherapy and EGFR TKI.20 With regard to "standard" treatment for fit, chemotherapy-naïve elderly patients with NSCLC, two basic schools of thought are operative. One group contends that platinum-based treatment remains the standard, even in the elderly, who are more prone to myelosuppression and other toxicities. Retrospective analyses of prospective clinical trials employing platinum-based doublets have demonstrated similar, if not identical, response and survival rates in those 70 years or older compared with their younger counterparts.21-27 But these conclusions are potentially biased by the selection of hardier individuals for these trials in which elderly enrollees are less likely to be representative of the older population at large. Another group argues, perhaps more persuasively, that monotherapy is the standard. Certainly, level 1 data support this contention. The ELVIS trial established a therapeutic advantage for vinorelbine compared with the best supportive care in treatment-naïve patients, with significantly improved survival and better QoL.11 However, the much larger Multicenter Italian Lung Elderly Study (MILES) trial failed to show an advantage for a nonplatinum combination (gemcitabine and vinorelbine) compared with the individual constituent agents,28 and while a subset analysis of outcome on Cancer and Leukemia Group B (CALGB) 9730, showed a 2-month increase in survival for the elderly receiving combination carboplatin and paclitaxel versus paclitaxel alone, this difference was not statistically significant.9 To date, there have been no dedicated, elderly-specific phase III trials showing a survival advantage for a platinum-based doublet (our standard in younger patients) compared with the nonplatinum constituent. To this end, an ongoing elderly-specific phase III trial in Japan compares docetaxel to combination weekly docetaxel and cisplatin; and the Geriatric Oncology Consortium (GOC) in the United States plans to embark on a trial comparing pemetrexed to combination pemetrexed and carboplatin in the same age group. Until then, monotherapy is a reasonable standard, particularly in those with compromised performance status or multiple comorbidities. How erlotinib fits into this research paradigm remains uncertain. Finally, it behooves investigators to determine the group of patients who are most likely to benefit from EGFR TKI. It has been postulated that studies evaluating trastuzumab in the context of cytotoxic therapy for metastatic breast carcinoma would never have proven positive had they been conducted in an unselected population.29,30 Identifying those most likely to benefit on the basis of 3+ immunohistochemical (IHC) expression or fluorescence in situ hybridization (FISH) positivity has enabled investigators to avoid the use of trastuzumab in those who are unlikely to benefit and to push the envelope in those who harbor the targeted molecular phenotype. In this regard, the positivity of BR21 is doubly remarkable since this study was conducted in an unselected population.3 Recent retrospective data from Hirsch et al31 suggest that those NSCLC patients most likely to benefit with respect to both response and survival have EGFR-positive tumors, either by IHC staining or FISH.31 Those whose tumors are negative on both accounts have extremely low response rates and survival. Jackman et al3 have demonstrated a clear correlation between mutation status and outcome and a negative correlation between ras mutation and response, though not survival. But relatively small percentages of patients harbor mutations for either EGFR32 or ras. If possible, it would be useful to further test tissue from patients on this trial and correlate outcome with EGFR expression by IHC and FISH. Finally, the attractiveness of oral therapy in patients of any age, particularly the elderly, is indisputable. However, erlotinib is an expensive option. One must be mindful of its toxicities, including frequent stereotypical acneiform rash and diarrhea, which, though usually grade 1 or 2, are at least annoying, if not psychologically disturbing.3 In addition, three cases of interstitial lung disease were identified, one of which proved fatal. Fifteen percent of enrollees stopped treatment because of toxicity—far more than the 5% of patients enrolled in BR 21 who curtailed treatment because of adverse effects.4 Finally, the cost of this agent, prorated on a monthly basis, is almost prohibitive. Current expenses in the Delaware Valley of Pennsylvania and New Jersey approach $2,500 per month. From a broader societal perspective, it is not clear if we can afford the price of "success." Unless these financial burdens can be controlled, minding our elders in this context, takes on a much more complex meaning. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or 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. Employment: N/A Leadership: N/A Consultant: Corey J. Langer, Genentech, OSI Pharmaceuticals Stock: N/A Honoraria: N/A Research Funds: Genentech, OSI Pharmaceuticals Testimony: N/A Other: N/A NOTES published online ahead of print at www.jco.org on January 16, 2007. REFERENCES
1. Hutchins LF, Unger JM, Crowley JJ, et al: Under-representation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999 2. Lewis JH, Kilgore ML, Goldman DP, et al: Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 21:1383-1389, 2003 3. Jackman DM, Yeap BY, Lindeman NI, et al: A phase II study of chemo-naïve patients 4. Shepherd FA, Pereira JR, Ciuleanu E, et al: Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353:123-132, 2005 5. Sandler A, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) trial - E4599. J Clin Oncol 23:2S, 2005 (suppl; abstr 4). 6. Kelly K, Crowley J, Bunn PA, et al: A randomized phase III trial of paclitaxel plus carboplatin (PC) versus vinorelbine plus cisplatin (VC) in the treatment of patients with advanced non-small cell lung cancer (NSCLC): A Southwest Oncology Group trial. J Clin Oncol 19:3210-3218, 2001 7. Schiller J, Harrington D, Belani C, et al: Comparison of four chemotherapy regimens for advanced non-small cell lung cancer: ECOG 1594. N Engl J Med 346:92-98, 2002 8. Scagliotti GV, DeMarinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small cell lung cancer. J Clin Oncol 20:4285-4291, 2002 9. Lilenbaum R, Herndon J, List M, et al: Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: The Cancer and Leukemia Group B (study 9730). J Clin Oncol 23:190-196, 2005 10. Jiroutek M, Johnson D, Blum R, et al: Prognostic factors in advanced non-small celllung cancer (NSCLC): Analysis of Eastern Cooperative Oncology Group (ECOG) trials from 1981-1992. Proc Am Soc Clin Oncol 17:461, 1998 (abstr 1774) 11. The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) Group: Effects of vinorelbine on quality of life and survival of elderly patients of advanced non-small cell lung cancer. J Natl Cancer Inst 91:66-72, 1999 12. Perrone F, Gridelli C, Cigolari S, et al: Baseline assessment of quality of life (QoL) is a strong prognostic factor for survival of elderly patients with advanced non-small cell lung cancer (NSCLC): A secondary analysis of the MILES study. Proc Am Soc Clin Oncol 21:337, 2002 (abstr 1346) 13. Extermann M: Measuring comorbidity in older patients. Eur J Cancer 36:453-471, 2000[CrossRef][Medline] 14. Yancik R, Ganz PA, Varricchio CG, et al: Perspectives on comorbidity and cancer in older patients: Approaches to expand the knowledge base. J Clin Oncol 19:1147-1151, 2001 15. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 18:2529-2536, 2000 16. Lilenbaum R, Axelrod R, Thomas S, et al: Randomized phase II trial of single agent erlotinib vs standard chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and performance status of 2. J Clin Oncol 24:369S, 2006 (suppl; abstr 7022) 17. Sederholm C, Hillerdal G, Lamberg K, et al: Phase III trial of gemcitabine plus carboplatin versus gemcitabine in the treatment of locally advanced or metastatic non-small cell lung cancer: The Swedish Lung Cancer Study Group. J Clin Oncol 23:8380-8388, 2005 18. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy J Clin Oncol 22:1589-1597, 2004 19. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000 20. Baselga J: Combining the anti-EGFR agent gefitinib with chemotherapy in non-small-cell lung cancer: How do we go from INTACT to impact? J Clin Oncol 22:759-761, 2004 21. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non-small cell lung cancer: Implications of the Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94:173-181, 2002 22. Bunn P, Lilenbaum R: Chemotherapy for elderly patients with advanced non-small cell lung cancer. J Natl Cancer Inst 95:341-343, 2003 23. Gridelli C, Aapro M, Ardizzoni A, et al: Treatment of advanced non-small cell lung cancer in the elderly: Results of an international expert panel. J Clin Oncol 23:3125-3137, 2005 24. Langer CJ, Vangel M, Schiller J, et al: Age-specific subanalysis of ECOG 1594: Fit elderly patients (70-80 yrs) with NSCLC do as well as younger pts (< 70). Proc Am Soc Clin Oncol 22:639, 2003 (abstr 2569) 25. Kelly K, Giarritta S, Akerley W, et al: Should older patient (pts) receive combination chemotherapy for advanced stage non-small cell lung cancer (NSCLC)? An analysis of Southwest Oncology Trials 9509 and 9308. Proc Am Soc Oncol 20:329, 2001 (abstr 1313) 26. Ramalingam S, Belani CP, Barstis J, et al: Treatment of elderly non-small cell lung cancer (NSCLC) patients with three different schedules of weekly paclitaxel in combination with carboplatin: Sub-analysis of a randomized trial. Proc Am Soc Clin Oncol 22:670, 2003 (abstr 2693) 27. Hensing TA, Peterman AH, Schell MJ, et al: The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV non-small cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 98:779-788, 2003[CrossRef][Medline] 28. Gridelli C, Perrone F, Gallo C, et al: MILES investigators, chemotherapy for elderly patients with advanced non-small cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003 29. Slamon D, Leyland-Jones B, Shah S, et al: Role of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpressed HER2. N Engl J Med 344:783-792, 2001 30. Norton L, Slamon D, Leyland-Jones B, et al: Overall survival (OS) advantage to simultaneous chemotherapy plus the humanized anti-HER2 monoclonal antibody Herceptin in HER2-overexpressing (HER2+) metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 18:127, 1999 31. Hirsch FR, Varella-Garcia N, McCoy J, et al: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol 23:6838-6845, 2005 32. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer –molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
70 years of age treated with erlotinib for advanced non-small cell lung cancer. J Clin Oncol 25:760-766, 2007
