Phase II Study of Taselisib in PIK3CA-Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I.

PURPOSE: PIK3CA mutations frequently contribute to oncogenesis in solid tumors. Taselisib, a potent and selective inhibitor of phosphoinositide 3-kinase, has demonstrated clinical activity in PIK3CA-mutant breast cancer. Whether PIK3CA mutations predict sensitivity to taselisib in other cancer types is unknown. National Cancer Institute-Molecular Analysis for Therapy Choice Arm EAY131-I is a single-arm, phase II study of the safety and efficacy of taselisib in patients with advanced cancers. METHODS: Eligible patients had tumors with an activating PIK3CA mutation. Patients with breast or squamous cell lung carcinoma, or whose cancer had KRAS or PTEN mutations, were excluded. Patients received taselisib 4 mg, orally once daily continuously, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival (OS), and identification of predictive biomarkers. RESULTS: Seventy patients were enrolled, and 61 were eligible and initiated protocol therapy. Types of PIK3CA mutations included helical 41 of 61 (67%), kinase 11 of 61 (18%), and other 9 of 61 (15%). With a median follow-up of 35.7 months, there were no complete or partial responses. Six-month PFS was 19.9% (90% CI, 12.0 to 29.3) and median PFS was 3.1 months (90% CI, 1.8 to 3.7). Six-month OS was 60.7% (90% CI, 49.6 to 70.0) and median OS was 7.2 months (90% CI, 5.9 to 10.0). Individual comutations were too heterogeneous to correlate with clinical outcome. Fatigue, diarrhea, nausea, and hyperglycemia were the most common toxicities, and most were grade 1 and 2. CONCLUSION: In this study, taselisib monotherapy had very limited activity in a heterogeneous cohort of heavily pretreated cancer patients with PIK3CA-mutated tumors; the presence of a PIK3CA mutation alone does not appear to be a sufficient predictor of taselisib activity.

Socioeconomic Factors Affect Outcomes in Well-Differentiated Thyroid Cancer.

OBJECTIVES: The effects of socioeconomic status (SES) on the incidence of well-differentiated thyroid cancer (WDTC) are well researched. However, the association between SES and outcomes is not delineated. Our objective was to determine if SES affected outcomes of WDTC. STUDY DESIGNS: Retrospective database review. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: The Henry Ford Virtual Data Warehouse Tumor Registry was used to identify cases of WDTC. Socioeconomic data were obtained through the 2010 US Census: median household income, percentage below poverty line, median household size, percentage rent versus own property, and general demographics. Survival was the primary outcome. Disease-specific survival was also calculated. Cox proportional hazards were calculated and a multivariate analysis performed. RESULTS: There were 1317 patients with WDTC. In multivariable analysis, median household income (hazard ratio [HR]: 0.85, 95% confidence interval [95% CI]: 0.79-0.91), household size (HR: 1.49, 95% CI: 1.09-2.14), younger age (HR: 1.97, 95% CI: 1.74-2.23), and female sex (HR: 0.50, 95% CI: 0.37-0.69) were significantly associated with survival. Controlling for stage revealed percentage below poverty line (stage I, HR: 0.51, 95% CI: 1.34-1.78; stage IV, HR: 1.28, 95% CI: 1.04-1.57) and median household income (HR: 0.84, 95% CI: 0.71-0.99) to be significant factors in survival. Median household income was a statistically significant variable for disease-related death (HR: 0.82, 95% CI: 0.69-0.96) CONCLUSIONS: Along with effects on incidence, lower SES correlates with worse survival in WDTC. This suggests that a patient's economic background, with younger age and female sex, influences one's outcomes with regard to both overall and disease-specific death.

Patients' perceptions of complementary and alternative medicine in head and neck cancer: a qualitative, pilot study with clinical implications.

PURPOSE: To describe head and neck cancer (HNC) patients' perceptions of Complementary and Alternative Medicine (CAM) and their attitudes towards a discussion regarding CAM. METHODS: We interviewed a convenience sample of HNC patients, using a structured interview tool. RESULTS: The participants' perceptions of CAM can be grouped into three categories: positive; open-minded: needing more input; and negative. Almost all of the 14 participants (93%) report that they would be comfortable having a CAM discussion with their physician, although only 43% of the participants had such a conversation. CONCLUSIONS: Participants' willingness to discuss CAM suggests that HNC patients might be open to learning about their options for participating in needed CAM-related research. The reported lack of CAM discussions, despite participants expressed comfort with them, and potential harms of interactions between CAM and conventional therapy, support our recommendation that physicians routinely initiate discussion with HNC patients regarding CAM usage.

Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN. METHODS: Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m(2) and then 250 mg/m(2) weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2. RESULTS: The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival. CONCLUSIONS: The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck.

Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study.

Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.

Paranasal sinus squamous cell carcinoma incidence and survival based on Surveillance, Epidemiology, and End Results data, 1973 to 2009.

BACKGROUND: Paranasal sinus squamous cell carcinomas (PNSSCC) account for 3% of all head and neck malignancies. There has been little information on the trends in incidence and survival, and no randomized trials have been conducted to guide therapy. METHODS: Patients with PNSSCC reported to the Surveillance, Epidemiology, and End Results (SEER) Program from 1973 through 2009 were categorized by sex, age, year of diagnosis, primary site, stage, and treatment. The incidence and survival were then compared across different demographic and disease-related categories by calculating rate ratios (RRs) and mortality hazard ratios along with the corresponding 95% confidence intervals (CIs). RESULTS: In total, 2553 patients with PNSSCC were identified. While incidence of PNSSCC showed a gradual decline, survival remained largely unchanged. The proportion of patients with advanced disease decreased from 14.7% during the period from 1983 to 1992 to 12.4% during 1993-2002 and to 9.5% during 2003-2009. Compared with whites, incidence was higher among African Americans (RR 1.63; 95% CI, 1.39, 1.90) and among all other racial groups (RR, 1.78; 95% CI: 1.53-2.07). After adjusting for age, sex, disease stage, tumor site, and treatment, mortality among African American patients also was increased (hazard ratio, 1.22; 95% CI, 1.04-1.43). Among patients with localized disease, the relation between race and mortality was no longer evident once the results were controlled for tumor classification. CONCLUSIONS: The current findings point to racial disparities in the incidence of PNSSCC and, to a lesser extent, in the outcome of patients with PNSSCC. Although there has been a decline in the proportion of patients presenting with advanced PNSSCC, the overall survival remained stable over time.

Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer.

We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non-small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m) and everolimus (5 mg orally once daily on days 1-19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

EGFR Monoclonal Antibodies in the Treatment of Squamous Cell Carcinoma of the Head and Neck: A View beyond Cetuximab.

Squamous cell carcinoma of the head and neck (SCCHN) is a prevalent disease both in the United States and worldwide with an overall poor prognosis, in part due to limited activity of existing therapy. Primary therapy is largely dictated by the anatomical origin of the cancer and whether distant disease is present. Many patients with localized disease are treated with chemoradiotherapy, either in the definitive or adjuvant setting, and those with metastatic disease are treated with palliative chemotherapy. The chemotherapy used in SCCHN can be toxic, whether given with radiation or alone. The epidermal growth factor receptor (EGFR) is highly expressed in SCCHN and serves as a logical therapeutic target. EGFR-directed monoclonal antibodies (MoAbs) have higher activity in SCCHN than small molecule tyrosine kinase inhibitors. Cetuximab, a widely studied EGFR MoAb, is FDA approved in the metastatic setting, as well as with radiation for locally advanced disease. Despite improvements in survival when cetuximab is incorporated with chemotherapy for metastatic disease, the prognosis of patients remains poor. Novel EGFR MoAbs are being developed with the goal of improving efficacy and tolerability. This paper will summarize the use of EGFR-directed MoAbs in treating SCCHN with a focus on novel agents being tested.

Single agent maintenance therapy for advanced stage non-small cell lung cancer: a meta-analysis.

BACKGROUND: Maintenance therapy is a new treatment paradigm for advanced non-small cell lung cancer (NSCLC). We conducted a meta-analysis of randomized studies with single agent maintenance therapy. METHODS: An electronic literature search of public databases (MEDLINE, EMBASE, Cochrane library) and manual search of relevant conference proceedings was performed. A formal meta-analysis was conducted using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as hazard ratio (HR). The primary outcome of interest was overall survival (OS) and secondary outcome was progression free survival (PFS). RESULTS: Twelve studies were included (5 meeting abstracts, 7 full manuscripts) with a total of 4286 patients (maintenance arm/control arm - 2449/1837, median age 61 years, males - 69%). The OS (HR 0.86, 95% confidence intervals [CI] 0.80-0.92; P=0.0003) and PFS (HR 0.80, 95% CI 0.77-0.84; P<0.0001) were superior with maintenance therapy. 'Switch' maintenance was associated with significant OS and PFS improvement (OS HR 0.84, 95% CI 0.77-0.91; P=0.00026; PFS HR 0.62, 95% CI 0.57-0.67; P<0.0001). Despite a modest improvement in PFS (HR 0.90, 95%CI 0.85-0.95; P=0.007), "continuation" maintenance was not associated with survival benefit (HR 0.927, 95%CI 0.78-1.09; P=0.33). Improvements in OS and PFS were observed with both EGFR-targeted agents (HR 0.83, 95% CI 0.74-0.92; P=0.004; HR 0.64, 95% CI 0.58-0.71 P<0.0001) and cytotoxic agents (HR 0.89, 95% CI 0.80-0.98; P=0.018; HR 0.85, 95% CI 0.80-0.89; P<0.0001). CONCLUSIONS: Single agent maintenance therapy improves overall survival, though statistical significance was only noted with 'switch' maintenance.

HPV positive squamous cell carcinoma of the oropharynx. Are we observing an unusual pattern of metastases?

UNLABELLED: To describe the clinical, histopathologic, immunohistochemical and molecular features of human papilloma virus (HPV)+ squamous cell carcinomas of the oropharynx that had an atypical clinical course. METHODS AND RESULTS: Four patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were identified retrospectively based on unanticipated clinical behavior. The histopathology, immunohistochemistry and molecular studies of both the primary tumor and the metastases were analyzed to look for any predictors to explain the clinical course. The four patients were all male (average age 55) who presented initially with a neck mass and had stage IVA disease. Three of the primary tumors were nonkeratinizing squamous cell carcinoma and one case was a hybrid tumor of both high-grade squamous cell carcinoma and nonkeratinizing type, and all were p16 and HPV 16/18 positive. All patients received concurrent chemoradiation as primary therapy and had a complete response. Disease-free survival ranged from 7 to 15 months and metastases in 3 patients occurred only in bone, including the sternum, humerus, clavicle, and vertebrae. In one patient, distant metastases were identified in the pancreas, liver, lung and skull base. All metastatic lesions were nonkeratinizing morphology and were p16 and/or HPV positive. Two patients died of their disease, one patient is alive with disease and one patient is disease-free. Although infrequent, unanticipated clinical outcomes can occur in HPV-related OPSCC including distant metastases and bone-only metastases. The tumor morphology of the metastases was comparable to the primary and retained p16 and HPV expression.

Adenoid cystic carcinoma of the head and neck: Incidence and survival trends based on 1973-2007 Surveillance, Epidemiology, and End Results data.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the head and neck (ACCHN) is a rare tumor of minor salivary, parotid, and submandibular glands. The biologic behavior of the disease is poorly understood, and nonsurgical treatment strategies have yet to be standardized. The long-term prognosis continues to be guarded, with an estimated 10-year survival of <60%. Population-based studies examining ACC are scarce. The authors aimed to analyze incidence rates and survival outcomes for patients diagnosed with ACCHN using national population-based data. METHODS: Data were obtained from the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Newly diagnosed ACCHN cases reported to SEER from 1973 through 2007 were categorized according to their sex, race, age, year of diagnosis, marital status, treatment interventions, primary tumor site, and disease stage. Incidence of ACCHN and postdiagnosis survival were examined over time and compared across different demographic and disease-related categories. RESULTS: The authors identified 3026 patients with ACCHN. The mean age at diagnosis among those cases was 57.4 years (range, 11-99 years). Analyses of incidence data demonstrated a decline in ACCHN rates between 1973 and 2007, noted across all sexes and races with no detectable inflexion points. The overall 5-year, 10-year, and 15-year survival outcomes for ACCHN patients were 90.3%, 79.9%, and 69.2%, respectively. Females, patients with localized disease, and younger patients were found to have significantly better survival across all time periods (all comparison-specific log-rank P values <0.001). Multivariate analyses revealed better prognosis among women compared with men (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.65-0.82), among married compared with unmarried individuals (HR, 0.81; 95% CI, 0.71-0.91), with certain sites of origin and stage of disease (HR, 2.788; 95% CI, 2.36-3.29), and in those who had surgery of the primary tumor site (HR, 0.45; 95% CI, 0.37-0.54). CONCLUSIONS: The overall incidence of ACC is declining. The noted differences in survival based on sex, marital status, site of origin, and treatment intervention require further investigation.

Fibroblast growth factor receptors are components of autocrine signaling networks in head and neck squamous cell carcinoma cells.

PURPOSE: We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and epidermal growth factor receptor (EGFR) dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR. RESULTS: FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed, whereas only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and extracellular signal-regulated kinase signaling in three HNSCC cell lines, whereas three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR tyrosine kinase inhibitors (TKI) with no contribution from FGFR pathways. CONCLUSIONS: FGFR signaling was dominant or codominant with EGFR in six HNSCC lines, whereas three lines exhibited little or no role for FGFRs and were highly EGFR dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC.

Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.

HYPOTHESIS: To explore whether the progression-free survival (PFS) with pemetrexed differs between anaplastic lymphoma kinase (ALK)-positive and other major molecular subtypes of non-small cell lung cancer. METHODS: In an ALK-enriched population, patients with metastatic non-small cell lung cancer were screened by ALK fluorescence in situ hybridization and for epidermal growth factor receptor (EGFR) and KRAS mutations. Triple-tested, pemetrexed-treated patients (monotherapy or combination therapy) were identified and PFS with pemetrexed captured retrospectively. RESULTS: Eighty-nine eligible cases were identified (19 ALK fluorescence in situ hybridization positive, 12 EGFR mutant, 21 KRAS mutant, and 37 triple negatives). Eighty-three cases (93%) were adenocarcinomas, two were adenosquamous, one squamous, and three had large cell histology. None of the ALK-positive patients had received crizotinib before pemetrexed. Pemetrexed was first-line therapy in 48% (72% as platinum-based combinations). Median PFS (95% confidence interval) data were EGFR mutant (5.5 months; 1-9), KRAS mutant (7 months; 1.5-10), ALK positive (9 months; 3-12), and triple negative (4 months; 3-5). In a multivariate analysis adjusting for line of therapy, mono- versus platinum and nonplatinum combination therapy, age, sex, histology, and smoking status, the only variable associated with prolonged PFS on pemetrexed was ALK+ (hazard ratio = 0.36 [95% confidence interval: 0.17-0.73], p = 0.0051). CONCLUSIONS: In this exploratory analysis, ALK-positive patients have a significantly longer PFS on pemetrexed compared with triple-negative patients, whereas EGFR or KRAS mutant patients do not. This information should be considered when sizing randomized studies in ALK-positive patients that involve pemetrexed. Pemetrexed should also be prioritized as a cytotoxic to explore further in patients with known ALK-positive disease.

Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.

PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangements, associated with sensitivity to an experimental ALK/MET inhibitor, occur in 3% to 5% of non-small cell lung cancers. Intratumoral fluorescence in situ hybridization (FISH) heterogeneity has been reported. We explored the heterogeneity basis, the requirements for accurately determining ALK FISH positivity, and the effect of enriching the tested population using clinical and molecular factors. EXPERIMENTAL DESIGN: Lung cancer patients were screened by ALK and MET FISH and for EGFR and KRAS mutations. RESULTS: Thirteen ALK-positive cases were identified from 73 screened patients. Gene copy number increases occurred together with classic rearrangements. All positive cases were adenocarcinomas, 12 were EGFR/KRAS wild-type, and 1 had a coexistent EGFR exon 20 mutation. No association with MET amplification occurred. ALK positivity was associated with <10-pack-year smoking status (P = 0.0004). Among adenocarcinomas, without KRAS or EGFR mutations, with <10-pack-year history, 44.8% of cases were ALK positive. ALK FISH positivity was heterogeneous, but mean values in tumor areas from ALK-positive patients (54% of cells; range, 22-87%) were significantly higher than in adjacent normal tissue or tumor/normal areas from ALK-negative patients (mean, 5-7%). Contiguous sliding field analyses showed diffuse heterogeneity without evidence of focal ALK rearrangements. One hundred percent sensitivity and specificity occurred when four or more fields (∼60 cells) were counted. CONCLUSIONS: Intratumoral ALK FISH heterogeneity reflects technique, not biology. The clinical activity of ALK/MET inhibitors in ALK-positive patients probably reflects ALK, but not MET, activity. Prescreening by histology, EGFR/KRAS mutations, and smoking status dramatically increases the ALK-positive hit rate compared with unselected series.

The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer.

The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority ( approximately 80-90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.

Surprised by stage III: unexpected N2 lymph node involvement found during surgery for early-stage NSCLC.

Dr. Camidge: To summarize, this patient is a relatively young, otherwise healthy female who is status post lobectomy. She has been diagnosed with stage IIIA NSCLC that is EGFR-positive by IHC and FISH, but EGFR and KRAS wild type. Optimal MLNS or MLND is ideally performed in the pre- and/or perioperative setting, but this did not happen in this case. While more extensive examination of the mediastinum after the primary operation could be undertaken--removing some of the unknowns about this patient's true stage and prognosis--the relative risks and benefits of such an additional procedure in the setting of PET-negative microscopic level 7 and 9 disease probably do not justify such an approach. Assuming the absence of additional information, the recommendation of the University of Colorado Clinical Thoracic Oncology program is to commence a course of four cycles of adjuvant cisplatin-based chemotherapy. The pros and cons of postoperative radiotherapy will be discussed with the patient. If she wishes to proceed with PORT, this will commence following the adjuvant chemotherapy. Due to the inadequate lymph node sampling, she would not be eligible for adjuvant therapy as part of the ECOG 1505 trial of cisplatin chemotherapy with or without bevacizumab, but if she declines PORT, she may be eligible for the RADIANT trial of erlotinib vs placebo following her adjuvant cisplatin-based therapy.

Contemporary empyema necessitatis.

Empyema necessitatis is defined by the extension of an empyema through the parietal pleura, into surrounding tissue. Clinical manifestations are generally subacute, representing the indolent nature of the most commonly implicated pathogens (Mycobacterium tuberculosis and Actinomyces israelii). Treatment with antimicrobials and surgical debridement has drastically reduced mortality; however, with proper initial assessment and treatment of pulmonary infection, this rare complication can often be avoided. We describe a patient with empyema necessitatis to illustrate the importance of timely diagnosis and treatment of parapneumonic pleural effusion, and the need to consider this diagnosis in patients presenting with constitutional symptoms and a chest wall mass.