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The Oncologist, Vol. 9, No. 5, 556-560, September 2004; doi:10.1634/theoncologist.9-5-556
© 2004 AlphaMed Press

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Non-Small Cell Lung Cancer in the Elderly

Paris D. Makrantonakis, Eleni Galani, Peter G. Harper

Guy’s Hospital, London, UK

Correspondence: Paris D. Makrantonakis, M.D., Medical Oncologist, Medical Oncology Department, 3rd Floor Guy’s Hospital, St. Thomas Street, SE1 9RT, London, United Kingdom. Telephone: 44-207-188-9275, ext. 5976; Fax: 44-207-188-4271; e-mail: makrant{at}otenet.gr


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Surgery
 Radiation Therapy
 Chemotherapy
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Describe the difference between chronologic and biologic age in patients with NSCLC.
  2. Discuss how clinical trials establish biologic rather than chronologic age in patients with NSCLC.
  3. Explain the effectiveness of surgery, radiation, and chemotherapy in geriatric patients with NSCLC.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
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 Learning Objectives
 Abstract
Introduction
 Surgery
 Radiation Therapy
 Chemotherapy
 Conclusions
 References
 
The population is aging both in developing and developed countries. What is clear is that currently over 50% of all patients with non-small cell lung cancer (NSCLC) are 65 years of age or older. When deciding a treatment strategy, the biological rather than the chronological age should be carefully assessed, and treatment should only be modified or withheld for very good reason. This applies equally to surgery, radiation therapy, and chemotherapy. Fortunately, recently published studies have focused on the issue and have provided strong evidence of improved progression-free survival, overall survival, and quality of life in elderly patients with appropriately treated NSCLC.

Key Words. Lung cancer • NSCLC • Surgery • Radiation therapy • Chemotherapy • Elderly


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Surgery
 Radiation Therapy
 Chemotherapy
 Conclusions
 References
 
Western populations are, as a group, aging, with lower birth rates and the first birth delayed until late in the second or early in the third decade. Despite obesity, elderly Western populations are generally fitter than in the past and one has to redefine the term "elderly." In the past, the border between middle age and old age was 65 years. Nowadays, as the older population has remained fitter for longer, this has been increased by some reports to 70 years and by others to 75 years. Extermann et al. [1] has defined the geriatric oncology group as "when the health status of a patient population begins to interfere with oncological decision-making guidelines." This should not be interpreted to mean there is an excuse for not treating the older patient. The biological age of each patient should be defined individually, based on comorbidities and performance scores. Within clinical trials, this is defined by exclusion criteria.

In developed countries where tumor registries are reasonably complete, median age of presentation of all cancer patients is 69 years in males and 67 years in females. Sixty percent of all cancers and two-thirds of cancer deaths occur over the age of 65 years [2, 3]. More than 50% of patients with lung cancer are over the age of 65 years and over 30% are above the age of 70 years [4–6].

Lung cancer is the second most prevalent cancer after prostate and breast cancers, but is by far the number one cause of cancer-related deaths. There is a rising trend in women, such that lung cancer has surpassed breast cancer deaths since 1987.


   SURGERY
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 Learning Objectives
 Abstract
 Introduction
 Surgery
Radiation Therapy
 Chemotherapy
 Conclusions
 References
 
Surgery remains the treatment of choice in early-stage non-small cell lung cancer (NSCLC), whatever the age [7, 8]. Nevertheless, all thoracic surgeons carefully assess for comorbid disease as the patient ages, understanding that prolonged anesthesia and the risks involved in intensive care are greater as the patient ages. However, if complete surgical resection of a tumor is possible, then outcome data would suggest that survival is the same as that of a younger patient [9–15]. Battafarano et al. [16] performed a retrospective analysis of 451 patients, looking at the impact of comorbidity on postoperative recovery and long-term survival in patients with stage I NSCLC who underwent complete resections. The relative risk of death in relation to the comorbidities was 1.44, 2.28, and 1.94 in mild, moderate, and severe comorbid situations, respectively. Comorbidity increases with age [17], thus a careful preoperative patient selection is needed.

Sioris et al. [18] retrospectively reviewed the outcome of 75 patients, aged 75 years or older, who underwent curative resections in a single institution between 1976–1996. They demonstrated a perioperative mortality of 9% and a morbidity of 29%. There was no significant difference in cancer-related survival after lobectomy or limited resection. The 5-year cancer-related survival in stages IA-IIB was 61%–79%. Mortality, morbidity, and overall survival were not different between the 75–79 years age groups and the ≥80 years group. They concluded that even after the age of 80 years, surgery was not contraindicated where curative resection could be attempted. In a similar study of 258 patients >70 years, Oliaro et al. [12] demonstrated a postoperative mortality of 3.1%, morbidity of 39.1%, and a 5-year survival of 73.6% in stage I tumors. Five-year survival in stage II and IIIA was 22% and 8.9%, respectively (Table 1Go).


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  		Table 1. Surgery for lung cancer in the elderly
 
Morandi et al. [11] in a retrospective analysis, compared the morbidity and the mortality of 87 patients >70 years of age with 130 younger patients undergoing similar pulmonary resections (1989–1993). There was no significant difference in the postoperative mortality or the overall complications between the two groups.


   RADIATION THERAPY
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 Learning Objectives
 Abstract
 Introduction
 Surgery
 Radiation Therapy
Chemotherapy
 Conclusions
 References
 
Comorbid diseases (cardiovascular and pulmonary dysfunctions) in the elderly patient with relatively early-stage NSCLC may influence their decision to receive radical radiotherapy, rather than curative surgery. Radical radiation is used with a curative intent in patients otherwise considered inoperable. It can also be used in the adjuvant or neoadjuvant setting.

Early-Stage NSCLC
Gauden et al. [19] reported on 347 patients treated with 50 Gy in 20 fractions, for early-stage NSCLC. There was no statistical difference in 5-year overall survival (22% versus 32%) or recurrence-free survival (18% versus 30%) between patients <70 years and patients ≥70 years. The incidence of both acute and late grade 3/4 toxicities was similar among all ages.

Noordijk et al. [20] reported on a group of 50 patients with peripherally located NSCLC considered T1-2 N0 M0, who were irradiated with 60 Gy. The median age of this group was 74 years. The response rate was 90%, with 50% complete responses in tumors smaller than 4 cm, an overall 5-year survival rate of 16%, and median survival of 27 months.

Advanced-Stage NSCLC
Lonardi et al. [21] reported on a group of patients ≥75 years for safety, effectiveness, and possible impact on survival with radiotherapy at a dose of 50 Gy. The patients did not develop grade 3/4 esophagitis, nausea, vomiting, dermatitis, or leukopenia. Fatigue was grade 1 in 67% of patients, and 23% of patients had mild weight loss. Overall survival was 48% at 6 months, 23% at 12 months, and 10% at 24 months, with a median survival of 5 months. In the group of patients in whom at least 50 Gy was delivered, median survival was greater at 8 months. In a phase III trial comparing concurrent cisplatin-based chemotherapy and thoracic radiotherapy (given once or twice daily [hyperfractionated]) versus sequential chemotherapy and radiotherapy, data were analyzed by age (<70 years, n = 488; ≥70 years, n = 104), revealing that older patients had a survival benefit with concurrent chemotherapy and radiation compared with sequential treatment. The risks for grade 3 neutropenia and grade 4 toxicities were increased in the older patients, but there was no difference in long-term toxicity. Grade 4 toxicities occurred in most older patients regardless of the treatment, but they were most common with the concurrent daily chemotherapy and radiation schedule [22].


   CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Radiation Therapy
 Chemotherapy
Conclusions
 References
 
Cisplatin-based chemotherapy increases both overall survival and improves the quality of life in patients with advanced NSCLC [23, 24]. Retrospective studies comparing time to progression and median survival between elderly and nonelderly patients who receive palliative chemotherapy have shown no significant difference between the two groups [25–27].

Single-Agent Versus Best Supportive Care
The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) phase III trial [28] of the Italian Lung Cancer Cooperative group compared vinorelbine at a dose of 30 mg/m2 on days 1 and 8, given every 3 weeks, versus best supportive care (not including chemotherapy). One hundred ninety-one patients were enrolled on study. Median survival time was 28 weeks versus 21 weeks (p = 0.03), and 1-year survival was 32% versus 14% (p = 0.03), giving a clear advantage to the chemotherapy-treated group. The relative risk of death was 0.65 (95% confidence interval: 0.45–0.93), again showing benefit to the chemotherapy-treated group. An important aspect of the ELVIS trial was the assessment of quality of life using both the EORTC QLQ30 and the LC 13 questionnaires. Again there was a clear advantage to the chemotherapy-treated group.

Nonplatinum Doublets Versus Single Agents
Frasci et al. [29] reported on a small study of 120 elderly patients with advanced NSCLC and compared vinorelbine plus gemcitabine with vinorelbine alone. They reported median survival times of 29 weeks in the combination arm versus 18 weeks in vinorelbine alone (p < 0.01) and 1-year survivals of 30% versus 13%, again in favor of the combination arm. It is to be remembered that within the ELVIS trial the single-agent vinorelbine group had a median survival of 28 weeks, quite different than the median survival within this trial. Patient selection certainly has a part to play in such randomized trials. Within this smaller trial, there was at least one concomitant disease in 75% of patients, while this was less than 50% in the ELVIS trial. Other factors should also be considered as the reason for the discrepant results between the ELVIS and Frasci et al. trials.

In the Multicenter Italian Lung Cancer in the Elderly Study phase III randomized trial, also from the Italian group, 698 elderly patients were randomized to vinorelbine, gemcitabine, or vinorelbine plus gemcitabine. Median survival time was not significantly different between the three arms (36, 28, and 30 weeks, respectively), 1-year survival was also similar at 38%, 28%, and 30%, respectively, and the authors concluded that the combination of navelbine and gemcitabine was no better than single-agent navelbine or gemcitabine. The single-agent protocols also had a better safety profile and tolerability [30] (Table 2Go).


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  		Table 2. Phase III trials with nonplatinum regimens for treatment of NSCLC in elderly patients
 
Platinum Combinations
Langer et al. [26] reported on cisplatin-based therapy in elderly patients with advanced NSCLC on behalf of the Eastern Cooperative Oncology Group. The data were retrospectively reviewed comparing outcomes for patients ≥70 years of age with younger patients and showed similar response rate, toxicity, and survival. It is the first indication that elderly patients can be treated with platinum-based chemotherapy. Perrone et al. [31] reported that the Langer et al. results are poor because there were selection biases of retrospective analyses. The percentage of elderly patients among patients diagnosed with lung cancer in clinical practice is much higher than the percentage of elderly patients among patients enrolled in clinical trials. A further selection bias can occur when physicians attempt to recruit particularly well-performing patients. The proportion of elderly patients was less than half of what would have been expected on the basis of population data [32].

Nonplatinum Versus Platinum Combinations
Lilenbaum et al. [33] studied 584 patients with a median age of 63.5 years, randomized to receive paclitaxel or paclitaxel and carboplatin. The combination appeared to give a prolongation of median survival time (9.5 months versus 6.5 months, p = 0.023) and 1-year survival of 35% and 31%, respectively, not reaching statistical significance. The analysis for the elderly subgroup (158 patients) revealed a benefit to combination chemotherapy, although this was not statistically significant.

In an attempt to get away from platinum-based chemotherapy (which would be very useful in an elderly group, whose renal function is often impaired), Georgoulias et al. [34], in a randomized trial of 441 patients, reported on a combination of docetaxel with gemcitabine compared with docetaxel with cisplatin. The median age of this group was 62 years. The median survival times were not different at 9.5 and 10 months, respectively, and 1-year survival were similar at 39% and 42%, respectively. The noncisplatin arm has a better safety profile and might be more useful in the treatment of an elderly subgroup.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Radiation Therapy
 Chemotherapy
 Conclusions
References
 
Undoubtedly, we will be seeing more NSCLC in elderly patients. It will be important to find a treatment pathway where age is not the sole criteria of how a patient is treated. We will need to apply known geriatric scoring systems, in an attempt to better define the role of comorbid disease in this group. Who should be treated, how should they be treated, and with what potential benefit are questions that need to be addressed. Whether non-cisplatin-based combination chemotherapies could be more effective and well tolerated in this group should be explored in well-designed clinical trials. There is no standard option for chemotherapy, but nonplatinum, single agent, or a combination seem prosperous. The introduction of less toxic biological agents given sequentially or in combination with chemotherapy will also be a further option. There is no way forward other than well-designed randomized phase III trials to provide secure information for the optimal treatment of this important group.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Surgery
 Radiation Therapy
 Chemotherapy
 Conclusions
 References
 

  1. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer 2000;36:453–471.
  2. American Cancer Society Centers for Disease Control and Prevention National Conference on Cancer and the Older Person. Proceedings. Atlanta, Georgia, February 10–12, 1994. Cancer 1994;74:1995–2214.
  3. Yancik R, Ries LA. Aging and cancer in America. Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000;14:17–23.[CrossRef][Medline]
  4. Silverberg E, Lubera JA. Cancer statistics, 1988. CA Cancer J Clin 1988;38:5–22.[Free Full Text]
  5. Gridelli C, Perrone F, Monfardini S. Lung cancer in the elderly. Eur J Cancer 1997;33:2313–2314.
  6. Gridelli C. Chemotherapy of non-small cell lung cancer in the elderly. Lung Cancer 2002;38(suppl 3):S67–S70.
  7. Smythe WR. Treatment of stage I non-small cell lung carcinoma. Chest 2003;123(suppl 1):181S–187S.
  8. Scott WJ, Howington J, Movsas B. Treatment of stage II non-small cell lung cancer. Chest 2003;123(suppl 1):188S–201S.
  9. Nugent WC, Edney MT, Hammerness PG et al. Non-small cell lung cancer at the extremes of age: impact on diagnosis and treatment. Ann Thorac Surg 1997;63:193–197.[Abstract/Free Full Text]
  10. Damhuis RA, Schutte PR, Kho GS et al. [Good surgery results in older patients with stage 1 lung carcinoma]. Ned Tijdschr Geneeskd 1995;139:1781–1785.[Medline]
  11. Morandi U, Stefani A, Golinelli M et al. Results of surgical resection in patients over the age of 70 years with non small-cell lung cancer. Eur J Cardiothorac Surg 1997;11:432–439.[Abstract]
  12. Oliaro A, Leo F, Filosso PL et al. Resection for bronchogenic carcinoma in the elderly. J Cardiovasc Surg (Torino) 1999;40:715–719.[Medline]
  13. de Perrot M, Licker M, Reymond MA et al. Influence of age on operative mortality and long-term survival after lung resection for bronchogenic carcinoma. Eur Respir J 1999;14:419–422.[Abstract]
  14. Ciriaco P, Zannini P, Carretta A et al. Surgical treatment of non-small cell lung cancer in patients 70 years of age or older. Int Surg 1998;83:4–7.[Medline]
  15. Yamamoto K, Padilla Alarcon J et al. Surgical results of stage I non-small cell lung cancer: comparison between elderly and younger patients. Eur J Cardiothorac Surg 2003;23:21–25.[Abstract/Free Full Text]
  16. Battafarano RJ, Piccirillo JF, Meyers BF et al. Impact of comorbidity on survival after surgical resection in patients with stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 2002;123:280–287.[Abstract/Free Full Text]
  17. Kadono K, Satoh H, Homma T et al. Radiotherapy for elderly non-small cell lung cancer patients. Oncol Rep 2002;9:1273–1276.[Medline]
  18. Sioris T, Salo J, Perhoniemi V et al. Surgery for lung cancer in the elderly. Scand Cardiovasc J 1999;33:222–227.[CrossRef][Medline]
  19. Gauden SJ, Tripcony L. The curative treatment by radiation therapy alone of Stage I non-small cell lung cancer in a geriatric population. Lung Cancer 2001;32:71–79.[Medline]
  20. Noordijk EM, vd Poest Clement E, Hermans J et al. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol 1988;13:83–89.[CrossRef][Medline]
  21. Lonardi F, Coeli M, Pavanato G et al. Radiotherapy for non-small cell lung cancer in patients aged 75 and over: safety, effectiveness and possible impact on survival. Lung Cancer 2000;28:43–50.[CrossRef][Medline]
  22. Langer C, Hsu C, Curran W et al. Do elderly patients with locally advanced non-small cell lung cancer (NSCLC) benefit from combined modality therapy? A secondary analysis of RTOG 94-10. Int J Radiat Oncol Biol Phys 2002;51:20–21.
  23. Quoix E, Dietemann A, Charbonneau J et al. [Is chemotherapy with cisplatin useful in non small cell bronchial cancer at staging IV? Results of a randomized study]. Bull Cancer 1991;78:341–346.[Medline]
  24. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899–909.[Abstract/Free Full Text]
  25. Earle CC, Tsai JS, Gelber RD et al. Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis. J Clin Oncol 2001;19:1064–1070.[Abstract/Free Full Text]
  26. Langer CJ, Manola J, Bernardo P et al. Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002;94:173–181.[Abstract/Free Full Text]
  27. Kloke O. [Chemotherapy of non-small-cell bronchial carcinoma in elderly patients]. Z Gerontol Geriatr 2001;34:277–279.[CrossRef][Medline]
  28. Gridelli C. The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. The Oncologist 2001;6(suppl 1):4–7.[Abstract/Free Full Text]
  29. Frasci G, Lorusso V, Panza N et al. Gemcitabine plus vinorelbine yields better survival outcome than vinorelbine alone in elderly patients with advanced non-small cell lung cancer. A Southern Italy Cooperative Oncology Group (SICOG) phase III trial. Lung Cancer 2001;34(suppl 4):S65–S69.
  30. Gridelli C, Perrone F, Gallo C et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) Phase III Randomized Trial. J Natl Cancer Inst 2003;95:362–372.[Abstract/Free Full Text]
  31. Perrone F, Gallo C, Gridelli C. Re: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 2002;94:1029–1030; author reply 1030–1031.[Free Full Text]
  32. Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341:2061–2067.[Abstract/Free Full Text]
  33. Lilenbaum R, Herndon J, List MG et al. Single-agent versus combination chemotherapy in advanced non-small cell lung cancer: a CALGB randomized trial of efficacy, quality of life and cost-effectiveness. Proc Am Soc Clin Oncol 2002; 21:1a.
  34. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001;357:1478–1484.[CrossRef][Medline]
Received October 17, 2003; accepted for publication June 24, 2004.





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