Commentary (Cohen/Khuri): Treatment of Non–Small-Cell Lung Cancer in Older Persons

The importance of cancer as a problem in the elderly is gaining increasing appreciation due, in part, to the demographic changes taking place in this country and around the world and their association to the incidence of cancer. Ongoing epidemiologic research over the past several decades has consistently confirmed the continuing trend toward an aging population. In the United States, an anticipated 20.1% of the population will be 65 years of age or older by 2030, the number of people 75 years of age or older will have tripled, and the 85-or-older age group will have doubled.[1]

As the population ages, the incidence and prevalence of cancer will rise, perhaps most importantly because of the length of time it takes to develop a clinically recognized malignancy. Recent estimates indicate that the median age of patients with the 10 most common tumors is 70 years, and death rates increase with each decade.[2]

Challenging Task

The simple fact that there is an intersection of these two trends however would not be sufficient justification to focus on the problem if there were no differences between older and younger patients.[3] Of course, a great deal is different about older patients; aging is associated with an increasing prevalence of health problems including comorbid diseases, restricted performance status, socioeconomic restrictions, diminished cognition, and modifications of body function including alterations in lean body mass and bone marrow reserves as well as changes in renal and liver function. These factors and the balance between benefit and expected risk or side effects in terms of quality of life and life expectancy interfere significantly with oncologic decision-making guidelines and make treatment of elderly cancer patients an extremely complex and challenging task.

In this issue of ONCOLOGY, Drs. Basche and Kelly present a cogent and thorough review of the treatment of elderly patients with non-smallcell lung cancer (NSCLC). The authors introduce the topic, cover the critical issues regarding resectional therapy, radiotherapy, and chemotherapy and offer concrete recommendations for appropriate management of various subsets of patients-recommendations based, for the most part, on the data examined. They make several points that deserve emphasis.

Surgery

Elderly patients with stage I or II NSCLC who are eligible for surgery should always be considered for possible resection. An anatomic lobectomy remains the standard procedure, although in compromised situations, a limited resection can be performed with an expected increase in locoregional recurrence and decreased 5-year survival.

The authors have clearly summarized the important advances in surgery, demonstrating that the question is no longer whether surgical resection is beneficial and safe, but rather, how patient selection can be enhanced and outcomes improved. Major prognostic predictors to consider when selecting patients for surgical treatment include type of procedure, performance status, and comorbidity, particularly cardiopulmonary diseases. An accurate evaluation of potential postoperative lung function is also of paramount importance.

Radiotherapy

When dealing with radiotherapy in the elderly, the main issues are related to tolerance and treatment strategies, given the supposedly indolent behavior of tumors in older persons and the reduced ability of older patients to tolerate radical irradiation. Surprisingly few data in the radiation oncology literature deal specifically with the indications and tolerance of lung cancer radiation treatment in the elderly, either because subjects have not been properly examined or because studies attempting to relate age to tolerance have produced negative results considered unworthy of publication. As the authors note, the few available relevant studies do support the aggregate view that radiation therapy produces clinical results and complications comparable to those observed in younger patients.

For patients with stage I or II disease who are not sufficiently fit for (or who decline) surgery, radical radiotherapy represents the first choice of treatment. Although results achieved with radiotherapy are inferior to those achieved with surgical resection, this approach remains an effective treatment and produces satisfactory outcomes. In fact, the 5-year survival rate approaches approximately 31% for patients with small tumors.[4-6]

Radiation at a total dose of 65 Gy delivered via continuous fractionation is recommended. However, it is important to recognize that the optimal radiation dose and treatment method, particularly with respect to mediastinal irradiation, remain uncertain. No doubt, more sophisticated techniques (computed-guided three-dimensional conformal radiation therapy, proton-beam therapy, and motion-gated approaches) will improve treatment planning in terms of both tumor coverage and the sparing of normal tissue.

For locally advanced disease, a combined-modality approach-particularly with concurrent treatments- does not seem to be useful in elderly patients. Individual trials evaluating combined-modality therapy have shown no impairment in survival for older patients, but retrospective analyses of the Radiation Therapy Oncology Group (RTOG) database have demonstrated that increased therapeutic intensity (compared to standard radiation alone) does not translate into improved outcome.[ 7,8] Weighted survival analyses that take into account time spent with progressive disease or significant toxicity have reinforced this notion.

Based on these findings, we agree with the authors' recommendations that combined-modality therapy, particularly if aggressive and administered concurrently, should be offered to selected elderly patients only- preferably within the context of a clinical trial.

Chemotherapy

Support for chemotherapeutic treatment of patients with metastatic NSCLC came from an international collaborative meta-analysis using updated data on patients from 52 randomized clinical trials.[9] The data suggested that patients treated with cisplatin-containing regimens demonstrated a 27% reduction in the risk of death. This was equivalent to an absolute improvement in survival of 10% at 1 year, with a 1.5-month improvement in median survival. No differences related to age were observed. Given these modest results, it is not surprising that the treatment of elderly patients with metastatic disease remains controversial.

Recent studies, including a retrospective analysis of elderly patients from the National Cancer Institute's Surveillance, Epidemiology, and End Results tumor registry showed that elderly patients who are otherwise fit can receive benefits comparable to those of younger patients and with no greater toxicity except for myelosuppression, to which the elderly are generally more susceptible.[10] These studies support the notion that age alone should not be a factor in the decision to treat patients with chemotherapy, but they do not indicate which treatment regimen is preferred.

Three separate studies from Italy have formally assessed the use of chemotherapy in the elderly.[11-13] The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) showed a survival advantage for single-agent vinorelbine (Navelbine) vs best supportive care.[11] This survival benefit was not achieved at the expense of a poorer quality of life, and toxicities were mild and easily managed. A second study showed the superiority of the combination of vinorelbine and gemcitabine (Gemzar) vs vinorelbine alone.

However, a much larger, more credible study demonstrated no benefit for the combination of vinorelbine and gemcitabine compared with vinorelbine alone or gemcitabine alone. Based on these results, single- agent chemotherapy should remain the standard treatment. Trials being conducted specifically in the elderly are currently addressing the role of taxanes and comparing platinum- and non-platinum-based combination therapy vs monotherapy or doublets.[14]

Supportive Care

The authors do not discuss the role of hematopoietic growth factors and other proactive approaches to minimizing the toxic effects of chemotherapy in elderly patients. For example, granulocyte colony-stimulating factor (G-CSF [Neupogen]) decreases the incidence, severity, and duration of chemotherapy-induced neutropenia, thus reducing the risk of infection without the need for drug dose delays and reductions. Some investigators recommend the use of G-CSF in all patients older than 70 who are receiving combination therapy at a dose intensity equivalent to that of a standard CHOP regimen (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone).[15]

The current guidelines of the American Society of Clinical Oncology recommend using G-CSF in the setting of secondary prophylaxis.[16] However, at least one study found that death due to neutropenic infection in patients aged 60 or older frequently occurs in the first cycle of chemotherapy.[ 17] Therefore, we believe that primary prophylaxis initiated 24 hours after the completion of the first cycle of treatment should be strongly considered in these patients.

Alternative Therapies

Notwithstanding the importance of chemotherapy as pointed out in the randomized clinical studies discussed above, alternative therapies including those that incorporate new biologic agents targeting specific aberrations in lung cancer are currently under development and evaluation. For the older patient, biologic strategies (particularly molecularly targeted approaches) offer potential advantages over cytotoxics, including better tolerability and oral administration at home.

Also under way are trials of agents directed at signal transduction pathways that regulate growth and survival events and tumor angiogenesis. ZD1839 (Iressa), a low-molecularweight inhibitor of epidermal growth factor receptor has gained the most attention in recent years. In early studies, clinically significant antitumor activity and improvement in symptoms and quality of life were observed in patients with advanced NSCLC treated with single-agent ZD1839.[18]

Conclusions

The overriding conclusion from this review is that chronologic age itself is not a sufficient reason to exclude NSCLC patients in good general condition from state-of-the-art curative surgery, curative radiotherapy, or palliative chemotherapy- even in experimental settings-when medically indicated. Such a statement should help dismiss the tremendous biases and false misconceptions that exist in the oncologic community regarding treatment of the elderly, and the therapeutic nilihism that conspires to maintain status quo. We congratulate Drs. Basche and Kelly on a wellwritten and timely paper.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1.

Yancik R, Ries LAG: Aging and cancer inAmerica: Demographic and epidemiologic perspectives.Hematol Oncol Clin North Am 14:17-23, 2000.

2.

American Cancer Society: Cancer Facts& Figures 2000. Atlanta, American CancerSociety, 2000.

3.

Cohen HJ: Oncology and aging, in HazardWR, Blass JP, Ettinger WH, et al (eds):Principles of Geriatric Medicine and Gerontology,4th ed. New York, McGraw-Hill, 1998.

4.

Krol AD, Aussems P, Noordijk EM, et al:Local irradiation alone for peripheral stage Ilung cancer: Could we omit the elective regionalnodal irradiation? Int J Radiat OncolBiol Phys 34:297-302, 1996.

5.

Talton BM, Constable WC, Kersh CR:Curative radiotherapy in non-small cell carcinomaof the lung. Int J Radiat Oncol Biol Phys19:15-21, 1990.

6.

Rowell NP, Williams CJ: Radical radiotherapyfor stage I/II non-small cell lung cancerin patients not sufficiently fit for or decliningsurgery (medically inoperable): A systematicreview. Thorax 56:628-638, 2001.

7.

Movsas B, Scott C, Sause W, et al: Thebenefit of treatment intensification is age andhistology-dependent in patients with locally advancednon-small cell lung cancer (NSCLC):A quality-adjusted survival analysis of RadiationTherapy Oncology Group (RTOG) chemoradiationstudies. Int J Radiat Oncol Biol Phys45:1143-1149, 1999.

8.

Langer C, Scott C, Byhardt R, et al: Effectof advanced age on outcome in Radiation TherapyOncology Group studies of locally advancedNSCLC. Lung Cancer 29(suppl 1):119,2000.

9.

Non-Small Cell Lung Cancer CollaborativeGroup: Chemotherapy in non-small celllung cancer: A meta-analysis using updateddata on individual patients from 52 randomizedclinical trials. Br Med J 311:899-909,1995.

10.

Earle CC, Tsai JS, Gelber RD, et al:Effectiveness of chemotherapy for advancedlung cancer in the elderly: Instrumental variableand propensity analysis. J Clin Oncol19:1064-1070, 2001.

11.

The Elderly Lung Cancer VinorelbineItalian Study Group: Effects of vinorelbine onquality of life and survival of elderly patientswith advanced non-small-cell lung cancer. JNatl Cancer Inst 91:66-72, 1999.

12.

Frasci G, Lorusso V, Panza N, et al:Gemcitabine plus vinorelbine versus vinorelbinealone in elderly patients with advancednon-small-cell lung cancer. J Clin Oncol18:2529-2536, 2000.

13.

Gridelli C, Perrone F, Cigolari S, et al:The MILES (Multicenter Italian Lung Cancerin the Elderly Study) phase 3 trial: Gemcitabine+ vinorelbine vs vinorelbine and vs gemcitabinein elderly advanced NSCLC patients(abstract 1230). Proc Am Soc Clin Oncol20:308a, 2001.

14.

Frasci G: Chemotherapy of lung cancerin the elderly. Crit Rev Oncol Hematol 41:349-361, 2002.

15.

Balducci L, Yates J: General guidelinesfor management of older patients with cancer.Oncology 14:221-227, 2000.

16.

Ozer H, Armitage JO, Bennett CL, et al:2000 update of recommendations for the use ofhematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. AmericanSociety of Clinical Oncology GrowthFactors Expert Panel. J Clin Oncol 18:3558-3585, 2000.

17.

Gomez H, Hidalgo M, Casanova L, et al:Risk factors for treatment-related death in elderlypatients with aggressive non-Hodgkin’slymphoma: Results of a multivariate analysis.J Clin Oncol 16:2065-2069, 1998.

18.

Douillard J-Y, Giaccone G, Horai T, etal: Improvement in disease-related symptomsand quality of life in patients with advancednon-small-cell lung cancer (NSCLC) treatedwith ZD1839 (‘Iressa’) (IDEAL 1) (abstract1195). Proc Am Soc Clin Oncol 21:299a, 2002.