Adjuvant Chemotherapy in Elderly Patients with Non-Small-Cell Lung Cancer

Cesare Gridelli, MD, Paolo Maione, MD, Daniela Comunale, MD, and Antonio Rossi, MD

Disclosures

Cancer Control. 2007;14(1):57-62. 

In This Article

Adjuvant Chemotherapy of Elderly NSCLC Patients

A meta-analysis evaluating data available from 4,357 patients included in clinical trials comparing surgery alone to surgery plus chemotherapy showed a survival benefit of 5% at 5 years for adjuvant cisplatin-based chemotherapy.[30] These results have stimulated clinical research in this field.[31,32,33,34,35] The Adjuvant Lung Project of Italy (ALPI) randomly assigned 1,209 patients with stage I, II, or IIIA NSCLC to receive surgery alone or surgery plus adjuvant chemotherapy consisting of the three-drug combination of mitomycin C, vindesine, and cisplatin. This trial failed to demonstrate a statistically significant survival benefit for adjuvant chemotherapy in completely resected NSCLC.[31] Similarly, the Big Lung Trial, with only 381 patients enrolled, failed to observe a survival benefit with adjuvant chemotherapy.[32] The International Adjuvant Lung Cancer Trial (IALT)[33] enrolled 1,867 patients with stage I–IIIA NSCLC who were randomly assigned to receive surgery followed by cisplatin-based chemotherapy compared with surgery alone. Chemotherapy consisted of cisplatin plus etoposide (56.5%), cisplatin plus vinorelbine (26.8%), cisplatin plus vinblastine (11.0%), or cisplatin plus vindesine (5.8%). Patients assigned to chemotherapy had a significantly higher 5-year survival rate than those assigned to observation (44.5% and 40.4%, respectively; hazard ratio [HR] for death 0.86; P<.03). The IALT trial was the first study to observe a survival benefit for adjuvant cisplatin-containing chemotherapy.

Two recent large randomized trials of third-generation platin-based adjuvant chemotherapy have reported positive results.[34,35] The National Cancer Institute-Canada (NCI-C) BR10 trial randomized 482 patients with stage IB and II NSCLC to receive surgery alone or surgery followed by chemotherapy with cisplatin plus vinorelbine. Overall survival was significantly prolonged for the cisplatin plus vinorelbine arm (94 months vs 73 months; HR for death 0.69; P=.011).[34] Similarly, the Cancer and Leukemia Group B (CALGB) Trial[35] that included 344 patients with stage IB NSCLC reported a statistically significant survival benefit for adjuvant chemotherapy with carboplatin plus paclitaxel (overall survival at 4 years was 71% in the chemotherapy group vs 59% in the observation group; HR for death 0.62; P=.028). A recent updated analysis shows only a trend toward improvement in overall survival that is not significant (HR for death 0.80; P=.10).[36] However, there is a significant improvement in disease-free survival and an advantage in the 3-year survival rate (79% vs 70%; P=.045) favoring adjuvant chemotherapy. Thus, this updated analysis no longer shows a significant overall survival advantage for adjuvant chemotherapy in stage IB NSCLC. This study does not have adequate power to detect small differences in overall survival that may be clinically significant.

Another randomized, prospective phase III trial by the Adjuvant Navelbine International Trialists Association (ANITA) compared the effectiveness of adjuvant cisplatin plus vinorelbine in early NSCLC.[37] Approximately 850 patients with stage I-IIIA completely resected NSCLC were enrolled. Median survival was 65.8 months in the chemotherapy arm and 43.7 months in the observation arm (HR 1.264 [1.05–1.52]; P=.0131). The 5-year survival rates for stage I, II, and IIIA were 62%, 52%, and 42%, respectively, in the chemotherapy arm and 63%, 39%,and 26%,respectively, in the observation arm. Thus, the ANITA results demonstrate a significant improvement in survival in patients with stage II and IIIA NSCLC treated with adjuvant cisplatin plus vinorelbine, although no benefit was observed in stage I.

Some randomized trials and a meta-analysis with data from 2,000 patients have shown that adjuvant single-agent chemotherapy with uracil/tegafur (UFT) significantly improves the survival of patients with completely resected early-stage NSCLC. In the metaanalysis, the 5-year survival rate was 81.8% in the UFT arm and 77.2% in the observation arm (HR for death 0.77; P=.011).[38,39] Moreover, a meta-analysis with data from 5,716 patients has confirmed the importance of cisplatin-based chemotherapy and single-agent UFT as adjuvant chemotherapy in the treatment of resected NSCLC (HR ratio for death 0.891; P=.012 for cisplatinbased chemotherapy; HR for death .799; P=.015 for single-agent UFT).[40]

Taken globally, these data suggest that postoperative chemotherapy improves survival after surgery in patients with stage II to IIIA NSCLC. These reports also suggest that awareness of the efficacy of this approach is growing in the scientific community, although the topic is currently controversial. However, clinical data obtained in the young population cannot be automatically adopted in the elderly counterpart. In fact, elderly patients tolerate chemotherapy poorly because of comorbidity and organ failure. Also, following lung surgery, they are considered at higher risk of chemotherapy-induced toxicity. Thus, there are many doubts regarding the use of platin-based chemotherapy in adjuvant-positive trials in resected elderly patients. In fact, the survival benefit obtained with platin-based chemotherapy may vanish or decrease in the elderly due to a potential higher toxic death rate or lower compliance to treatment. An updated analysis of the CALGB trial[36] in stage IB NSCLC,which recently failed to show a significant improvement in overall survival, raises the question if there is sufficient promise for elderly patients to benefit from currently available adjuvant regimens to justify the toxicity and morbidity of treatment. Modified schedules or attenuated doses of platincontaining chemotherapy should be investigated in this clinical setting by specifically designed trials. The survival benefit achieved in the UFT adjuvant trials[38,39,40] suggests that new-generation single-agent chemotherapy (vinorelbine, gemcitabine, taxanes) could be investigated in future adjuvant trials for patients unsuitable for even modified or attenuated platin-containing chemotherapy as several resected elderly NSCLC patients. Specific prospective data on adjuvant chemotherapy in elderly patients are not available.

A subgroup analysis of the report from the Non- Small Cell Lung Cancer Collaborating Group using updated data from 52 randomized clinical trials[30] showed no evidence that any group of patients specified by age benefited more or less from adjuvant chemotherapy. The Adjuvant Navelbine International Trialist Association[40] 02 study of adjuvant single-agent vinorelbine (30 mg/m2 weekly for a total of 16 administrations) in patients who cannot receive cisplatinbased chemotherapy may produce interesting data, even if stopped early due to slow accrual. A recent retrospective analysis evaluated the influence of age on survival, chemotherapy delivery and toxicity in the above-mentioned positive NCI-C BR10 trial.[41] Pretreatment characteristics and survival benefit from treatment were compared for patients 65 years of age and less and those over age 65. Data from 327 young and 155 elderly patients were included in the analysis. Baseline prognostic factors by age were similar with the exception of histology (adenocarcinoma = 58% young, 43% elderly; squamous cell = 32% young, 49% elderly; P=.001) and performance status (PS 0 = 53% young, 41% elderly; P=.01). Overall survival by age showed a trend favoring the young in univariate (HR for death 0.77; P=.084) and multivariate analysis (HR for death 0.75;P=.059). Patients aged 75 years or more had significantly shorter survival than those aged 66 to 74 (HR for death 1.95; P=.02). However, overall survival for patients greater than age 65 was significantly better with chemotherapy than with observation (HR for death 0.61; P=.04). The elderly received significantly fewer doses of chemotherapy (both cisplatin and vinorelbine). Fewer elderly patients completed treatment and more refused treatment compared to the younger participants (P=.03). There were no significant differences in toxicities, the use of granulocyte colony-stimulating factor (G-CSF), or hospitalization by age group, except for myalgias and mood alteration (more frequent among the young). Thus, this retrospective study suggests that despite receiving less chemotherapy than younger patients, those aged 65 or greater achieved improved overall survival with adjuvant chemotherapy with acceptable toxicity.

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