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Maintenance therapy refers to the use of an active therapeutic agent for extended duration following frontline induction therapy for patients with advanced stage non-small cell lung cancer (NSCLC). Multiple clinical trials reported within the last few months have shown a beneficial role for maintenance therapy especially in select patient groups characterized by histology and/or molecular profile. With the recent approval by the U.S. Food and Drug Administration and European Medicines Agency of pemetrexed for maintenance therapy, a new treatment paradigm has been introduced to the treatment of NSCLC. This article reviews recent data with maintenance therapy in advanced NSCLC and discusses the implications for routine patient care and future drug development., (Copyright 2010 AACR.)

We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin in a Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed in NSCLC cells by MTT assay after 72 hr of continuous drug exposure. Vorinostat (1 microM) inhibited growth by: 17% +/- 7% in A549, 28% +/- 6% in 128-88T, 39% +/- 8% in Calu1 and 41% +/- 7% in 201T cells. Vorinostat addition to carboplatin or paclitaxel led to significantly greater growth inhibition than chemotherapy alone in all 4 cell lines. Vorinostat (1 microM) synergistically increased the growth inhibitory effects of carboplatin/paclitaxel in 128-88T cells. When colony formation was measured after drug withdrawal, vorinostat significantly increased the effects of carboplatin but not paclitaxel. The % colony formation was control 100%; 1 microM vorinostat, 83% +/- 10%; 5 microM carboplatin, 41% +/- 11%; carboplatin/vorinostat, 8% +/- 4%; 2 nM paclitaxel, 53% +/- 11%; paclitaxel/vorinostat, 46% +/- 21%. In A549 and 128-88T, vorinostat potentiated carboplatin induction of gamma-H2AX (a DNA damage marker) and increased alpha-tubulin acetylation (a marker for stabilized mictrotubules). In A549, combination of vorinostat with paclitaxel resulted in a synergistic increase in alpha-tubulin acetylation, which reversed upon drug washout. We conclude that vorinostat interacts favorably with carboplatin and paclitaxel in NSCLC cells, which may explain the provocative response observed in our clinical trial. This likely involves a vorinostat-mediated irreversible increase in DNA damage in the case of carboplatin and a reversible increase in microtubule stability in the case of paclitaxel.

The introduction of targeted biological agents represents the most promising approach to improve the disease control and outcome for patients with non-small cell lung cancer. The epidermal growth factor and the vascular endothelial growth factor signaling pathways have been successfully targeted using both orally administered small molecule tyrosine kinase inhibitors and monoclonal antibodies, with associated improvement in overall survival. Although the trials that established the efficacy of these agents allowed the enrollment of patients older than 70 years, the elderly patients constituted the minority. Given the stringent enrolment criteria in terms of organ function and performance status for most clinical trials, the elderly patients on clinical trials are not entirely representative of the overall elderly patient population. Therefore, the applicability of these data to the overall patient population deserves critical appraisal in the absence of trials dedicated specifically to the elderly. Preplanned and unplanned subset analysis of registration trial data is becoming increasingly common as a substitute measure to provide valuable information to guide the use of targeted agents in the elderly. Using this approach, it has been demonstrated that elderly patients are able to tolerate targeted biological therapies but suffer increased rate of toxicities. However, they derive benefit from such agents when they are carefully selected and have their drug doses adjusted appropriately to minimize potential toxicities. This article reviews the use of targeted agents for the treatment of NSCLC in elderly patients.

Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer cases. Approximately 40% of those cases are diagnosed in patients older than 70 years, and this proportion continues to rise in contrast to the continued decline in incidence of SCLC among the general population. The optimal strategy to manage limited-stage SCLC involves a combined modality approach with platinum-based chemotherapy and external-beam thoracic radiation therapy. For extensive-stage disease, platinum-based combination chemotherapy is a mainstay of therapy. Elderly patients present unique challenges in terms of drug metabolism and organ reserve, which impact the outcome of therapeutic interventions. However, limited data are available to guide management decisions for SCLC in elderly patients, and therefore this article discusses recommendations for treatment.

Purpose: To study the burden and outcome of lung cancer in the elderly, particularly for patients aged 80 years and older., Patients and Methods: The national Surveillance, Epidemiology, and End Results database was analyzed for lung cancer outcomes during the period 1988 to 2003. A comparison was carried out between patients with lung cancer 80 years and older, 70 to 79 years, and younger than 70 years for demographics; stage distribution; 5-year relative survival; and survival based on histology, sex, race, stage, and treatment. The temporal trends in survival during the years 1988 to 1997 and 1998 to 2003 were also analyzed., Results: Of 316,682 patients eligible for the analysis, 45,912 (14%) were 80 years or older (ie, very elderly); 103,963 (33%) were 70 to 79 years; and 166,807 (53%) were younger than 70 years. The distribution by stage and histology was comparable for all the three groups. Overall survival rate at 5 years was lower in the very elderly (7.4% v 12.3% v 15.5%; P < .0001) across sex, histologic subtypes, stages, and racial categories. Patients aged 80 years or older were less likely to receive local therapy (no surgery or radiation) than younger patients (47% v 28% and 19% for the age subgroups >/= 80 years, 70 to 79 years, and < 70 years, respectively). Overall outcomes for patients who underwent surgical therapy or radiation were comparable across the three age groups. In general, survival outcomes for the subgroup aged 70 to 79 years were similar to those of the subgroup aged 80 years and older who received single modality local therapy., Conclusion: Patients 80 years or older account for 14% (70 years or older accounted for 47%) of all lung cancers, are less likely to be subjected to surgery or radiation, and have inferior outcomes when compared with younger patients.

Unlabelled: The renin angiotensin system (RAS) has been implicated as one mediator of the cardiovascular effects of estrogen. Since changes in angiotensin type 1 (AT(1)) receptor expression are central to modulation of the RAS, we used the noninvasive PET imaging technique to study for the in vivo effects of estrogen on membrane and intracellular AT(1) receptors., Methods: Dynamic PET measurements of canine AT(1) (cAT(1)) receptors using the radiolabeled AT(1) receptor antagonist, (11)C-L-159,884, were performed during 2-wk consecutive periods of estrogen deprivation induced by ovariectomy and 17beta-estradiol (E(2)) replacement., Results: Kinetic modeling of time-activity curves in the kidney and adrenal showed lower receptor expression in the estrogen replete state (21% and 30% decrease in Gjedde-Patlak slope, influx constant, respectively). These in vivo findings correlated with in vitro radioligand-binding assays with (125)I-[Sar(1),Ile(8)]angiotensin II showing reduced AT(1) receptor number in the adrenal (35%), glomeruli (30%), myocardium (35%), and liver (21%) in the estrogen-replenished compared with estrogen-depleted animals., Conclusion: Although other endogenous systems are known to regulate AT(1) receptors and could compete with estrogenic actions, these PET studies reveal that estrogen attenuates AT(1) receptor expression in vivo. Thus, estrogen modulation of AT(1) receptors may contribute to the cardiovascular protective effects associated with estrogen.

A total of 254 cases of colorectal neoplasms were studied. A male predominance was noted with both benign and malignant neoplasms (M:F of 4.6:1 and 1.1:1 respectively). The peak incidence was in the fifth decade. The rectum was the commonest site for both benign and malignant neoplasms (75% and 63% respectively) followed by the sigmoid colon (11% and 16% respectively). Right-sided cancers presented commonly as fungating masses (74%) while left sided cancers were predominantly of the ulcerating/infiltrating pattern (81%). The commonest benign neoplasm was tubular adenoma (39%) while the commonest malignant neoplasm was adenocarcinoma (90%) followed by squamous cell carcinoma (4%). Advanced stage on presentation was noted with these cancers, especially the mucinous adenocarcinoma variant. This may be explained by the usual late presentation of patients to orthodox doctors in our environment.