One of the main reasons for the increased acceptance of chemotherapy for both early and advanced non-small-cell lung cancer is the clinical availability of several new cytotoxic drugs. These less toxic, yet highly effective, new
ABSTRACT: One of the main reasons for the increased acceptance ofchemotherapy for both early and advanced non-small-cell lung cancer is theclinical availability of several new cytotoxic drugs. These less toxic, yethighly effective, new drugs not only benefit younger patients, but also offernew treatment opportunities for the elderly; advanced age alone should notpreclude appropriate cytotoxic therapy. Vinorelbine (Navelbine) was the firstnew agent tested in randomized trials with elderly patients having advanced non-small-celllung cancer. Results proved that vinorelbine does indeed have a survivaladvantage over best supportive care for these patients. Gemcitabine (Gemzar) isprobably the most effective cytotoxic agent in the treatment of non-small-celllung cancer today, showing high antitumor activity as a single agent and incombination. Moreover, it has a favorable toxicity profile. Since it can beeffectively used for the palliation of tumor-related symptoms and can thuspositively influence performance status, gemcitabine may be of great clinicalimportance in the treatment of elderly and unfit patients. Docetaxel (Taxotere)has recently become the first agent to be registered for second-linechemotherapy in non-small-cell lung cancer. This decision was based onsurvival advantages and clinical benefit data stemming from two randomized phaseIII studies. Nonetheless, chemotherapy for elderly patients continues to be amajor unresolved oncologic problem. Clinical research with the new cytotoxicagents should be intensified to further define the most appropriate use forthese drugs as single agents or in combination for the treatment of elderlypatients. [ONCOLOGY 15(Suppl 6):46-51, 2001]
The issue of treating elderly patients with chemotherapy is ofgreat clinical relevance today.[1-3] In the United States and Europe, theleading cause of cancer death in men and women is lung cancer. The largemajority of lung cancer patients are more than 55 years old, and the number ofpatients over the age of 65 has grown considerably in the course of the pastdecade. When incidence rates are calculated for age specificity, lung cancerrates escalate to more than 500,000 persons for those 70 to 85 years ofage.[4,5]
Age itself is not one of the definitive prognostic factors oflung cancer. Because untreated lung cancer patients have an extremely poorprognosis, the question of which treatment patients should receive should not bebased on age. Older patients should be offered the same general treatment asyounger, healthier patients. This general principle should apply to alltreatment modalities: surgery, radiotherapy, and chemotherapy.[7-9] At the sametime, daily contact with older patients shows that standard recommendations forthe proper dose and application time are often difficult to fulfill and must bemodified for the elderly.
Many older patients have additional complex medical problems,including chronic obstructive airway disease, congestive heart failure, anddecreased renal function, which must be considered. In addition to the problemsof comorbidity, poor performance status, and polypharmacy, specific mental,emotional, and social-economic conditions are often found in the elderly anddiffer from their younger counterparts. There are, for example, many cases ofcognitive and emotional disturbances, family dysfunctions, limited access toclinic and hospital care, confused reactions to complex medical schedules, andless motivation to withstand the ordeal of aggressive treatmentall of whichmay adversely influence cancer treatment and result in inadequate treatmentcompliance.
Of all the treatment modalities, the use of chemotherapy in theelderly has remained the most controversial.[10-12] The skepticism oftenexpressed is related to (1) the perception of chemotherapy’s limitedbenefit in general; (2) older data suggesting that chemotherapy is of benefitmainly to patients younger than 70 years and that the recommended therapy shouldbe platinum-based combination chemotherapy; (3) the potential for increasedtoxicity in the elderly; (4) the small number of studies dedicated to theelderly and the fact that the elderly were, in the past, frequently excludedfrom clinical studies; (5) preselection as a major problem in interpreting datafrom retrospective reviews; and (6) the widespread reluctance to treat elderlypatients in the same way that younger patients are treated. With the generalimprovements in cytotoxic therapy over the past few years, new possibilities arebeing opened to elderly patients for more individualized treatment, which iseasier to adapt to the specific age group and general condition of the patientsbeing treated.
The new generation of chemotherapeutic agents largelyresponsible for these positive changes belong pharmacologically to theantimetabolites, the topoisomerase I inhibitors, and the antitubulins. These newagents show great single-agent efficacy in both first- and second-line therapy,and are therefore especially attractive for use as single agents in the olderpopulation. Furthermore, the toxicity profile of these new drugs differs fromthat found in traditional chemotherapy and is generally found to be bettertolerated. In addition, these drugs can be administered flexibly in variousschedules and dosages, thus opening new options for platinum-free combinationchemotherapy, for chemoradiotherapy regimens, as well as for the application ofcytotoxic drugs on an outpatient basis.
Among the new drugs with probably the greatest impact on thetreatment of elderly patients are the classical antitubulin vinorelbine(Navelbine), the antimetabolite gemcitabine (Gemzar), and the taxane docetaxel(Taxotere).[15-19] This has been demonstrated in a number of nonrandomizedstudies, in a few randomized trials, and in several retrospective analyses.
Vinorelbine was probably the first new agent tested innonrandomized and randomized trials in elderly patients with non-small-celllung cancer.[20-24] One milestone was the study of the elderly done by theElderly Lung Cancer Vinorelbine Italian Study Group, which has become known asthe ELVIS trial. Here, elderly patients over the age of 70 were randomizedto either single-agent vinorelbine or best supportive care alone. Astatistically significant survival advantage was seen in patients receivingvinorelbine (Figure 1). This trial clearly established the potential benefit ofsingle-agent therapy for the elderly population. Vinorelbine is, therefore,widely considered to be more or less the "standard arm" for upcomingcomparative studies, especially for testing the value of new agents in elderlypatients with non-small-cell lung cancer.
Another agent that has proven to be active and well tolerated innon-small-cell lung cancer patients is gemcitabine. Gemcitabine is anovel deoxycytidine analog with structural similarities to cytosine arabinoside.Gemcitabine was the first cytotoxic drug registered for use in the palliation oftumor-induced symptoms and was shown to be effective as a single agent inboth first- and second-line therapy.
When administered once weekly on days 1, 8, and 15 of a 28-daycycle at a dose of 800-1,250 mg/m2, gemcitabine showed an objective responserate of 20% to 26% in chemotherapeutically nonpretreated patients. The medianduration of response ranged from 3.3 to 12.7 months, and the overall mediansurvival time was 8.1 to 9.4 months. Single-agent gemcitabine was shown to beespecially effective in reducing tumor-induced dyspnea, pain, and hemoptysis. Itwas also well tolerated by elderly patients. In the majority of cases,gemcitabine promises a better quality of life; in one-third of the cases, itleads to an improvement in performance status. Gemcitabine has also proven to besuperior to best supportive care in advanced non-small-cell lung cancer.
A specific review of single-agent gemcitabine investigations inpatients over 65 years old enrolled in four phase II trials has recently beenpublished. In these studies, 250 patients were under the age of 65 and 105patients were 65 or older. Baseline patient characteristics for gender,performance status, stage of disease, and histology did not differ significantlybetween the age groups. There were no statistically significant differences forthe overall response rates, which showed 16% for the younger and 24% for theolder patients, respectively (Table 1).
Of interest is the fact that the group under age 65 had a mediansurvival of 8 months and a 1-year survival rate of 27%, whereas the olderpopulation had a median survival of 9.1 months and a 36% 1-year survival rate.Gemcitabine was well tolerated and toxicities were similar for both age groups (Table2). The number of cycles associated with dose reductions and/or doseomissions and the mean number of treatment cycles administered were alsosimilar. The feasibility and effectiveness of single-agent gemcitabine inpatients older than 70 years of age has recently been confirmed by a number ofother investigators.[28-31]
Because of their mild side-effect profiles, the new drugs arealso good candidates for combination chemotherapy. The question of whether theaddition of gemcitabine to vinorelbine improves survival and the quality of lifeamong elderly patients has recently been addressed in a randomized study of theSouthern Italy Co-Operative Oncology Group and the Inter-Regional Associationfor the Study of Lung Cancer Italy. A total of 120 patients 70 years of ageor older with advanced non-small-cell lung cancer were randomized. In thevinorelbine/gemcitabine group, median survival was 7 months, and the 1-yearsurvival rate was 30% compared with 2.5 months and 13% for single-agentvinorelbine. This difference was statistically significant. The combinationtherapy was also associated with a clear delay in symptom and quality-of-lifedeterioration (Table 3).
Another important ongoing clinical trial is the phase III MILEStrial (Multi-agent Italian Lung Cancer Elderly Trial), in which the combinationof gemcitabine and vinorelbine is being compared to single-agent vinorelbine andsingle-agent gemcitabine. Patients are eligible if they are 70 years of age orolder and if they are diagnosed as having inoperable stage III or IV non-small-celllung cancer. The primary end point of the MILES study is survival, and more than600 patients are to be enrolled. Preliminary response data from 98 patients whoreceived single-agent gemcitabine at 1,200 mg/m2 on days 1 and 8 every 3 weeks(49 patients) or gemcitabine at 1,000 mg/m2 combined with vinorelbine at 25mg/m2 on days 1 and 8 every 3 weeks (49 patients) were recently published.The data showed that nine patients responded to single-agent gemcitabine (9partial responses) and that another nine responded to gemcitabine/vinorelbine (8partial responses, 1 complete response) giving an identical response rate of18.4% (95% confidence interval [CI] = 8.8%-32.0%) for each treatment arm.
Our own experience with combination chemotherapy for elderlypatients having advanced non-small-cell lung cancer comes from a randomized,two-arm phase II study, where gemcitabine and docetaxel were givensequentially.
Patients were randomized either to gemcitabine at 1,000 mg/m2 ondays 1, 8, and 15, every 4 weeks or to docetaxel at 35 mg/m2 also given on days1, 8, and 15 every 4 weeks for up to six cycles. In case of tumor progressionduring or after completion of first-line therapy, treatment crossover wasplanned (Table 4).
Patients were included only if they had documented non-small-celllung cancer either in stage IIIB disease with pleural effusion and/orsuperclavicular lymph node involvement or in stage IV disease. Patients also hadno prior chemotherapy, no prior radiotherapy of measurable lesions, aperformance status of 0-2, adequate hematology and biochemistry, no clinicalevidence of brain metastases, and were 18 years of age or older, and gaveinformed, written consent. About 25% of the patients enrolled were 70 years ofage or older.
The major pretreatment characteristics for the two age groupswere well balanced (Table 5). For patients who were assigned initially toreceive single-agent gemcitabine and then, in case of progression, were switchedto or planned to cross over to docetaxel, the 1-year survival rates were almostidentical (30%). The median survival rate was about 8 months between the two agegroups (Table 6).
In spite of the great skepticism about using platinum-basedchemotherapy for older and unfit patients, the investigation of therapy regimensusing new drugs in combination with cisplatin (Platinol) for the elderlycontinues.[34-37] From a randomized phase III study of gemcitabine pluscisplatin vs cisplatin, subset analyses of 260 patients treated with gemcitabine/cisplatin werecarried out by Nguyen for patients over 70 years of age. These resultsshowed that gemcitabine/cisplatin was as well tolerated in the elderly as inyounger patients. There were also no statistically significant differences intumor response, time to progression, and median survival (Table7).
The feasibility and efficacy of cisplatin-based chemotherapy inelderly patients has lately been confirmed by a retrospective analysis using theEastern Cooperative Oncology Group (ECOG) 5592 database. Response, toxicity,and survival for fit, elderly non-small-cell lung cancer patients were similarto the rates shown by younger patients. The authors therefore concluded thatadvanced age alone should not preclude appropriate platinum-based chemotherapy.
Chemotherapy for elderly patients with advanced non-small-celllung cancer continues to be a major unresolved clinical problem. Theavailability of new chemotherapeutic agents, however, has increased thechemotherapeutic treatment options for patients with non-small-cell lungcancer in general, but even more so for the elderly.
For advanced disease, as the recently published results ofrandomized studies indicate, single-agent therapy using new chemo- therapeuticagents or their combinations may offer an appropriate alternative to aplatinum-based combination chemotherapy for elderly patients. Physiologicallyfit elderly patients with early-stage non-small-cell lung cancer who are ingood clinical condition should not be excluded from the clinical investigationof platinum-based two- or even three-drug combinations to determine their rolewithin multimodality treatment concepts.
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