Aerorespiratory tract cancer in older patients

Aerorespiratory Tract Cancer in Older Patients Aqeel A. Gillani and Steven M. Grunberg Lung cancer and head and neck cancer present distinctive management challenges in the elderly population. Cumulative tobacco exposure is a risk factor for both types of cancer. Smoking-related comorbidities, including cardiovascular disease and chronic obstructive pulmonary disease, will also increase with cumulative tobacco exposure and can complicate surgical or radiotherapeutic management. Some differences in natural history, such as a greater tendency toward localized disease in non–small cell lung cancer and a lesser correlation with tobacco/alcohol exposure in head and neck cancer, have been noted for older patients. However, standard treatment modalities do appear to maintain efficacy in the elderly population. If comorbidities and physiologic age (rather than strict chronologic age) are taken into account, effective interventions can be devised with benefits similar to those seen in younger populations. Although prevention remains the mainstay of management of aerorespiratory cancers, carefully planned treatment can result in therapeutic benefit with maintenance of quality of life. Semin Oncol 31:220-233. © 2004 Elsevier Inc. All rights reserved.

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HE AERORESPIRATORY cancers present a unique set of risks and opportunities for improving the health of the elderly population. Lung cancer is now the most common cause of cancerrelated death for both men and women. Head and neck cancer has a much lower incidence but can result in significant disfigurement and morbidity when treated aggressively. Both of these cancers are strongly smoking related, with risk proportional to overall exposure, generally expressed in terms of the intensity and duration of tobacco use (pack-years of exposure). Therefore, the very factors that increase risk of tumor incidence also increase the morbidity of aggressive intervention (particularly surgical intervention) through the concomitant development of chronic obstructive pulmonary disease and coronary artery disease. On the other hand, the etiologies of these cancers are

From the Division of Hematology/Oncology, The University of Vermont, Burlington, VT. Address reprint requests to Aqeel A. Gillani, MD, Division of Hematology/Oncology, The University of Vermont, UHC Campus, St Joseph 3400, 1 South Prospect St, Burlington, VT 05401. © 2004 Elsevier Inc. All rights reserved. 0093-7754/04/3102-0010$30.00/0 doi:10.1053/j.seminoncol.2003.12.032 220

well identified, thus providing the greatest opportunity for effective preventive intervention. Although this review will concentrate on treatment of patients with lung and head and neck cancers, generally an older population, programs designed to have maximum impact on these diseases must target younger populations to encourage healthy lifestyles and preventive behavior as well. TREATMENT OF NON–SMALL CELL LUNG CANCER

Early Stage Disease Surgery and radiotherapy remain the best options for localized or early stage (I to II) non–small cell lung cancer (NSCLC).1 Use of surgery in the general population is limited because lung cancer is usually not detected at a localized stage,2 and the main environmental risk factor for lung cancer (smoking) also induces both cardiovascular and pulmonary comorbid conditions that independently increase the risk of surgery.3 In contrast, the demographics of lung cancer in the elderly are particularly favorable for the use of potentially curative surgery because the frequency of localized lung cancer at presentation is higher in patients over 75 years of age (25.4%) as compared with patients under 54 years of age (15.3%)4; squamous carcinoma, which tends to be localized, is the most frequent histology of lung cancer in older patients (53%).5 However, Smith et al,6 using data from the Virginia Cancer Registry (1985 to 1989) and Medicare claims records, found that the elderly are much less likely to be offered surgery as initial therapy. Review of 2,812 cases showed that the use of surgery as all or part of the initial therapy decreased from 44% in patients aged 65 to 69 years to 6% in those over 85 years old. This did not represent increased use of radiotherapy as a less aggressive alternative for primary treatment of lung cancer, but rather a greater tendency to offer no therapy at all. More recent studies continue to reflect this trend.7,8 The reason why the elderly are less likely to be offered surgery as primary therapy remains unclear. The argument that curative surgery would not improve overall survival because of the limited life expectancy of elderly patients must be rejected Seminars in Oncology, Vol 31, No 2 (April), 2004: pp 220-233

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because the life expectancy of older adults generally exceeds the average survival of patients with uncontrolled lung cancer.9 Long-term outcomes for appropriately selected older patients undergoing surgical resection are comparable to those of younger individuals,10,11 although the association of comorbid conditions with advancing age may increase the risk of surgery. Five-year survival for appropriately selected octogenarians was quite favorable in two small surgical series,12,13 and the investigators concluded that the surgical decision should be based on stage of disease and cardiopulmonary status rather than on age. Historical series based only on age can be misleading. In a prospective single-institution study of 500 patients, Bernard et al14 found that age was associated with increased risk of postoperative mortality only in the univariate analysis. Similarly, Ginsberg et al15 reported postoperative mortality rates as much as six times higher in patients over 70 years compared with those under 60 years of age by univariate analysis. Common causes of surgical mortality included pneumonia, respiratory failure, bronchopleural fistula, empyema, and myocardial infarction. However, these results describe outcomes for surgery performed 20 years ago and do not reflect advances in surgical technique or postoperative care. Additionally, because only univariate analysis was performed, these results do not determine whether the more powerful predictor of surgical risk is advancing age or the comorbid diseases commonly associated with aging.16 The extent of the surgical procedure and the volume of lung resection performed also influence postoperative risk in the elderly. Dyszkiewicz et al17 compared pneumonectomy with lobectomy among 90 patients older than 70 years and found that postoperative complications developed in 79% versus 58%, respectively. Wedge resection using video-assisted thoracoscopic surgery may be an alternative. This technique is associated with decreased postoperative pain, shorter hospital stay, and better postoperative pulmonary function, and may be especially useful in the older patient. Landreneau et al18 found inferior 5-year survival compared with formal lobectomy (58% for open wedge, 65% for video-assisted wedge, 70% for lobectomy; P ⫽ .02), but these differences in survival were related to an increased death rate from other causes. Therefore, there is an immense need to develop validated methods to risk stratify older

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patients for lung resection so that age alone will not exclude a patient from consideration for surgical therapy. Radiotherapy remains a viable option for patients with localized disease who are ineligible for surgery. Standard-fractionation treatments are well-tolerated and may also provide rapid relief of symptoms. Using definitive radiotherapy doses, Furuta et al19 treated 32 patients over 75 years of age with stage I or II NSCLC and reported a 2-year survival of 57% and 5-year survival of 36%. The mean age of patients in this series was 79 years, including 11 patients over 80 years of age. Guaden and Tripcony20 conducted a retrospective analysis of 347 patients with early stage NSCLC treated at a single institution between 1985 and 1992 with standard-fractionation radiotherapy to a total dose of 50 Gy. The 5-year survival for the 173 patients at least 70 years of age was 34%, comparable to results in the patients younger than 70 years and without a significant difference in toxicity. When used in noncurative settings, radiotherapy can relieve thoracic pain and hemoptysis in 80% of cases while cough or hoarseness can be controlled in 50% to 70% of cases.21 As a result of recent advances in radiation techniques, including 3-dimensional conformal radiation and stereotactic radiosurgery, wider applicability of this therapeutic modality among older populations is anticipated. LOCALLY ADVANCED DISEASE

A combined-modality approach has become the cornerstone of therapy in locally advanced NSCLC. In this group, which generally includes patients with medically inoperable stage II/IIIA or unresectable stage IIIA/B disease, concurrent chemoradiation has shown a significant survival advantage in several large randomized trials.22-26 The addition of adjuvant combination chemotherapy to surgery for patients with resectable stage II or IIIA disease has also recently been suggested to provide some survival benefit.27 Until 1994, elderly patients on Radiation Therapy Oncology Group (RTOG) trials evaluating bimodality therapy in locally advanced NSCLC did not appear to benefit from increased therapeutic intensity or combined modality therapy compared with thoracic radiotherapy alone.28 WernerWasik et al29 analyzed a database of 1,999 patients treated in nine RTOG trials between 1983 and 1994 with thoracic radiotherapy. Three hundred

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thirty-five of these patients also received chemotherapy. Recursive partitioning analysis was applied to identify five patient subgroups, two of which specifically included elderly patients. Median survival (MS) was significantly shorter for patients over the age of 70 with Karnofsky Performance Status ⬍90 (5.6 to 6.4 months) and for those older than 70 with pleural effusion (2.9 months). Additionally, cisplatin-based chemotherapy in combination with thoracic radiotherapy improved overall survival for excellent prognosis locally advanced NSCLC patients compared with radiotherapy alone. However, advanced age and malignant pleural effusion were negative prognostic factors for survival. Similarly, Sause et al30 conducted a phase III Intergroup trial including RTOG, Eastern Cooperative Oncology Group (ECOG), and Southwest Oncology Group (SWOG) to compare standard radiotherapy in combination with concomitant cisplatin and vinblastine with standard radiotherapy or with hyperfractionated radiotherapy in surgically unresectable NSCLC (stage II, IIIA, and IIIB). Of the 490 patients accrued in the trial, only 66 were over age 70. For patients under age 60, the best MS was achieved in patients treated on the combined chemoradiotherapy arm. However, for patients over age 70, MS on the radiotherapy-alone arm (13.1 months) exceeded MS in the combination therapy arm (10.9 months). Nonsquamous histology was also associated in this study with longer survival (15.6 months v 11.4 months). More recent trials have had more promising results. RTOG 9410 compared sequential therapy with concurrent chemoradiotherapy and concurrent chemotherapy/hyperfractionated radiotherapy in locally advanced, unresectable NSCLC (inoperable or unresectable stage II/III). Patients on the sequential arm (arm 1) received cisplatin and vinblastine followed by thoracic radiotherapy (60 Gy), arm 2 used identical chemotherapy and concurrent single fraction daily radiotherapy (60 Gy), and arm 3 used a regimen of cisplatin/oral etoposide and hyperfractionated radiotherapy (69.6 Gy in 1.2 Gy per fraction twice daily). Eligibility was restricted to “good prognosis” patients. From 1994 to 1998, 610 patients were enrolled out of which 104 (17%) were age 70 or older. A significant trend in MS favoring concurrent chemoradiotherapy over sequential therapy (17.1 months v 14.6 months; P ⫽ .038) was shown, whereas no signif-

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icant difference was seen in the hyperfractionated arm (15.6 months v 14.6 months; P ⫽ .298). Langer et al31 performed a secondary analysis of the elderly patients included in this dataset. Sequential therapy was administered to 40 elderly patients, concurrent therapy to 24 patients, and hyperfractionated therapy to 39 patients. Shortterm toxicities were acceptable, though more pronounced in the elderly than in the overall population. Grade 4 or greater toxicity of any type occurred in 68%, 75%, and 55% of older patients, compared with 57%, 63%, and 38% of younger patients in the sequential, concurrent, and hyperfractionated arms, respectively. The rate of grade ⬎3 neutropenia was 10% to 20% higher in older patients across all arms, but was most significant in the hyperfractionated arm (68% v 48%; P ⫽ .02) while the frequency of grade ⬎3 esophagitis was also higher in elderly patients receiving concurrent and hyperfractionated therapy (33% and 60%) compared with those under 70 years of age (23% and 42%). Median survival in the elderly favored concurrent chemoradiation: 22.4 months for concurrent arm versus 16.4 months for hyperfractionated arm versus 10.8 months for sequential arm (P ⫽ .069). Thus, in contrast to the historical precedent, fit elderly patients enrolled on RTOG 9410 benefited from concurrent standard chemoradiotherapy both with respect to survival and esophagitis rates. Carboplatin-based chemoradiotherapy has been evaluated to attempt to identify regimens better tolerated in the older population. Atagi et al32 conducted a multicenter phase II study using daily low-dose carboplatin and radiotherapy (50 to 60 Gy over 5 weeks) in 38 patients with locally advanced NSCLC (median age, 79 years). One patient had a complete response and 18 patients had partial responses, for a total response rate (RR) of 50% (95% confidence interval [CI], 33.4% to 66.6%). For stage IIIA/B patients, MS time was 15.1 months and 1- and 2-year actuarial survival rates were 52.6 and 20.5%, respectively. Hematologic toxicity was common but tolerable. Lau et al33 and the SWOG conducted a phase II study to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiotherapy in poor-risk patients with stage III NSCLC. Patients eligible for this study had been excluded from cisplatin-based protocols because of poor pulmonary or renal function, congestive heart failure,

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hearing loss, peripheral neuropathy, or weight loss. Thirty of the 60 enrolled patients (50%) were between ages 66 to 79 but more than 80% had performance status 0-1. The majority of these patients were considered poor risk because of compromised pulmonary function (FEV1 ⬍2.0 L). The confirmed RR for the entire population was 29%, and median overall survival was 13 months (95% CI, 11 to 14 months). The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. Overall, this chemoradiotherapy regimen was well-tolerated in these poor-risk patients and yielded a MS similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. In summary, there is conflicting data regarding the utility of aggressive combined-modality therapy in an elderly population because survival benefit can be achieved only at the expense of mild to moderate increase in toxicity. However, supportive care as well as radiotherapy techniques have improved considerably over the past decade. Hence, there is a need to conduct further phase III locally advanced NSCLC studies specifically targeting the elderly. Until such studies are completed, it is recommended that good-performancestatus patients with limited comorbidity and regionally inoperable NSCLC be offered combined chemoradiotherapy. TREATMENT OF ADVANCED NON–SMALL CELL LUNG CANCER

Cytotoxic chemotherapy is widely used in the treatment of advanced NSCLC. While the MS of patients with stage IV NSCLC receiving best supportive care is 16 to 17 weeks, cisplatin-based chemotherapy can improve MS by roughly 10 weeks.34 Since elderly patients may tolerate chemotherapy poorly as compared with their younger counterparts due to progressive reduction of organ function and comorbidities related to age, older patients are often not considered for aggressive chemotherapy. Fortunately, the evaluation of cytotoxic therapies for older patients with lung cancer has recently become a major focus of clinical research and attempts to develop less toxic regimens have resulted in the completion of three randomized controlled trials in this population (Elderly Lung Cancer Vinorelbine Italian Study Group [ELVIS], Multicenter Italian Lung Cancer

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in the Elderly Study [MILES], and Southern Italy Cooperative Oncology Group [SICOG], see below). The Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS) conducted the first large randomized trial that restricted enrollment to elderly patients with advanced NSCLC.35 This trial compared single-agent intravenous (IV) vinorelbine 30 mg/m2 (days 1 and 8 every 21 days) with best supportive care in patients ⱖ70 of age with stage IIIB or IV NSCLC and performance status 0-2. Although the study was closed after only 191 of the 350 planned patients were accrued because of a low enrollment rate, an objective response of 19.7% was reported for the 76 patients treated with vinorelbine, and a statistically significant survival advantage for patients receiving vinorelbine (MS, 28 weeks v 21 weeks; P ⫽ .03) was shown. Only 10% of patients reported grade 3-4 toxicity with treatment cessation because of toxicity in only five patients. Importantly, quality-of-life measures including the Lung Cancer Symptom Scales favored the vinorelbine arm. Frasci et al36 and the Southern Italy Cooperative Oncology Group (SICOG) performed a small randomized trial of vinorelbine alone versus vinorelbine plus gemcitabine in patients ⱖ70 of age with advanced NSCLC and an ECOG performance status of 0-2. An interim analysis after 120 of the targeted 240 patients were enrolled showed a significant survival advantage for the combination regimen, with a RR of 22% for the combination versus 15% for the single agent. Median survival for the combination arm was 29 weeks versus 18 weeks for vinorelbine alone (P ⫽ .01) and time to symptom deterioration was greater in the combination arm (21 v 13 weeks; P ⫽ .002). However, the combination regimen resulted in significantly more toxicity and there were two toxic deaths in the combination arm versus one in the vinorelbine-alone arm. This study was criticized because the single-agent arm produced unexpectedly inferior results similar to those observed historically after best supportive care, possibly because patients with brain metastases were allowed on this trial. Gridelli et al37 and the Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial reported a much larger study that showed no advantage for the two-drug combination of vinorelbine (V) plus gemcitabine (G) compared with either agent alone. Eligibility criteria included patients

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ⱖ70 years of age with stage IIIB/IV NSCLC and a performance status 0-2. Among the 698 patients available for intention-to-treat analysis, no significant difference in MS was shown between the arms (V, 36 weeks; G, 28 weeks; V⫹G, 30 weeks). Quality of life was also similar. Combination treatment resulted in more thrombocytopenia and hepatotoxicity than single-agent vinorelbine and also more neutropenia, vomiting, fatigue, cardiotoxicity, and constipation than single-agent gemcitabine. Therefore, single-agent therapy appears to be comparable to nonplatinum doublets. Although, gemcitabine and taxanes have also been investigated as single agents and have shown reasonable activity and toxicity,38,39 many investigators still regard vinorelbine as the agent of choice in this population Aggressive chemotherapy with cisplatin-based combinations may be an option in certain subgroups of the elderly population. Although randomized trials are not available that directly compare more aggressive with less aggressive chemotherapy, retrospective elderly specific subgroup analyses of cisplatin combinations have been performed. Overall, outcomes are comparable to younger age groups, although a trend toward greater toxicity has been noted. Langer et al40 evaluated data from patients enrolled in ECOG 5592, a phase III study comparing cisplatin/etoposide with cisplatin/paclitaxel. In this study, 86 of 574 patients were ⱖ70 years of age. Outcomes (⬍70 years v ⱖ70 years) were similar with respect to RR (21.5% v 23.3%), MS (9.05 months v 8.53 months), and 1-year survival (38% v 28%) for both age groups. The incidence of neutropenia and neuropsychiatric toxicity was higher in the older age group. The SWOG has performed two relevant trials. SWOG 9308 randomized patients to cisplatin alone or cisplatin combined with vinorelbine, while SWOG 9509 randomized patients to cisplatin and vinorelbine or to paclitaxel and carboplatin. Kelly et al41 performed a pooled analysis on data from these two trials to determine the effect of age on survival and toxicity. A nonsignificant trend toward decreased MS was observed among the older patients (6.9 months v 8.6 months). However, in a multivariate analysis accounting for age, treatment arm, stage, performance status, and weight loss, there was no significant effect of age on MS. The incidence of severe

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toxicity was 94% in the elderly patients compared with 88% in younger patients (P ⫽ .06). More recently, Cancer and Leukemia Group B (CALGB 9730)42,42a showed superiority of paclitaxel plus carboplatin over paclitaxel alone. Of the 584 patients entered from 1997 to 2001, 158 patients (27%) were ⬎70 years of age. The overall RR and MS of patients receiving the combination were superior to those of patients receiving paclitaxel alone (RR 27% v 17%, P ⬍.001; MS 8.8 v 6.7 months, P ⫽ .01). Results in the elderly patient subset were similar to those of the younger patient subset (RR 36% v 21%; MS 8.0 v 5.8 months). In summary, good-performance-status elderly patients may be candidates for combination chemotherapy and those with poor risk features may still benefit considerably from single-agent therapy. However, further randomized clinical trials focused on the benefits and tolerance of chemotherapy in the elderly are essential. TREATMENT OF SMALL CELL LUNG CANCER

Although the proportion of patients with small cell lung cancer (SCLC) in the general population decreased from 17.4% in 1986 to 13.8% in 1998,43 the number of elderly patients (⬎70 years) with SCLC is increasing. Small cell lung cancer now accounts for 25% to 40% of lung cancer cases in patients at least 70 years old at diagnosis.44,45 It is characterized by rapid growth, early dissemination, and development of drug resistance during the course of disease.46 Polychemotherapy is the cornerstone of treatment in this disease, and results in overall RRs of 70% to 80% for limited disease and 60% to 70% for extensive disease, unequivocally improving survival. In limited disease, MS is approximately 12 to 16 months, with 4% to 5% of patients becoming long-term survivors. In extensive disease, MS is 9 to 11 months.47 However, the effect of age on response and survival in SCLC is less clear. TREATMENT OF LIMITED-DISEASE SMALL CELL LUNG CANCER

The standard treatment for LD-SCLC consists of a combination of chemotherapy and thoracic radiotherapy, with concurrent chemoradiotherapy seeming to offer longer survival than the sequential chemoradiotherapy.48,49 Albain et al50 analyzed the SWOG database of 2,580 patients par-

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ticipating in 10 SCLC trials between 1976 and 1988. Recursive partitioning amalgamation analysis of 1,137 patients in both limited and extensive disease trials showed that normal or abnormal LDH, absence or presence of a pleural effusion, and age less than 70 or ⱖ70 years were important prognostic factors in limited disease, but only LDH was significant in extensive disease. Siu et al51 performed a retrospective analysis of data from two multicenter, randomized trials of LD-SCLC conducted by the National Cancer Institute of Canada, in which 88 of the 608 patients were ⱖ70 years of age. Younger and older age groups were well-matched in terms of treatment protocol, performance status, and serum LDH level. Age was found to be a significant negative predictor of overall survival when analyzed as a continuous variable in a univariate model, but was no longer an independent prognostic factor in a multivariate regression analysis because advanced age correlated with a higher rate of dose omissions. Pignon et al52 conducted a meta-analysis of 13 trials containing 2,140 patients comparing chemotherapy alone with chemoradiotherapy in limited-disease SCLC (LD-SCLC). The relative risk of death in the combined therapy group as compared with the chemotherapy group was 0.86 (95% CI, 0.78 to 0.94; P ⫽ .001), providing a 5.4% benefit in overall survival at 3 years. However, this benefit was confined to the younger age group. The relative risk of death in the combined therapy group was 0.72 for patients less than 55 years old as compared with 1.07 for patients over 70 years. Yuen et al53 performed a retrospective subset analysis evaluating the outcomes for elderly patients with LDSCLC enrolled in Intergroup trial 0096 (ECOG/ RTOG). In this study, patients received cisplatin and etoposide for four cycles and either once- or twice-daily concurrent thoracic radiotherapy to 45 Gy. Of 381 patients, 50 (13%) were ⱖ70 years of age. The older and younger groups did not differ significantly with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (grade 4-5: 61% v 84%; P ⬍.01) and fatal toxicity (1% v 10%; P ⫽ .01) occurred more often among older patients. There were no differences in the frequency of nonhematologic toxicities. Response rate (88% v 80%; P ⫽ .11), event-free survival rate (5-year, 19% v 16%; P ⫽ .18), time to local failure, and duration of response did not differ between groups. Overall 5-year sur-

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vival rates (22% v 16%; P ⫽ .05) favored those younger than 70 years. However, much of this difference was caused by early deaths in the elderly during the first 6 months of the study. The literature on chemoradiotherapy treatments specifically designed for elderly patients with LD-SCLC is limited. Murray et al54 performed a phase II study evaluating an abbreviated treatment for elderly or infirm patients with LDSCLC, in which 55 patients (median age, 73 years) were treated with one cycle of cyclophosphamide, doxorubicin, and vincristine (CAV) followed 3 weeks later by one cycle of etoposide and cisplatin (EP). Thoracic radiation (20 to 30 Gy) was delivered concurrently with EP. The objective RR was 89% (CR 51% ⫹ PR 38%) with a MS time of 12.6 months and the 2- and 5-year survival rates were 28% and 18%, respectively. Jeremic et al55 performed a phase II study of a short-term combination regimen consisting of two cycles of carboplatin and etoposide with accelerated hyperfractionated radiotherapy for elderly patients with LD-SCLC. Seventy-five patients aged 70 years or older with a performance status of 60 or greater and no other major medical problems were enrolled in this study. The overall RR was 75% (CR 57% ⫹ PR 18%). Median survival was 15 months and 2- and 5-year survival rates were 32% and 13%, respectively. Grade 3 leukopenia, thrombocytopenia, and esophagitis were observed in 8.3%, 11%, and 2.8% of these patients. Only one patient experienced grade 4 acute toxicity (thrombocytopenia). Although elderly patients with LD-SCLC may not benefit to the same extent as younger patients, these studies suggest a modest but real improvement in long-term survival. Therefore, elderly patients should not be treated with the assumption of palliative intent alone, and further studies using modified regimens that specifically target the elderly population are warranted. TREATMENT OF EXTENSIVE-DISEASE SMALL CELL LUNG CANCER

Although cure is seldom achieved, combination chemotherapy for extensive-disease SCLC (EDSCLC) can palliate symptoms, prolong survival, and improve quality of life. However, aggressive chemotherapy in an older population with EDSCLC may be limited by increased toxicity. Oshita et al56, using a cisplatin-based regimen in

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patients over 75 years old, and Findlay et al57, using an intensive combination of vincristine, cyclophosphamide, doxorubicin (OCA regimen) in patients over 70 years old, have both reported a level of toxicity (particularly myelosuppression) greater than anticipated. Oshita et al observed that nine of 10 eligible patients in his study experienced grade 4 neutropenia and six patients had infectious episodes requiring antibiotics, while grade 3 anemia and thrombocytopenia occurred in one and two patients, respectively. Similarly, Findlay et al observed that three of the 32 patients treated on the OCA regimen died and 26 patients experienced grade 3-4 hematologic toxicity. However, growth factor support was not used. Kelly et al58 analyzed data from 34 elderly (⬎65 years) and 62 young patients with SCLC treated with combination chemotherapy including vinca alkaloids and noted peripheral neuropathy to be more common in patients over 65 years old. In view of these concerns, single-agent chemotherapy has been promoted as a means of palliating symptoms of ED-SCLC and providing elderly patients with a “gentler” treatment option. Oral etoposide has been used as a single-agent in the treatment of elderly patients with SCLC, largely because of its ease of administration and acceptable toxicity. Four phase II studies59-62 in SCLC patients aged more than 70 years showed RRs between 53% and 71% with good tolerance. Bork et al63 found no statistical difference in terms of RR or survival when oral etoposide was used continuously versus every 3 weeks. Tenoposide, an alternative epipodophyllotoxin, also has some activity against SCLC.64,65 However, combination chemotherapy, even with less toxic agents, has now shown superior RRs and survival as well as improved palliation of symptoms and quality of life as compared with single-agent oral etoposide. In a Medical Research Council Lung Cancer Working Party study, Girling66 compared oral etoposide with IV multidrug chemotherapy consisting of either etoposide and vincristine (EV) or cyclophosphamide/doxorubicin/vincristine (CAV) for four cycles. Approximately 170 patients with a median age of 67 years were enrolled in each arm of this study. Planned interim analysis showed a disadvantage in MS for the oral etoposide group (130 days v 183 days in the multidrug group; P ⫽ .03) and a lower overall RR (45% v 51%). Grade 2 or greater hematologic

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toxicity also occurred more commonly in the single-agent arm (29% v 21%). Souhami et al67 compared oral etoposide with IV chemotherapy consisting of alternating cycles of cisplatin/etoposide (PE) and CAV in poor-risk patients with advanced SCLC. Six cycles of chemotherapy were administered every 21 days in both regimens. Interim analysis after entry of 155 patients showed inferior results for the oral etoposide arm in terms of progression-free survival (3.6 months v 5.6 months; P ⬍.001) and overall RR (32.9% v 46.3%; P ⬍.01), resulting in closure of the study. With the exception of acute nausea and vomiting associated with IV chemotherapy, all aspects of symptom control and quality of life were either equivalent or inferior in the oral etoposide group. With the availability of an increasing choice of chemotherapeutic agents, regimens designed with the specific purpose of decreasing toxicity have been adapted for use against SCLC in the elderly or in poor-prognosis populations. Numerous phase II studies of the combination of etoposide and carboplatin in the treatment of SCLC have been performed.68-71 Although, myelosuppression is frequently observed, the combination appears to be active and feasible in elderly patients who may otherwise be deprived of the benefits of combination chemotherapy. The combination of oral etoposide and oral cyclophosphamide has also been investigated. Grunberg72 treated 57 poor-risk patients with ED-SCLC (SWOG PS 2 or serum albumin ⬍3.5 g/dL) with this combination (days 1 to 14 every 28 days) and showed reasonable efficacy (RR, 40%; MS, 7 months) with only modest toxicity. Some investigators have also attempted to design regimens specifically targeting the elderly population. Phase II results of the PAVE regimen have been published by Westeel et al73 from the Lung Tumor Group in Canada. The objectives of this study were to develop a regimen for older patients (⬎65 years of age) with SCLC that would maintain efficacy, diminish toxicity, enhance compliance, and ease administration at acceptable costs. Patients received cisplatin 30 mg/m2 IV on day 1, doxorubicin 40 mg/m2 IV on day 1, vincristine 2 mg IV on day 1, and etoposide 100 mg/m2 IV on day 1 and orally on days 3 and 5 every 3 weeks for four cycles. Twenty-five patients with LD-SCLC and 41 patients with ED-SCLC were treated with a MS of 70 weeks and 46 weeks, respectively. Only one treatment-related death oc-

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curred, and severe toxicity was infrequent. Another phase II effort developing a gemcitabinebased combination in elderly patients with extensive stage SCLC (the G-STEP study) is currently in progress.74 ROLE OF PROPHYLACTIC CRANIAL IRRADIATION IN ELDERLY PATIENTS WITH SMALL CELL LUNG CANCER

The use of prophylactic cranial radiotherapy (PCI) in the elderly population remains controversial. Brain metastases are common in SCLC and occur in about 50% to 60% of patients within 2 years following complete response to induction therapy.75 Prophylactic cranial radiotherapy will reduce the rate of brain metastases as a first site of recurrence from 45% to 19%.76 Auperin et al77 conducted a meta-analysis of seven randomized trials of PCI in complete responders and showed that PCI also resulted in a significant increase in disease-free survival and an improvement in 3-year survival rate of 5.4%. This advantage seemed to be preserved in older age groups. Several series reporting long-term follow-up after cranial radiotherapy have raised concerns regarding the possibility of neuropsychiatric deterioration.78-80 Long-term follow-up of the National Cancer Institute Navy series81 of patients who received PCI for the treatment of SCLC has shown a steady and measurable decrease in neuropsychiatric function persisting for many years following therapy. Of 15 long-term survivors (6 to 13 years) who were re-evaluated, 13 had neurologic symptoms, 10 had an abnormal neurologic examination, seven had an abnormal mental status examination, 12 had abnormal neuropsychologic testing, 12 had abnormal cranial computed tomography scans, and seven had white-matter abnormalities on magnetic resonance imaging scans of the brain. The higher incidence of pre-existing arteriosclerotic disease in the elderly population could be considered to be a predisposing factor for neurotoxicity. Neurocognitive deterioration in older SCLC regimens could also be attributed to specific chemotherapy agents and radiotherapy doses and schedules. However, Cull et al82 prospectively assessed cognitive function and showed significant differences between SCLC patients and controls before treatment initiation, with up to 40% of patients showing significant impairment. Significant further deterioration was not observed

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in a subsequent large multicenter trial conducted in the United Kingdom.83 Similarly, Van Oosterhout et al84 performed careful neurologic and neuropsychologic examinations on 59 SCLC survivors (⬎2 years from diagnosis) who underwent cranial computed tomography or magnetic resonance imaging and found no statistical evidence for excessive neurotoxicity with PCI. Therefore, the need for PCI should be carefully evaluated in each individual patient. UPPER AERODIGESTIVE TRACT CANCER IN OLDER PATIENTS

Tumors of the head and neck region represent approximately 5% of all cancer in the United States. Approximately 70,000 cases per year are reported, with 80% of these being squamous cell carcinomas.85 Although the peak incidence of head and neck squamous cell carcinoma (HNSCC) is between the fifth and seventh decades of life, occurrence in the older population is not rare. It has been estimated that as many as 24% of head and neck cancers are found in older patients.86,87 Head and neck cancer is historically a predominantly male disease. The usual male: female ratio for head and neck cancer may vary between 8:1 and 15:1.88-90 However, Sarini et al91 found a relatively higher proportion of females among older patients compared with younger patients (male:female ratio, 6:1 v 23:1; P ⬍.001). Lusinchi et al92 found an unusual male:female sex ratio of 5:4 in France. This lower ratio in elderly head and neck cancer patients may be explained on the basis of a longer life expectancy in females. There are notable differences between younger and older age groups in terms of etiology, presentation, and molecular-biologic mechanisms of HNSCC. The etiology of this cancer is well-established and predominantly involves tobacco and alcohol consumption. However, significantly lower smoking and drinking rates were found in a group of elderly HNSCC patients in comparison to a control group of HNSCC patients younger than age 70 treated at the Johns Hopkins Hospital between 1988 and 1993.93 In the elderly group, 47 out of 79 patients (59.5%) had a smoking history, while 89 out of 100 patients (89%) in the younger age group were smokers. Thirty (37%) of the older patients had significant alcohol consumption compared with 69 (69%) of the control group. Furthermore, there were 28 (34.6%) individuals in

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the older group who were neither drinkers nor smokers, compared with only seven patients (7%) in the younger group. Similarly, Nelson and Ship94 noted in 1971 that less than 60% of their 52 elderly patients with oral cancers indulged in heavy alcohol or tobacco consumption. There is no marked difference noted in the distribution of primary tumor sites. The larynx, oropharynx, and oral cavity are the three tumor sites usually found in elderly patients, although in some series there is a trend toward fewer patients with cancer of the hypopharynx and more patients with cancer of the oral cavity in the older patient group.91 Elderly groups have been found to present with more locally advanced lesions (T4) but fewer nodal metastases in the neck.95 Overall, the distribution of disease stage seems comparable in both age groups. No major differences have been found in tumor differentiation between younger and older groups.92,95,96 Because elderly populations with HNSCC have a lower rate of exposure to known risk factors, one can infer that advanced age itself may play a role in the development of this malignancy. Some investigators view HNSCC as a degenerative disorder related to the aging process. A number of theories have been proposed to explain an agerelated risk for HNSCC. First, advanced age allows for the accumulation of mutations that arise spontaneously or from exposure to environmental factors. The efficiency of DNA repair may decrease with advancing age as well.97 Another possible age-related mechanism of cancer progression is alteration in the immune system resulting in decreased efficiency of immune surveillance against cancer.98 Abnormalities in p53, the tumor suppressor gene, are the most frequent molecular events in human neoplasms.99 Boyle et al100 has specifically studied p53 status in elderly patients with head and neck carcinomas and found a significantly lower rate of p53 mutation in the elderly population. Brennan et al101 had previously shown that patients whose tumors lack mutation in the p53 gene have a lower incidence of tobacco and alcohol use than those with tumors containing a p53 mutation. The same group93 expanded this analysis to show that elderly patients with HNSCC have both significantly fewer p53 mutations and significantly less exposure to carcinogens. They also showed that elderly patients with HNSCC are significantly more likely to have second primary

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cancers, particularly outside the head and neck areas. Thirty-one percent of older patients had second cancers (including two individuals who had three primary malignancies), while 20% of the patients in the control group had two primary cancers. These observations again support the concept of an age-related mechanism for the development of malignancy in elderly patients with HNSCC. TREATMENT CONSIDERATIONS FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA IN THE ELDERLY

In general, the same management principles apply to the treatment of HNSCC in the older population as for the treatment of lung cancer. For fit patients with a reasonable performance status, current therapeutic recommendations include definitive surgery or radiotherapy alone for early stage lesions, while more advanced disease is best treated with combination therapy. The role of chemotherapy either in the neoadjuvant or adjuvant setting remains less well-defined. There is conflicting data as to whether advancing age impacts the choice of treatment. In European Organization of Research and Treatment of Cancer trials including a total of 1,589 patients with HNSCC, subjects older than 70 years of age accounted for only 12% of the trial population; patients ⱖ75 represented only 1.9%.88 This tendency for less aggressive therapy was confirmed by Sarini et al91 in a retrospective review of 273 cases. Surgery was less often used for older patients than for younger patients both for the primary site (13.9% v 27.4%; P ⬍.001) and for nodal metastases (15.4% v 35.6%; P ⬍.001). Radiotherapy was used equally in both groups but the combination of surgery and radiotherapy or chemotherapy was less frequently used in older patients. However, in a series of 139 patients with oropharyngeal cancer, Chin et al102 found no evidence for age as a selective factor for treatment intent when patients over 70 years of age were compared with those less than 70 years. In this study, factors that independently predicted treatment intent were T stage and performance status. Although elderly patients are frequently considered high-risk surgical candidates, appropriate surgical therapy of head and neck cancer can be as effective in elderly patients as in younger patients, and without a significant increase in complication

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rates. Head and neck surgery is actually better tolerated than other major surgical procedures in the elderly population,103 and a higher rate of complications or surgical mortality in older patients following major head and neck surgery has not been seen.104 Koch et al93 assessed the rate of postoperative complications seen in 52 of 57 elderly patients who underwent surgery for HNSCC. Two thirds of the patients who suffered major complications of surgery were known to have cardiovascular disease or diabetes mellitus. McGuirt and Davis,103 in a retrospective analysis of 217 elderly patients, found that only nine patients died within 30 days of surgery (defined as “surgical mortality”). This mortality rate of 4% is comparable to that for patients younger than 65 years who undergo head and neck cancer surgery.105 During the last three decades, reconstructive techniques following radical head and neck surgeries have markedly advanced. Bridger et al106 concluded, for example, that advanced age should not preclude the use of free-flap reconstruction for head and neck cancer. Any preoperative assessment of the elderly head and neck cancer patient should therefore take into consideration age-related risk factors that impact on perioperative and surgical management such as cardiovascular and respiratory status. There is a limited literature focusing on either radiotherapy or combined modality therapy in older patients with head and neck cancer. Chin et al102 observed that age is not directly related to the risk of locoregional failure, but that older patients receive lower doses of radiation. Similarly, no significant differences exist in terms of RRs and survival between younger and aged patients receiving similar therapy. Decreasing the rate of curative radiation is generally attributed to concern about increasing toxicity.107 However, radiotherapy used for treatment of head and neck cancer in the elderly does not seem to generate drastically different toxicity patterns compared with that of the general population. Ampil et al108 conducted a retrospective analysis between 1977 and 1992 of 43 elderly patients (mean age, 63 years) with stage III or IV head and neck cancer who underwent curative surgery and postoperative radiotherapy (n ⫽ 33) or neoadjuvant chemotherapy (CDDP/5-FU/VP16) plus radiotherapy (n ⫽ 10). The survival rate at 3 years was 27% (9/33) in patients managed by surgery plus radiotherapy, and 30% (3/10) in individuals

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treated with chemoradiotherapy; the corresponding locoregional failure rates were 23% (7/30) and 30% (3/10); and distant failure rates were 13% (4/30) and 0% (0/10), respectively. There was greater acute toxicity among the chemoradiotherapy patients (30%; 3/10) compared with the surgery/radiotherapy group (12%; 4/33); while late complication (eg, dental caries necessitating teeth extractions) rates were 10% (1/10) and 0% (0/33), respectively. There were no deaths from toxicity and no cases of osteoradionecrosis. Similarly, Lusinchi et al92 analyzed 331 older HNSCC patients (⬎70 years of age) with severe comorbid diseases and found a 5-year survival rate of 19% for this group. Fifty-nine patients had surgery and radiotherapy, 249 had radiotherapy alone with curative intent, and 54 patients received palliative radiotherapy. Of the 331 patients, 57 (17%) developed severe mucositis requiring nasogastric tube feeding in 31 cases. With respect to late side effects, only 3.6% developed mucosal necrosis, 2.1% osteonecrosis, and 2.7% laryngeal edema. These results are totally comparable with the toxicity patterns for older patients in The European Organization of Research and Treatment of Cancer trials.88 Patients over 65 years of age with good performance status accounted for more than 20% of 1,589 patients with HNSCC treated with radiotherapy in these trials. No significant difference was found in terms of response and survival between younger and aged patients. However, older patients had more severe (grade 3 and 4) acute toxicity (P ⬍.001) and only 18% were free of late effects at 5 years. CONCLUSION

Aerorespiratory cancers continue to be a major health problem for the elderly population, with inherent contradictions in etiology and staging. Although increased age implies an increased duration of carcinogen exposure and concomitant comorbid conditions, the tendency toward earlier stage disease in the elderly can be considered encouraging in terms of treatment planning. The importance of consideration of physiologic rather than chronologic age in determining treatment and estimating prognosis for this group of patients is thus increased. Aggressive but appropriate intervention can have significant benefit. Familiarity of oncologists with the components of a complete geriatric assessment will become more necessary

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