Elderly Patients with Lung Cancer: Biases and EvidenceCorey J. Langer, MD

AddressFox Chase Cancer Center, 71 Burholme Avenue, Philadelphia, PA 19111, USA.E-mail: cj_langer@fcc.eduCurrent Treatment Options in Oncology 2002, 3:85–102Current Science Inc. ISSN 1527-2729Copyright © 2002 by Current Science Inc.

IntroductionMore than 60% of newly diagnosed patients with non–small-cell lung cancer (NSCLC) are older than age 60 and30% to 40% are 70 years of age or older [1]. Yet this agegroup is underrepresented in clinical trials. Two facts con-tribute to this: the incidence of functional dependencyand comorbidities, and the risk of chemotherapy-related

toxicity escalates more rapidly after the age of 70. Otherfactors include the following: 1) exclusion of olderpersons based on eligibility criteria; 2) presence of exclu-sionary comorbidities; 3) use of aggressive treatment thatcould conceivably produce unacceptable toxicity for olderpersons; 4) lack of trials designed specifically for the

Opinion statementAlthough 60% of those diagnosed with non–small-cell lung cancer are 60 years of age or older, the elderly are often undertreated. Furthermore, those older than age 70 are under-represented in clinical research trials. Tremendous bias exists against treating the elderly; therapeutic nihilism and constrained societal/financial resources conspire to maintain the status quo. In limited stage small cell carcinoma of the lung (SCLC), a pivotal meta-analysis by Pignon et al. showed no obvious benefit for chemoradiation over chemotherapy alone in patients older than 70 years of age. However, more recent trials have revealed a clear-cut benefit for fit elderly patients to receive combined modality therapy versus chemotherapy alone, even though outcome generally remains superior for younger patients. For patients with locally advanced non–small-cell lung cancer, conflicting results exist. Individual trials evaluating combined modality therapy have shown no impairment in survival for older patients, but retrospective analyses of the Radiation Therapy Oncology Group database have demonstrated that increased therapeutic intensity does not translate into improved outcome compared with standard, single daily fraction radiation alone. Weighted survival analyses that deduct time spent with progressive disease or significant toxicity have reinforced this notion. In advanced non–small-cell lung cancer, fit elderly patients who receive platinum-based regimens do as well, or nearly as well, as patients younger than age 70, although the incidence of neutropenia and fatigue is often higher. Platinum doses above 75 mg/m2 every 3 weeks to 4 weeks are relatively more toxic in the elderly than are lower doses. Three separate studies from Italy have formally assessed the elderly. One showed superiority for single-agent vinorelbine versus best supportive care regarding survival rates and quality of life. A second showed a marked survival advantage for combination vinorelbine and gemcitabine versus vinorelbine alone. However, a much larger, more credible study demonstrated no benefit for combination vinorelbine and gemcitabine versus the constituent single agents. To date, no elderly-specific trials have addressed the role of taxanes or of platinum-based combination therapy versus non-platinum monotherapy or doublets. Comprehensive evaluation of comorbidities and their influence on outcome have not been conducted, and there are virtually no data for patients older than age 80.

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elderly; 5) limited therapeutic expectations by physicians,relatives, and patients; 6) failure to refer patients to cen-ters where trials are available; and 7) lack of financial,social, or logistical support for participation in trials [1].These factors help fuel age bias but they should not pre-clude enrollment on appropriate treatment trials, particu-larly if performance status and other eligibilityqualifications are satisfied.

Persons 65 years of age and older are the fastestgrowing portion of the US population and will consti-tute 20.1% of the population by 2030, more than dou-bling to approximately 70 million. The percentage ofAmericans 75 years of age or older will triple by 2030;those 85 years or older will double in the same period

[2]. The scant data for elderly patients with cancer ingeneral, and lung cancer in particular, make evidence-based guidelines difficult, but not impossible. Duringthe past 3 years to 4 years, many retrospective studieshave specifically focused on outcome in the elderly; inthe past 2 years to 3 years, three separate elderly-specificphase III randomized studies in advanced NSCLC haveattempted to determine optimal therapy.

ACKNOWLEDGMENTThe author is deeply indebted to Judy Herman, with-out whom production of this article would not havebeen possible.

Treatment of small-cell carcinoma of the lung

Extensive small-cell lung cancer (SCLC)• A retrospective assessment of Spanish patients with SCLC [3] demonstrated

that age was not a relevant factor. The authors evaluated clinical parameters such as stage, comorbidities, performance status, and treatment delivery, and assessed results in two separate groups: younger than 70 years and 70 years or older. Of those assessed with SCLC, 38% were in the older age category, but only 9% of those enrolled on clinical trials were age 70 or older (P = 0.02). There were no differences in response rate, toxicity, or survival between the two age categories, even though older patients were more likely to receive less treatment, decreased dose intensity, and lower doses of radiation.

• A separate multiple regression analysis demonstrated that age was not a factor in prognosis; extent of involvement (limited versus metastatic), serum albumin, serum LDH, and weight loss status were predictive of survival [4].

• Although age per se is not an adverse prognostic factor in SCLC [5], age has an impact on a patient's ability to tolerate "standard" induction therapy, which could conceivably adversely affect survival [6,7]. Shepherd et al. [6] reviewed the clinical course of 122 elderly SCLC patients (70 years or older) treated at the University of Toronto between 1976 and 1988. Median sur-vival of patients with limited-disease SCLC (LD-SCLC) was 11.9 months versus only 5.2 months for patients with extensive disease (ED). Survival strongly correlated with the treatment delivered. Median survival for patients receiving no therapy was just 1.1 months; patients able to tolerate four or more cycles of chemotherapy had a median survival of 10.7 months, whereas patients receiving three or fewer cycles of treatment lived an average of just 3.9 months. Fewer than 50% of older patients could receive six scheduled cycles of therapy; only two patients could complete all planned chemotherapy without dose reduction. The most common reason for dosing compromise was myelosuppression.

• In a similar effort, Findley et al. [7] showed that standard chemotherapy was associated with a higher response rate (84% versus 54%, P = 0.006) compared with single agent etoposide or radiotherapy alone. However, increased response rate did not translate into improved survival and was associated with substantially more toxicity. Only two of 72 patients aged 70 to 80 years survived 2 or more years. Recently, randomized trials indi-cated that gentler treatment (eg, oral, single agent etoposide) was inferior

Elderly Patients with Lung Cancer: Biases and Evidence Langer 87

to standard combination etoposide-cisplatin [8,9], even though prior studies in elderly or infirm patients suggested comparable efficacy and reduced toxicity [10].

• Relatively few recent studies have specifically targeted the elderly with SCLC. The Vancouver British Columbia Group in the late 1990s reported the results of Phase II study of the PAVE regimen in elderly patients [11]. The investigators' goal was to design a therapeutic regimen with dimin-ished toxicity, enhanced compliance and acceptable costs. Patients received cisplatin 30 mg/m2 IV day 1, doxorubicin 40 mg/m2 IV day 1, vincristine 2 mg IV day 1, and etoposide 100 mg/m2 IV day 1, and orally days 3 and 5, 3 weeks for four cycles. There were no treatment-related deaths, and severe toxicity was relatively infrequent. The median survival for limited disease patients was 46 weeks; for extensive stage patients it was 46 weeks, compa-rable to published results of standard, potentially more toxic regimens in patients with “better prognostic features.”

Limited disease small-cell lung cancer (LD-SCLC)• Pignon's meta-analysis of 13 separate trials comparing chemotherapy alone

to chemoradiation in limited disease demonstrated a 5.4% absolute improvement in 3-year survival rate for patients receiving combined modality therapy [12•]. However, this benefit was confined to patients younger than age 70, particularly those younger than 55 (hazard ratio 0.72, CI 0.56–0.93). In the older age group, the hazard ratio for death was slightly higher at 1.07 (CI 0.70–1.64). As a result, in Europe and in many other parts of the world, elderly patients with limited disease are treated almost identically to patients with extensive disease. But this observation is relevant only to trials that were included in the meta-analysis, virtually all of which concluded enrollment before 1990.

• More recent trials have strongly suggested a potential benefit for the elderly. In particular, Yuen et al. [13••] evaluated outcome of elderly patients with LD-SCLC enrolled on Intergroup trial 0096 Eastern Cooperative Oncology Group/Radiation Therapy Oncology Group (ECOG/RTOG), which assessed cisplatin and etoposide in combination with thoracic radiation, adminis-tered either once or twice daily. Given our current treatment strategies for limited disease, which strongly support the superiority of concurrent chemo-radiation upfront, this retrospective assessment is probably the most relevant to date. Of 381 evaluable patients, 50 were 70 years or older. There was no significant difference regarding gender distribution, performance status, or weight loss. However, grade 4 or greater hematologic toxicity (61% versus 84%, P < 0.01) and fatal toxicity (P = 0.01) occurred more often in older patients. Consequently, treatment completion rate was 90% for younger patients versus 72% for those older than 70 years (P =0.02). Despite this, response rate overall was 88% for younger patients, compared with 80% for older patients (P = 0.11). Five-year event-free survival was no different (19% versus 16%; P = 0.18) nor was there any difference in time to local failure or duration of response. Overall, 5-year survival rate for younger patients was 22% versus 16% for older patients (P = 0.05). The bulk of this difference was due to early deaths in the first 6 months on study. Despite the borderline significant advantage for younger patients, the long-term survival rate cited by Yuen in the elderly was unprecedented and had not been previously substantiated in the Pignon meta-analysis or in other individual series. Hence, fit elderly patients with SCLC, regardless of disease extent, merit aggressive therapy and stand a reasonable chance of benefit.

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• Cisplatin and carboplatin in combination with etoposide is the most com-monly used regimen in small-cell lung cancer. Cisplatin is used at a fixed meter squared dose; carboplatin dosing is almost exclusively calculated using the Calvert formula to determine the area under the curve (AUC) dose from the creatinine clearance [31]. Carboplatin dosing can be simplified further by using the serum creatinine to calculate the creatinine clearance using the Cockroft-Gault formula [32]. Chemotherapy with platin and etoposide are usually given every 21 days for six cycles. The CAV regimen or the CAE regimen is used less commonly in the US, but is still popular in Europe.

Cisplatin

Standard dosage 60 mg/m2 to 75 mg/m2 on day 1 of each 21-day cycle; alternatively 20 to 25 mg/m2 per day X 3 Q 21 d.

Contraindications Should not be used in patients with renal dysfunction, hearing loss, or significant neuropathy.

Drug interactions Aminoglycosides.Main side effects Nausea and vomiting, renal and ototoxicity, neurotoxicity.

Special points Forced diuresis with excess chloride is usually given to minimize nephrotoxicity. Pretreatment with serotonin antagonists such as ondansetron and granisetron is critical.

Cost effectiveness No data exist.

Carboplatin

Standard dosage AUC (5) using the Calvert formula for dosing day 1 of a 21-day cycle.Contraindications No known contraindications other than previous hypersensitivity.Drug interactions No known drug interactions.Main side effects Neutropenia and thrombocytopenia.

Special points No prehydration required; dose adjusted for kidney function.Cost effectiveness Usually more expensive than cisplatin, but costs are mitigated by decreased need

for anti-emetics, intravenous fluids, nursing time, and adverse event management.

Cyclophosphamide

Standard dosage 1000 mg/m2 day 1 of each 21-day cycle. Usually given as part of the CAV regimen for four to six cycles.

Contraindications No known contraindications other than previous hypersensitivity.Drug interactions No known drug interactions.Main side effects Nausea and vomiting are common. Hematologic toxicity is dose dependent.

Bladder toxicity or hemorrhagic cystitis can occur using higher doses of drug.Cost effectiveness No data exist.

Etoposide

Standard dosage 100 mg/m2 to 120 mg/m2 intravenously days 1 to 3 of each 21-day cycle; generally in combination with carboplatin or cisplatin.

Contraindications No contraindications other than previous hypersensitivity.Drug interactions No known drug interactions.Main side effects Myelosuppression; nausea and vomiting are less common.

Cost effectiveness No data exist.

Pharmacologic therapy for small-cell lung cancer

Elderly Patients with Lung Cancer: Biases and Evidence Langer 89

Doxorubicin

Standard dosage 45 mg/m2 intravenously day 1 of each 21-day cycle. Usually given as part of the CAV regimen.

Contraindications Conclusive data are not available on pre-existing heart disease as a cofactor for increased adriamycin-induced cardiac toxicity. Preliminary data suggest that in such cases, cardiac toxicity may occur at doses lower than the recommended cumu-lative limit.

Drug interactions No known interactions.Main side effects Cardiac toxicity is rare but of great concern and is related to cumulative dosage,

generally greater than or equal to 400 mg/m2 to 450 mg/m2. It may occur at lower doses in the elderly. Myelosuppression can occur. Nausea and vomiting are common. Doxorubicin is a potent vesicant, and extravasation precautions are mandatory.

Cost effectiveness No data exist.

Vincristine

Standard dosage 1.2 mg/m2 intravenously (dose cap of 2 mg) day 1 of each 21-day cycle. Usually given as part of the CAV regimen.

Contraindications No known contraindications.Drug interactions No known interactions.Main side effects Cumulative peripheral neuropathy.

Cost effectiveness No data exist.

Thoracic irradiationThoracic irradiation improves local control for all LSCLC patients and increases the probability of cure for LSCLC patients in whom distant disease has been controlled and clones resistant to chemotherapy persist within the thoracic irradiation vol-ume. The rationale that thoracic irradiation must eliminate disease resistant to chemotherapy requires that the treatment volumes be based on prechemotherapy disease since there is no biological reason for resistant clones to be confined to post-chemotherapy volumes.

Standard regimen Dose-fractionation regimes may range from 45 Gy in 15 fractions to 60 Gy in 30 fractions. Twice-daily fractionation (1.5 Gy twice a day to 45 Gy) is also an appropriate standard of care and has been shown to be superior to once daily RT in combination with etoposide and cisplatin. Standard regimens should start on Monday to minimize weekend interruptions. Unnecessary treatment breaks should be avoided. In the absence of infection, thoracic irradiation should not be interrupted for neutropenia, regardless of its severity. The radiotherapy volumes should encompass all areas of gross primary and mediastinal disease, based on CT planning. Thoracic irradiation ideally should be administered during the first or second chemotherapy cycle of EP. If the initial volume is unduly large, delay of thoracic irradiation to the second or third cycle and treatment to a reduced volume may be acceptable.

Contraindications Inadequate pulmonary function, compromised performance status or functional status, pregnancy, collagen vascular disease with active vasculitis.

Main drug interactions Administration of chemotherapeutic agents that radiosensitize normal tissues con-currently with thoracic irradiation should be performed according to data from appropriate published clinical protocols.

Main side effects Esophagitis, dermatitis, pneumonitis, fatigue. Thoracic irradiation increases the probability of long-term survival, but is associated with an increase in second lung cancers if patients continue to smoke. Thoracic irradiation does not increase the risk of second lung cancers if patients discontinue smoking [33].

Special points Application of newer imaging and conformal radiotherapy planning techniques offers the possibility of improved sparing of normal tissue and of escalating the dose to known tumor.

Radiation therapy for small cell lung cancer

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Palliative radiation therapyRadiation therapy can be beneficial in the palliative setting in patients with meta-static small-cell lung cancer. Brain metastasis occurs in 10% of patients at presen-tation and in 50% of patients at some time during the course of the disease [34]. Short, 2-week courses of radiation therapy result in relief of neurologic symptoms in 60% to 85% of patients [35]. Impending spinal cord compression and painful bone metastasis are other sites that can be palliated by radiation therapy. Due to the rapid doubling time of small-cell lung cancer, the use of chemotherapy should not be delayed by prolonged courses of radiation therapy, work-up, or observation.

Standard regimen 3000 cGy in 10 fractions during 2 weeks.Contraindications Myelosuppression due to previous chemotherapy.

Complications No significant complications with low-dose radiotherapy for local disease control.Main side effects Myelosuppression, nausea and vomiting, dryness of skin, and itching.

Special points Steroids are often given concurrently with radiation in symptomatic patients (often dexamethasone, 4 mg to 8 mg, 3 to 4 times per day).

Cost effectiveness No data exist.

Treatment of non–small-cell lung cancer

Locally advanced disease• Unlike small-cell carcinoma of the lung in which aggressive therapy may

benefit the elderly, age to date appears to be a factor in therapeutic outcome in locally advanced NSCLC.

• The Radiation Therapy Oncology Group (RTOG) performed a recursive partitioning analysis of 1999 patients enrolled on various protocols and identified five separate groups with different survival expectations [14]. Nine separate RTOG trials assessing various forms of thoracic radiation therapy (RT) with or without chemotherapy were reviewed. The following characteristics were significantly associated with improved survival: use of chemotherapy, chemotherapy delivered without major deviation; normal hemoglobin, total protein, LDH and blood urea nitrogen (BUN), unin-volved lymph nodes, T1 or T2 stage, absence of malignant pleural effusion, weight loss of less than 8%, Karnofsky performance score (KPS) of at least 70, female gender, and age younger than 70 years. Recursive partitioning analysis delineated five separate prognostic subgroups. Two of these specif-ically included the elderly. Patients older than age 70 with KPS less than 90 had a median survival time of 5.6 months to 6.4 months; those older than 70 with pleural effusion had a median survival time of only 2.9 months.

Retrospective age-specific RTOG analyses• RTOG trial 8808, which compared single daily fraction external beam

radiotherapy (XRT) to either hyperfractionated XRT (69.6 Gy) or sequential chemotherapy (vinblastine and cisplatin) followed by RT, demonstrated a statistically significant improvement in median and long-term survival for patients enrolled on the combined modality arm [15]; but this benefit in a retrospective analysis appeared to be confined to younger patients. Median survival in patients younger than age 60 receiving combined modality ther-apy was 15.4 months versus 11.7 months and 11.5 months, respectively, for single daily and hyperfractionated RT; the corresponding 5-year survival rates were 13%, 5%, and 2% (P = 0.02). However, for patients older than age 70, there were no long-term survivors regardless of treatment assign-

Elderly Patients with Lung Cancer: Biases and Evidence Langer 91

ment. The median survival time for patients receiving standard single daily RT was 13.1 month versus 10.9 months for combined modality therapy, and 9.4 months for hyperfractionated RT [16].

• This observation prompted a much larger retrospective analysis of RTOG combined modality trials with a more focused assessment of the effect of age on toxicity and therapeutic outcome [17]. Six separate trials, each of which assessed combined modality therapy, or compared combined modality therapy to RT alone or to twice-a-day RT were analyzed. Of 765 patients enrolled, 114 (15%) were 70 years of age or older. By and large, enrollment was restricted to "good prognosis" patients with KPS 70 or more and weight loss 5% or less in the 3 months before treatment. Enroll-ees had locally advanced stage IIIA/B or medically inoperable stage II/IIIA NSCLC, with no evidence of pleural effusion, distant metastasis, prior che-motherapy or XRT. Acute grade 4 or higher toxicities were strictly confined to patients receiving combined modality therapy, and the incidence of esophagitis was highest in patients receiving concurrent chemotherapy and hyperfractionated RT. Grade 3 or higher hematologic toxicities and renal toxicities did not occur in patients receiving RT alone. There was no signifi-cant difference in the incidence of late grade 3 or greater toxicities between altered fractionation and combined modality arms, although patients receiving standard single daily RT alone had absolutely no significant or life-threatening late toxicities. The best median survival time (MST) was achieved in patients receiving induction chemotherapy followed by less intensive concurrent chemoradiation (14.2 months). More aggressive forms of chemoradiation (hyperfractionated XRT and concurrent chemo-therapy) resulted in inferior MST of 11.1 months. The median survival time for patients 70 years or older enrolled on all six trials was 47.3 weeks versus 59.8 weeks for those younger than age 70; the respective 1-, 3-, and 5-year survival rates for those aged 70 or older were 46%, 11%, and 3% versus.. 57%, 18%, and 10% for those younger than 70. Treatment completion rates were generally lower for the elderly. Twenty-four percent of those receiving unimodal therapy did not complete treatment, and 21% of those receiving combined modality therapy did not complete treatment as planned, com-pared with 10% and 15%, respectively, for those younger than 70. However, the predominant cause of death remained underlying NSCLC (78%), not protocol complications (5%) or unrelated comorbidities (8%).

• In contrast to the overall patient population, in particular to younger patients, patients 70 years or older did not appear to benefit from increased therapeutic intensity. Grade 4 and 5 toxicities in older patients were con-fined to those receiving combined modality therapy, and survival was not improved. Regardless of treatment modality administered, treatment com-pletion rates in the elderly were lower. The best median survival was observed in those elderly patients receiving combined induction and less intensive concurrent chemoradiation. Long-term survival in the elderly was rare (less than 4%).

• These observations have been reinforced by Movsas et al. [18•] who reported an adjusted survival analysis (Q-time) of RTOG efforts and dem-onstrated the benefit of treatment intensification was age and histology dependent. Q-time in this analysis was calculated by weighing median sur-vival against the duration of specific toxicities and time spent with local or distant tumor progression. Six prospective Phase II and Phase III trials con-ducted between 1983 and 1995 were analyzed. Patients older than age 70 achieved the best Q-time with XRT alone.

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• These observations raise an important question: Should Phase III studies specifically targeting the elderly with LA-NSCLC be conducted? Several out-standing issues remain. Is the absence of benefit for combined modality therapy in the elderly due to a higher incidence of comorbidities, decreased therapeutic tolerance, or intrinsic resistance? Do older patients have a higher incidence of radiation therapy treatment interruptions or delays that might conceivably compromise benefit? Are elderly patients with locally advanced NSCLC biologically different from younger patients?

• The impact of age in more recent trials has not been borne out [19]. A recent retrospective analysis of patients enrolled in RTOG 9410 showed a statistically significant benefit for patients receiving concurrent chemo-radiation versus sequential therapy, and the extent of this benefit was higher and relatively more pronounced in the elderly. But this benefit came at some cost. The median survival in patients aged 70 years or older receiving concurrent chemotherapy and single daily fraction radiation therapy (CON-QD) was 22.4 months versus 16.4 months in those receiving CON-BID and 10.8 months in those receiving sequential therapy.

• The reason for this apparent benefit is not readily discernible. Potential explanations include serendipity; patient selection (a potential tendency to enroll relatively more fit elderly patients compared with younger patients), improved toxicity management and supportive care, and our intrinsic learning curve. As combined modality therapy has become the established therapeutic paradigm in LA-NSCLC, we have grown more comfortable managing toxicities pre-emptively and avoiding dose reductions or omissions.

• Another retrospective analysis in patients receiving combined modality therapy similarly showed no apparent compromise in outcome for older patients [20]. Cancer and Leukemia Group B (CALGB) 9130 randomized patients receiving induction chemotherapy with vinblastine and cisplatin to either RT alone or to definitive thoracic RT and weekly carboplatin. This study was confined to good prognosis patients (PS 0-1) with stage III dis-ease. There was no significant difference in survival between the two arms, and no apparent disadvantage for older patients. Two-hundred and fifty patients were accrued, of whom 54 (22%) were age 70 or older. Treatment completion rates were no different in older patients compared with younger patients. Hematologic toxicity, in particular leukopenia and renal toxicity, were more pronounced in older patients (P = 0.028), but this did not translate into a survival decrement. Median survival for the eldest group was 13.4 months, with a range of 10.9 months to 15.4 months for the four separate age-specific cohorts. Of note, no enrollees were older than age 80.

• In summary, although older studies have shown no definite benefit for aggressive combined modality therapy, more recent studies appear to buck this trend. Hence, age alone should not exclude patients from combined modality protocols designed to determine the optimal integration of cyto-toxic therapy and radiation in LA-NSCLC.

Elderly Patients with Lung Cancer: Biases and Evidence Langer 93

Platinum agents• Both cisplatin and carboplatin have activity and radiosensitizing ability in

NSCLC. Experience is much greater with cisplatin, which remains the most established agent in locally advanced NSCLC in combination with XRT. Carboplatin is being used more frequently in clinical trials and yields potentially less toxicity.

Cisplatin

Standard dosage 100 mg/m2 every 4 weeks; often dose attenuated to 75 mg/m2 in elderly. Doses of 25 mg/m2 to 30 mg/m2 weekly in conjunction with concurrent XRT cisplatin can also be given at a dose of 5 mg/m2 to 6 mg/m2 IV daily during XRT.

Contraindications Caution should be used in patients with renal insufficiency and ototoxicity.Main drug interactions Ototoxicity may be worsened if used with ethacrynic acid. Renal toxicity may be

exacerbated by aminoglycosides.Main side effects Emesis, electrolyte disturbances, myelosuppression, neurotoxicity, and nephrotoxicity.

Special points Cisplatin has been used as induction and concurrent therapy. Can be given daily or weekly during RT.

Cost effectiveness No consistent data exist.

Carboplatin

Standard dosage Area under the curve of 6.0 to 7.5 every 3 weeks X 2-3 during induction; generally attenuated to AUC 2 weekly during XRT.

Contraindications Caution should be used in face of bone marrow suppression.Main drug interactions Aminoglycosides increase risk of ototoxicity.

Main side effects Myelosuppression, emesis, electrolyte disturbances.Special points Can be used daily or weekly during XRT.

Vinca alkaloidsVinblastine

Standard dosage 5 mg/m2 weekly during XRT.Main drug interactions Phenytoin, mitomycin, and ritonavir.

Main side effects Myelosuppression. Vesicant; neuropathy less common.Special points Usually used in combination with a platinum compound.

Vinorelbine

Standard dosage 15 mg/m2 weekly during XRT day 1, day 8 every 3 weeks.Main drug interactions Mitomycin. Simultaneous use of cisplatin can cause higher incidence

of granulocytopenia.Main side effects Emesis, myelosuppression, and peripheral neuropathy. Vesicant.

Topoisomerase inhibitorsEtoposide

Standard dosage Various doses used depending on protocol; can be dosed at 80 mg/m2 to 100 mg/m2 daily X 3 every 3 weeks during XRT, or administered at dose of 50 mg/m2 d1-5, 29 to 33 during XRT.

Main drug interactions Warfarin, methotrexate.Main side effects Myelosuppression.

Special points Topoisomerase II inhibitor can be given orally or intravenously.

Pharmacologic treatment for locally advanced NSCLC

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Irinotecan

Standard dosage 45 mg/m2 to 60 mg/m2 weekly during XRT but differs upon combination used. Lower doses (20 mg/m2 to 30 mg/m2) used in combination with weekly cisplatin.

Main drug interactions Prochlorperazine.Main side effects Diarrhea, vasodilatation (flushing, hypotension), fever, myelosuppression,

and dyspnea.Special points Topoisomerase I inhibitor used in this setting and with RT is still largely experi-

mental.

TaxanesPaclitaxel

Standard dosage 135 mg/m2 to 175 mg/m2 Q 3 weeks with radiation and 225 mg/m2 during induc-tion every 3 weeks. Dosing varies with different protocols. Alternatively (and more commonly), 45 mg/m2 to 50 mg/m2 weekly during XRT in conjunction with carbo-platin AUC 2 weekly.

Contraindications Hypersensitivity.Main drug interactions Cisplatin may decrease clearance.

Main side effects Hypersensitivity reactions, peripheral neuropathy, myalgias and arthralgias, and myelosuppression.

Special points Has been used as 7-day continuous infusion, twice weekly, or weekly during XRT.

Docetaxel

Standard dosage Not yet established. 20 mg/m2 to 30 mg/m2 has been tolerated in phase I trials.Main side effects Myelosuppression, myalgia, fever, hypersensitivity reactions, fluid retention.

Special points Experience with docetaxel in this setting is gaining, but still experimental.

Standard radiation therapy

Standard regimen 60 Gy or more given in daily fractions of 2 Gy, 5 days a week, during 6 weeks.Main side effects Skin necrosis, esophagitis, and pneumonitis. Toxicities are exacerbated by

concurrent administration of systemic cytotoxics.Complications Long-term complications include esophageal stricture, chronic pneumonitis,

and myelopathy.

Hyperfractionated radiation therapy

Standard regimen 69.6 Gy given in twice daily fractions of 1.2 Gy, 5 days a week, over 5.5 weeks.Main side effects Higher incidence of acute toxicities, especially esophagitis, compared with stan-

dard radiation therapy.Complications Same as standard radiation therapy, with equal to slightly higher incidence.

Accelerated hyperfractionated radiation therapy

Regimen 54 Gy given in thrice daily fractions of 1.5 Gy during 12 consecutive days (CHART). Alternatively, 57.6 Gy in thrice daily fractions of 1.6 Gy during 15 days has been used (HART).

Main side effects Earlier onset, more severe, but less protracted esophagitis, often occurring after RT is concluded.

Complications Same as standard radiation therapy.

Radiation therapy for locally advanced NSCLC

Elderly Patients with Lung Cancer: Biases and Evidence Langer 95

Treatment of advanced non–small-cell lung cancer

Single-agent therapy in the ederly• Gemcitabine has been evaluated specifically in patients older than age 70 with

advanced (stage IIIB/IV) NSCLC. At a conventional dose of 1 g/m2 weekly times 3 every 4 weeks, one complete remission (CR) and nine partial remissions (PR) were observed in 48 patients for an overall response rate of 22.2%. Median time to disease progression was 5.1 months (95% confidence interval: 3.5-6.7). Median survival was 6.75 months. There were no significant grade 4 or grade 5 toxicities. As such, gemcitabine was considered reasonable therapy for elderly patients with advanced NSCLC [21].

• Similar results have been obtained with vinorelbine. The landmark Elderly Lung Vinorelbine Italian Study (ELVIS) trial was reported by Gridelli et al. at ASCO and published in the Journal of the National Cancer Institute in 1999 [22••]. Patients age 70 years or older with stage IV or IIIB NSCLC and performance status 0-2, were randomly allocated to best supportive care or to vinorelbine at a dose of 30 mg/m2 days 1 and 8 for a total of six cycles. Quality of life and survival were the primary endpoints. The study was stopped early because of declining enrollment rate after 191 of 350 targeted patients were accrued. A statistically significant survival advantage was observed for patients receiving vinorelbine: a median survival of 6.5 months, and 1-year survival rate of 32% was observed for treated patients compared with 4.9 months and 14%, respectively, for best supportive care (BSC). Response rate for vinorelbine was 20%. Toxicity was tolerable and quality of life and lung cancer related symptom scales favored the treatment arm. The relative hazard of death for patients receiving vinorelbine was 0.65 (95%, CI = 0.45 to 0.93).

Monotherapy versus doublets• A subsequent study by Frasci et al. [23] of the Southern Italian Cooperative

Oncology Group (SICOG) evaluated vinorelbine either alone or in combination with gemcitabine. Patients received vinorelbine 30 mg/m2 days 1 and 8 every 3 weeks, either alone, or in conjunction with gemcitabine 1200 mg/m2 days 1 and 8. Forty-nine patients had stage IIIB disease, 71 had stage IV. Although the study targeted an accrual of 240 (120 patients per arm), an interim analysis after only 120 patients were enrolled indicated a significant advantage for the combination regimen. Median survival was 7 months for the combination arm versus only 4.5 months for single-agent vinorelbine; one-year survival rates were 30% and 13%, respectively. The combination regimen produced significantly more toxicity, but was associated with a clear delay in symptom and/or quality of life deterioration. The response rate for the combination arm was 22% versus 15% for single agent. This study also demonstrated that a higher degree of comorbidity adversely affected treatment tolerance and survival. These results, although positive for the combination arm, were disquieting in that the single-agent arm yielded unexpectedly inferior results, no better than those observed historically for the best supportive care arm in the ELVIS trial.

• A much larger, and potentially more credible, trial was reported by Gridelli et al. [24•] at ASCO in 2001. Eligibility stipulated age 70 years or older, treatment-naïve stage IIIB (N3 or pleural effusion) or stage IV NSCLC, and PS 0-2. Patients were assigned to either vinorelbine 30 mg/m2 days 1 and 8 every 3 weeks; gemcitabine 1200 mg/m2 days 1 and 8 every 3 weeks, or a

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combination of each agent at attenuated doses of 25 mg/m2 and 1000 mg/m2, respectively, days 1 and 8 every 3 weeks. Approximately 30% of patients had stage IIIB disease. Response rates were comparable across all three arms: 18.5% for single agent vinorelbine, 17.3% for gemcitabine, and 20% for combination. There was absolutely no advantage for the combina-tion arm regarding time to progression, median survival, and 1-year sur-vival rate (Table 1). Toxicities were comparable.

• Each of these three randomized studies was conducted in Italy (Table 2), focus on non-platinum regimens. They constitute the "prospective evidence-based literature" available for the elderly with advanced NSCLC. In aggregate, monotherapy appears to be comparable to non-platinum combinations, and vinorelbine is considered by many clinician-investigators to be the standard of comparison. As a single agent, it consistently yields response rates in the 20% range, median survival of 6.5 months to 8 months, and 1-year survival rates exceeding 30%.

Platinum-based therapy in the elderly with advanced NSCLC• To date, there have been no formal Phase III trials comparing single-agent

therapy to cisplatin-new agent combinations in the elderly. However, many retrospective elderly-specific subanalyses of platinum-combinations have been reported.

• Nguyen et al. [25] retrospectively evaluated all patients who received cisplatin and gemcitabine in combination in a Phase III effort that ultimately showed superiority of this doublet to single-agent cisplatin. Patients aged 70 years or older represented roughly 20% of those accrued (53 versus 207). There was no significant difference in dose delivery or grade 3/4 toxicities between the two age cohorts. Overall response rate was nonsignificantly lower at 15%, compared with 29% for those younger than age 70. Median time to progression and survival were 4.8 months and 7.7 months for older patients versus 5.5 months and 9.4 months for younger enrollees; this difference was nonsignificant.

• Martins [26] evaluated the outcome of combination vinorelbine 25 mg/m2 d1 and 8 and cisplatin 60–90 mg/m2 dL in 44 patients older than age 70. Toxicity was acceptable. Overall response rate was 54%; median survival was 7.2 months, and 1-year survival rate was 37%.

• At ASCO 2000, Langer et al. [27•] evaluated patients enrolled on ECOG 5592; subjects with chemotherapy-naive stage IIIB, IV and recurrent NSCLC received a fixed dose of cisplatin (75 mg/m2) combined with either etoposide (100 mg/m2 daily times 3) or paclitaxel (135 mg/m2 or 250 mg/m2 during 24 hours with granulocyte colony-stimulating factor

Table 1. Multicentre Italian Lung Elderly Study

VNR GEM VNR/GEM

Patients, n 233 233 232Stage IIIB, % 29 30 31Response rate, % 18.5 17.3 20TTP, w 18 18 19Median survival, mo 8.8 6.6 7.61-year survival rate 41% 26% 31%

GEM—gemcitabine; TTP—time to progression; VNR—vinorelbine.(Adapted from Gridelli et al. [24].)

Elderly Patients with Lung Cancer: Biases and Evidence Langer 97

[G-CSF support]). Between August 1993 and December 1994, 574 evaluable patients were enrolled. Only 86 (15%) were age 70 or older. Basic demographics were similar to those younger than 70 years, although older patients had a higher incidence of cardiovascular (P = 0.009) and respiratory (P = 0.04) comorbidities; and nonanalgesic medication used (P = 0.02). Leukopenia (P = 0.0001) and neuropsychiatric toxicity (P = 0.003) were more common in elderly patients. The heightened incidence of neuropsychiatric toxicity may have represented an amalgam-ation of side effects, including fatigue, cumulative cognitive dysfunction, and lassitude. Unfortunately, separate scores for each of these toxicities did not exist in the ECOG lexicon. Remaining toxicities were similar.

• Outcome (age 70 or younger versus age 70 or older) regarding response rate (21.5%; 23.3%), time to progression (4.37 months, 4.3 months), median survival (9.05 months, 8.53 months), 1-year survival (38%, 28%), and 2-year survival (14%, 12%) were similar in both groups enrolled in the ECOG effort (Fig. 1). Baseline quality of life and treatment outcome indices were similar, and both groups experienced equivalent declines over time in function and well being. Seven grade 5 adverse events occurred in the elderly, five in the high dose paclitaxel group, of which three were attributed to neutropenic fever. Only 24 patients were older than age 75. This group experienced a relatively higher incidence of grade 3 or greater (4) leukopenia compared with patients between the ages of 70 and 75 (84% (56%) versus 72% (32%), P = 0.06), but there was no significant difference in the incidence of anemia, thrombocytopenia, nausea and vomiting, or neurosensory toxicity for this oldest cohort. The authors concluded that advanced age alone did not appear to compromise overall outcome in fit elderly patients receiving platinum-based therapy. However, only two patients were age 80 or older. Hence, inferences regarding this oldest age group cannot be made.

• Kelly et al. [28] from Southwest Oncology Group (SWOG) conducted a similar analysis of older patients receiving combination chemotherapy for advanced NSCLC. The goal of these investigators was to determine the effect of age on survival, toxicity, and drug delivery in patients with good performance status receiving combination therapy. SWOG 9308 randomized patients to cisplatin alone or to cisplatin in combination with vinorelbine. SWOG 9509 randomized patients to the new standard regimen of vinorelbine and cisplatin versus paclitaxel and carboplatin. A total of 117 patients were age 70 or older, compared with 491 (82%) younger than age 70. Both age groups (younger than age 70 and 70 years or older) were well-balanced regarding baseline stage, performance status, and weight loss.

Table 2. Randomized studies of chemotherapy in elderly patients with advanced non–small cell lung cancer

Author Regimen N Response, % Median survival, mo 1-Year overall survival, %

Gridelli [22••] Vinorelbine 78 20 6.5 32*BSC 76 --- 4.9 14

Frasci [23] Gemcitabine + vinorelbine 76 22 7 30*Vinorelbine 76 15 4.5 13

Gridelli [24•] Vinorelbine 233 18.5 8.8 41Gemcitabine 233 17.3 6.6 26

Gemcitabine + vinorelbine 232 20 7.6 31

NSCLS–Non–small-cell lung cancer*Statistically significant survival difference.

98 Lung Cancer

• Time to progression was similar: 4.2 months for those younger than 70 versus 3.9 months for those age 70 or older (P = 0.62). There was a nonsignificant trend for reduced median survival in the elderly (6.9 versus 8.6 months (P = 0.06)) with a commensurate reduction in long-term survival: one and 2-year survival rates were 30% and 10%, respectively, for those greater than 70 compared with 40% and 16%, respectively, for those younger than age 70. However, in a multivariate analysis, including age, treatment arm, stage, performance status, and weight loss, there was no significant effect of age on either progression-free survival (P = 0.74) or survival (P = 0.10). The overall incidence of grade 3 to grade 5 toxicity was 94% in the elderly compared with 88% in younger patients (P = 0.06). Treatment completion rates and dose intensity were similar, although treatment suspensions for toxicity were more common in elderly patients receiving the more toxic vinorelbine/cisplatin combination, compared with younger patients (P = 0.003). There was no difference in treatment completion rates between elderly and younger patients receiving paclitaxel and carboplatin, strongly suggesting that high-dose, platinum-based therapy was not well-tolerated in the elderly, compared with carboplatin-based combinations.

Carboplatin-based combination regimens in the elderly• The SWOG analysis reinforces previous and contemporaneous observations

by other investigators. Fox Chase Cancer Center patients receiving carboplatin (AUC 7.5) in combination with paclitaxel (either 24-hour infusion or 1 hour) were retrospectively analyzed. Of 110 patients enrolled, 23 were age 70 or older. There was no increase in myelosuppression or neurotoxicity for the elderly, although relatively more fatigue was observed. The respective response rates, median survival, and 1-year survival were 32%, 9.7 months, and 44% for the elderly compared with 50%, 12 months, and 50% for the entire group [29].

• Hensing et al. [30] evaluated patients randomized to a truncated course of therapy (four cycles) versus treatment until disease progression (Table 3). Doses employed were identical in both arms: carboplatin (AUC 6), pacli-

Figure 1. Overall survival.

Elderly Patients with Lung Cancer: Biases and Evidence Langer 99

taxel (200 mg/m2) every 21 days. Sixty-three percent were male, 88% had stage IV disease. Sixty-seven patients (29%) were age 70 or older. All had KPS 70 or greater. Toxicity patterns were virtually identical. There was a nonsignificant trend toward more fatigue in the older group. The median survival for patients younger than age 70 was 7.8 months versus 7.1 months for those older than age 70. The relative 1- and 2-year survival rates were 30% and 15%, respectively, for those younger than age 70, and 34% and 9% for those older than age 70; the difference was not significant.

Single-agent vinorelbine

Standard dosage 25 mg/m2 to 30 mg/m2 IV days 1 and 8 Q 3 weeks.Main side effects Myelosuppression, constipation, vesicant.

Main drug interactions Phenytoin, mitomycin, and ritonavir.

Single-agent gemcitabine

Standard dosage 1000 mg/m2 to 1250 mg/m2 IV days 1, 8 Q 3 weeks or days 1, 8, and 15 Q 28 daysMain side effects Myelosuppression, especially thrombocytopenia, fever, rash, myalgias.

Main drug interactions None known.

Carboplatin and paclitaxel

Standard dosage The dose and schedule employed by the cooperative groups are carboplatin AUC = 6.0 mg/mL X min and paclitaxel 225 mg/m2 during 3 hours, both drugs administered every 21 days. Variations include the use of weekly paclitaxel at a dose of 80 mg/m2 to 100 mg/m2 weekly or weekly times 3 every month; attenuated doses of paclitaxel (175 mg/m2 to 200 mg/m2 Q 3 weeks), and 1-hour administration of paclitaxel. The equivalence of these alternative schedules is unclear. A recent study by Kosmidis et al. [36] compared 175 mg/m2 with 225 mg/m2, both combined with carboplatin at AUC = 6.0. This study found that the 175 dose was associated with a significantly shorter time to progression and a trend toward inferior survival.

Main side effects The regimen is usually well-tolerated. Myelotoxicity can occur and it produces cumulative neuropathy, especially with higher doses of paclitaxel.

Table 3. Elderly subanalysis: PCb times 4 cycles versus PCb (indefinite)

Age cohort <70 (N = 163) >70 (N = 67)

Grade > 2 toxicity, %Neutropenia 38 35Anemia 9 13Thrombocytopenia 7 9Peripheral neuropathy 13 16Nausea/vomiting 14 15Myalgia 15 9Fatigue 8 15

OutcomeMedian survival (mo) 7.8 7.11-y survival (%) 30 342-y survival (%) 15 9

Cb—carboplatin; P—paclitaxel.(Adapted from Hensing et al. [30].)

Pharmacologic treatment for advanced NSCLC

100 Lung Cancer

Special points This regimen represents the community standard and has been used as the comparator regimen by ECOG, SWOG, and the CALGB.

Cost effectiveness See comments under cisplatin/vinorelbine.

Vinorelbine and cisplatin

Standard dosage Cisplatin is administered at 100 mg/m2 day 1 and vinorelbine at 25 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Variations of this regimen include cisplatin at a higher dose during the first few cycles or administration of therapy on a 21-day schedule.

Main side effects The toxicities of this regimen are neutropenia, nausea and vomiting, asthenia and fatigue, and are clearly more pronounced in the elderly.

Special points The vinorelbine and cisplatin regimen was the first to clearly demonstrate superiority over an older platinum-based therapy.

Cost effectiveness A prospective economic analysis of SWOG 9504 was performed comparing the costs of cisplatin/vinorelbine with carboplatin/paclitaxel. This analysis demonstrated that cisplatin/vinorelbine was significantly less expensive than the carboplatin/paclitaxel regimen ($33,499 versus $43,826, US dollars), with virtually all the savings coming from lower drug costs [37].

Gemcitabine and cisplatin

Standard dosage Gemcitabine 1000 mg/m2 on days 1, 8, and 15, and cisplatin 100 mg/m2 every 28 days. A better tolerated variation is administered on a 21-day schedule with gemcitabine administered on days 1 and 8. The cisplatin dose may also be decreased to 75 mg/m2 without loss of efficacy.

Main side effects The primary toxicity of this regimen is myelotoxicity, particularly thrombocytopenia. This problem is largely eliminated by the 21-day schedule (ie, gemcitabine on days 1 and 8). Nausea and vomiting are also significant and can be alleviated by reducing the cisplatin dose to 60 mg/m2 to 75 mg/m2.

References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

1. Kennedy BJ: Specific considerations for older patients with cancer. In Medical Oncology. Edited by Calabresi PE, Shine PS. New York: McGraw Hill; 1993:1219–1230.

2. Yancik R, Reis LA: Aging in cancer in America. Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000, 14:17–23.

3. Jara C, Gomez-Aldaravi JL, Tirado R, et al.: Small-cell lung cancer in the elderly: is age of patient a relative issue? Acta Oncol 1999, 38:781–786.

4. Tamura M, Ueoka H, Kiura K, et al.: Prognostic factors of small-cell lung cancer in Okayama Lung Cancer Group trials. Acta Med Okayama 1998, 52:105–111.

5. Johnson DH: Treatment of the elderly patient with small-cell lung cancer. Chest 1993, 103(Suppl 1):72S–74S.

6. Shepherd F, Goss P, Evans W, et al.: Treatment of small-cell lung cancer in the elderly. Proc Am Soc Clin Oncol 1991, 10:241.

7. Findley MPN, Griffin AM, Raghavan D, et al.: Retrospective review of chemotherapy for small-cell lung cancer in the elderly: does the end justify the means? Eur J Cancer 1991, 27:1597–1601.

8. Souhami RL, Spiro SG, Rudd PM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 1997, 89:577–580.

9. Medical Research Council Lung Cancer Working Party: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomized trial. Lancet 1996, 348:563–566.

10. Clark PI, Cottier B, Joel SP, et al.: Two prolonged schedules of single-agent oral etoposide of differing duration and dose in patients with untreated small-cell lung cancer. Proc Am Soc Clin Oncol 1991, 10:268.

11. Westeel V, Murray N, Gelmon K, et al.: New combina-tion of old drugs for elderly patients with small cell lung cancer: A Phase II study of the PAVE regimen,. J Clin Oncol 1998; May; 16 (5):1940–7.

Elderly Patients with Lung Cancer: Biases and Evidence Langer 101

12.• Pignon JP, Arriagada R, Ihde D, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 1992, 327:1618.

Influential meta-analysis that confirmed the primacy of combined modality therapy in limited small-cell lung cancer versus chemotherapy alone. This benefit was confined to patients younger than age 70, which has deterred many investigators from offering aggressive therapy to the elderly.13.••Yuen AR, Zou G, Turrisi AT, et al.: Similar outcome of

elderly patients on Intragroup Trial 0096: cisplatin, etoposide and thoracic radiotherapy administered once or twice daily in limited stage lung cancer. Cancer 2000, 89:1953–1960.

Retrospective analysis of a pivotal Phase III trial in limited small-cell lung cancer that showed that the elderly benefit from combined modality therapy, albeit not as broadly as younger patients do.14. Werner-Wasik M, Scott C, Cox JD: Recursive

partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally advanced non–small-cell lung cancer (LA-NSCLC): identification of five groups with different survival. Int J Radiat Oncol Biol Phys 2000, 48:1475–1482.

15. Sause WT, Scott CB, Taylor SGN, et al.: RTOG 88-08 and ECOG 4588: preliminary results of a phase III trial in regionally advanced unresectable non–small-cell lung cancer. J Natl Cancer Inst 1995, 37:198–205.

16. Sause WT, Kolesar P, Taylor SG, et al.: Five-year results: phase III trial of regionally advanced unresectable non–small-cell lung cancer, RTOG 88-08, ECOG 4588, SWOG 8992. Proc Am Soc Clin Oncol 1998, 17:A-1743.

17. Langer C, Scott C, Byhardt R, et al.: Effect of advanced age on outcome in Radiation Therapy Oncology Group studies of locally advanced NSCLC (LA-NSCLC). Lung Cancer 2000, 29(Suppl 1):104.

18.• Mosvas B, Scott C, Sause W, et al.: The benefit of treatment intensification is age and histology dependent in patients with locally advanced non–small-cell lung carcinoma (NSCLC): a quality adjusted survival analysis of the Radiation Therapy Oncology Group chemoradiation studies. Int J Rad Onc Biol Phys 1999, 45:1143–1149.

One of the very few quality-of-life analyses of elderly patients who receive combined modality therapy for LA-NSCLC.19. Langer CJ, 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. Paper presented at the ASTRO 43rd Annual Meeting, San Francisco, 2001.

20. Rocha Lima CMS, Herndon JE, II, Kosty M, et al.: Therapy choices among older patients with lung cancer: evaluation of two trials of the Cancer and Leukemia Group B. Cancer Submitted.

21. Ricci S, Antuzzo A, Galli L, et al.: Gemcitabine monotherapy in elderly patients with advanced non–small-cell lung cancer: a multicenter Phase II study. Lung Cancer 2000, 27:75–80.

22.••The Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS): Effects of vinorelbine on quality of life and survival of elderly patients with advanced non–small-cell lung cancer. J Natl Cancer Inst 1999, 91:66–72.

Critical study that established the superiority of vinorelbine to best supportive care in elderly patients with advanced non–small-cell lung cancer.23. 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 2000, 18:2529–2536.

24.• Gridelli C, Perrone F, Cigolari S, et al.: The MILES (Multicenter Italian Lung Cancer in the Elderly Study) phase III trial: gemcitabine and vinorelbine vs. vinorelbine vs. gemcitabine in elderly advanced NSCLC patients. Proc Am Soc Clin Oncol. 2001, 20:A-1230.

Largest randomized trial performed to date in the elderly with advanced non–small-cell lung cancer. No advantage was observed for a non-platinum combination versus its constituent single agents.25. Nguyen B, Sandler A, Denham C, et al.: The safety and

efficacy of gemcitabine plus cisplatin in elderly chemo-naive SCLC patients (age < 70 years) as compared to those with age < 70 years. Proc Am Soc Clin Oncol 1999, 18:A-1818.

26. Martins SJ, Pereira JR, Ikari FK, et al.: Chemotherapy with cisplatin and vinorelbine for elderly NSCLC patients. Proc Am Soc Clin Oncol 1999, 18:A-1804.

27.• Langer CJ, Manola J, Bernardo P, et al.: Advanced age alone does NOT compromise outcome in fit non–small-cell lung cancer (NSCLC) patients receiving platinum (DDP) based therapy: therapeutic implications of ECOG 5592. Proc Am Soc Clin Oncol 2000, 19:A-1912.

Elderly patients who were and fit and who received platinum-based therapy experienced more leukopenia and neuropsychiatric toxicity compared with younger patients, but there was no difference in response rate, time to progression, survival, or quality of life in either age cohort.28. Kelly K, Giarritta S, Hayes S, et al.: Should older

patients receive combination chemotherapy for advanced non–small-cell lung cancer (NSCLC)? An analysis of Southwest Oncology Trials 9509 and 9308. Proc Am Soc Clin Oncol 2001, 21:A-1313.

29. Rosvold E, Langer CJ, McAleer C, et al.: Advancing age does not exacerbate toxicity or compromise outcome in NSCLC patients receiving paclitaxel/carboplatin. Proc Am Soc Clin Oncol 1999, 18:A-1846.

30. Hensing TA, Socinski MA, Schell MJ, et al.: Age does not alter toxicity or survival for patients with stage IIIB/IV NSCLC treated with carboplatin and paclitaxel. Proc Am Soc Clin Oncol 2001, 20:A-1382.

31. Calvert AH, Newell DR, Gumrell LA, et al.: Carboplatin dose: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989, 7:1748–1756.

32. Cockroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976, 16:31–41.

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33. Tucker MA, Murray N, Shaw EG, et al.: Second primary cancers related to smoking and treatment of small-cell lung cancer. J Natl Cancer Inst 1997, 89:1782.

34. Van Hazel GZ, Scott M, Eagen RT: The effect of CNS metastasis on the survival of patients with small-cell cancer of the lung. Cancer 1983, 51:933–937.

35. Carmichael J, Crane JM, Bunn PA, et al.: Results of therapeutic cranial irradiation in small cell lung cancer. Int J Radiat Oncol Biol Phys 1988, 14:455–459.

36. Kosimidis PA, Mylonakis N, Skarlos D, et al.: A multi-center randomized trial of paclitaxel (175 mg/m2) plus carboplatin (AUC 6) versus paclitaxel (225 mg/m2) plus carboplatin (AUC 6) in advanced non–small-cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 1999, 18:463a.

37. Ramsey SD, Moinpour CM, Lovato LC, et al.: An economic analysis of Southwest Oncology Group Trial S9509: cisplatin/vinorelbine vs carboplatin/paclitaxel for advanced non–small-cell lung cancer. Proc Am Soc Clin Oncol 2000, 19:489a.