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• There has been relatively little progress in the treatment of small cell lung cancer. • Disialoganglioside 2 is commonly expressed in SCLC. • Dinutuximab, an anti-GD2 antibody is approved for neuroblastoma and is synergistic with irinotecan. • Dinutuximab + irinotecan vs. topotecan vs irinotecan in recurrent SCLC did not improve outcomes. Topotecan is approved as second-line treatment for small cell lung cancer (SCLC). Irinotecan is also frequently used given its more convenient schedule and superior tolerability. Preclinical studies support disialoganglioside (GD2) as an SCLC target and the combination of dinutuximab, an anti-GD2 antibody, plus irinotecan in this setting. We tested dinutuximab/irinotecan versus irinotecan or topotecan as second-line therapy in relapsed/refractory (RR) SCLC. Patients with RR SCLC and Eastern Cooperative Oncology Group performance status 0–1 were randomized 2:2:1 to receive dinutuximab 16–17.5 mg/m2 intravenous (IV)/irinotecan 350 mg/m2 IV (day 1), irinotecan 350 mg/m2 IV (day 1), or topotecan 1.5 mg/m2 IV (days 1–5) in 21-day cycles. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR; complete response [CR] + partial response [PR]), and clinical benefit rate (CBR; CR + PR + stable disease). Safety/tolerability were also assessed. A total of 471 patients were randomized to dinutuximab/irinotecan (n = 187), irinotecan (n = 190), or topotecan (n = 94). Age, sex, performance status, prior therapies, and metastatic disease sites were similar between groups. Survival and response rates were not improved for patients receiving dinutuximab/irinotecan versus those receiving irinotecan or topotecan (median OS 6.9 vs 7.0 vs 7.4 months [ p = 0.3132]; median PFS 3.5 vs 3.0 vs 3.4 months [ p = 0.3482]; ORR confirmed 17.1% vs 18.9% vs 20.2% [ p = 0.8043]; and CBR 67.4% vs 58.9% vs 68.1% [ p = 0.0989]), respectively. Grade 3/4 adverse events (≥5% receiving dinutuximab/irinotecan) included neutropenia, anemia, diarrhea, and asthenia. Dinutuximab/irinotecan treatment did not result in improved OS in RR SCLC versus irinotecan alone. Irinotecan administered every 21 days demonstrated comparable activity to topotecan administered daily × 5 every 21 days. ClinicalTrials.gov Identifier. NCT03098030. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Three phase III trials have shown pemetrexed to be associated with improved clinical outcomes among patients with adenocarcinoma and large cell histology compared with patients with squamous histology in advanced non-small cell lung cancer (NSCLC). The current retrospective analysis examined whether differences were present by histology in a three-arm trial of gemcitabine–carboplatin (GCb) or gemcitabine–paclitaxel (GP) versus a standard regimen of paclitaxel–carboplatin (PCb). Materials and methods: 1135 chemonaïve patients with stage IIIB or IV NSCLC were randomly allocated to receive: gemcitabine 1000mg/m2 days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 day 1 (GCb); or gemcitabine 1000mg/m2 days 1 and 8 plus paclitaxel 200mg/m2 day 1 (GP); or paclitaxel 225mg/m2 plus carboplatin AUC 6.0 day 1 (PCb). Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient histology. Results: 202 patients (17.8%) had squamous, 555 (48.9%) had adenocarcinoma, 45 (4.0%) had large cell, and 333 (29.3%) had another histologic type. The overall response rate for squamous patients was greater than non-squamous (35.1% versus 27.8%, P =0.04). Median survival (9.5 months for squamous and 8.3 months for non-squamous) and median time to progression (5.0 months for squamous and 4.4 months for non-squamous) did not significantly vary by histologic group. For squamous histology, median survival was 6.6 months for GCb, 10.2 months for GP, and 10.3 months for PCb. For non-squamous disease, median survival was 8.2 months for GCb, 8.4 months for GP, and 8.3 months for PCb. A formal test for a histology-by-treatment interaction effect between GCb and PCb was significant (P =0.04). Conclusion: In this trial of commonly used agents for advanced NSCLC, overall survival and time to progression were similar when comparing patients across histologies. The effect of treatment, however, varied across histologies. [Copyright &y& Elsevier]

Abstract: Introduction: Despite advances in Stage III NSCLC, the mortality from the disease remains >70%. Disease recurrence can occur both locally and systemically. Trimodality therapy may improve outcome by maximizing local control. The purpose of this study was to perform a phase I trial of bortezomib (PS-341, Velcade) in addition to chemotherapy with carboplatin AUC=2 and paclitaxel 50mg/m2 and concurrent radiotherapy (61Gy) as induction treatment in a trimodality approach. Methods: Patients with pathologically documented Stage III a (N2) or selected IIIb (N3) disease were eligible. Bortezomib was administered on days 1, 4, 15, 18 during the 6-week induction chemoradiotherapy. Cohorts of three patients were entered and observed for toxicity during chemoradiotherapy and for 2 weeks afterwards. Surgical resection was attempted in the patients who had mediastinal sterilization. All patients were to receive consolidation chemotherapy with carboplatin AUC=6 and paclitaxel 200mg/m2. Results: Twelve patients in three cohorts were enrolled. The addition of bortezomib was well tolerated, with no unexpected toxicities during the induction phase. However, there were three postoperative deaths (two pneumonitis and one from failure of the bronchopulmonary flap). The trial was halted as a consequence of these toxicities. Conclusions: While this approach was well tolerated in terms of acute toxicity, the apparently delayed toxicity was severe and unpredictable. It does not appear that bortezomib can be safely administered as part of preoperative chemoradiotherapy for lung cancer. However, there was a high incidence of complete pathologic response and cautious exploration of this agent in the non-operative setting is appropriate. [Copyright &y& Elsevier]

Platinum-based chemotherapy regimens have been the mainstay of systemic chemotherapy in advanced NSCLC. However, substantial toxicity impairs the survival and symptom control advantages of cisplatin- and even carboplatin-containing regimens. With the advent of newer active agents in the 1990s, investigators began conducting clinical studies with the aim of potentially eliminating platinum from initial therapy for patients with advanced NSCLC. Conceptually, three major hypotheses were tested in phase III trials: (i) single, non-platinum agents are equal in efficacy to platinum in combination with these agents; (ii) non-platinum combinations are potentially more effective than platinum-based therapy; and (iii) non-platinum combinations are at least equally efficacious, but less toxic than, platinum-based therapy. An overall analysis of phase III data indicates that combinations of these newer agents with platinum are superior to the single agent alone and that combinations of non-platinum agents are no more effective than platinum-based therapy. Non-platinum therapy has a different and perhaps marginally improved toxicity spectrum compared with platinum-based therapy. In the few studies utilizing a formal quality-of-life analysis, no differences have been detected. Therefore, while several non-platinum regimens have been validated in phase III trials as reasonable alternatives to platinum-based therapy, they have not been proven to be clearly superior. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate possible clinical and dosimetric predictors of acute esophagitis in patients with locally advanced non–small-cell lung carcinoma treated in a prospective Phase I-II trimodality protocol.Methods and materials: The data from 36 patients with Stage III non–small-cell lung carcinoma treated in a Phase I-II high-dose concurrent chemoradiotherapy protocol were analyzed for possible predictors of acute esophagitis. The median age was 58 years (range, 38–77 years). Patients included in this study had either Stage IIIA (n = 24) or IIIB (n = 12) disease. All patients were treated with induction concurrent carboplatin (area under the plasma concentration-time curve 1), vinorelbine (5–15 mg/m2), and hyperfractionated radiotherapy (69.6 Gy) followed by consolidation chemotherapy (carboplatin area under the plasma concentration-time curve 6, vinorelbine 25 mg/m2, docetaxel 75 mg/m2) or surgery (n = 19) plus consolidation chemotherapy. Acute toxicities were graded using the Radiation Therapy Oncology Group criteria. The following clinical and dosimetric parameters were analyzed: age, gender, race, T stage, N stage, pretreatment body mass index, percentage of weight lost during therapy, pretherapy serum albumin, tumor location, length of esophagus in treatment field, percentage of esophagus volume treated to >40, >45, >50, >55, >60, and >65 Gy. These parameters were coded and analyzed against Grade 2 and worse esophagitis using univariate and multivariate regression analyses.Results: Of the 36 patients, Grade 1, 2, and 3 acute esophagitis was observed in 16 (44%), 12 (33%), and 2 (5.5%) patients, respectively. Grade 4 or 5 toxicity was not observed in this patient cohort. Only the pretreatment body mass index (ρ = -0.431, p = 0.004) and percentage of esophagus volume treated to >50 Gy (ρ = 0.297, p = 0.040) demonstrated a statistically significant correlation with the incidence of Grade 2 or worse esophagitis on univariate analysis. These parameters retained their statistical significance on multivariate regression analysis (p = 0.029 and 0.049, respectively).Conclusion: In patients undergoing concurrent high-dose chemotherapy and hyperfractionated radiotherapy, a low pretherapy body mass index and percentage of esophagus volume treated to >50 Gy were significantly associated with acute Grade 2 or worse esophagitis. [Copyright &y& Elsevier]

Purpose. Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50–100 μM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 μM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule. Patients and methods. Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter. Results. The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30–74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 μM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression. Conclusion. Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing. [ABSTRACT FROM AUTHOR]

Several chemotherapeutic regimens have emerged in the past 5 years with the capability to improve survival and quality of life of patients with advanced non-small cell lung cancer (NSCLC). Among these treatments, the regimen of gemcitabine (Gemzar) and carboplatin (Paraplatin) has gained increasing acceptance. The combination of these two drugs was initially hampered by unacceptable platelet toxicity. However, the use of a 21-day schedule with the administration of gemcitabine on days 1 and 15 or the use of a 28-day schedule with the omission of day-15 gemcitabine has clearly been well tolerated and active. Unlike taxane based regimens, there is no need for steroid premedication, and neurotoxicity and alopecia are absent. This regimen is well tolerated and easily administered on an outpatient basis. It therefore represents an excellent “platform regimen” for the addition of new agents, particularly those associated with minimal myelotoxicity. Three-drug regimens consisting of gemcitabine/carboplatin and a taxane have been evaluated both with concurrent and sequential administration of the drugs. Trials are under way or planned for the addition of novel agents such as C225, UCN-01, PKC-alpha antisense, bexarotene, COX-2 inhibitors and other agents. [Copyright &y& Elsevier]

Several chemotherapeutic regimens have emerged in the past 5 years with the capability to improve survival and quality of life of patients with advanced non-small cell lung cancer (NSCLC). Among these treatments, the regimen of gemcitabine (Gemzar) and carboplatin (Paraplatin) has gained increasing acceptance. The combination of these two drugs was initially hampered by unacceptable platelet toxicity. However, the use of a 21-day schedule with the administration of gemcitabine on days 1 and 15 or the use of a 28-day schedule with the omission of day-15 gemcitabine has clearly been well tolerated and active. Unlike taxane based regimens, there is no need for steroid premedication, and neurotoxicity and alopecia are absent. This regimen is well tolerated and easily administered on an outpatient basis. It therefore represents an excellent “platform regimen” for the addition of new agents, particularly those associated with minimal myelotoxicity. Three-drug regimens consisting of gemcitabine/carboplatin and a taxane have been evaluated both with concurrent and sequential administration of the drugs. Trials are under way or planned for the addition of novel agents such as C225, UCN-01, PKC-alpha antisense, bexarotene, COX-2 inhibitors and other agents. [Copyright &y& Elsevier]

PURPOSE: Current diagnostic methods to determine programmed death 1 (PD-1) receptor and its ligand (PD-L1)/PD-1 immunotherapy (immune checkpoint inhibitor [ICI]) efficacy in recurrent or metastatic non–small-cell lung carcinoma (rmNSCLC) are imprecise. Although previously shown that patients with high tumor PD-L1 (≥ 50%) demonstrate clinical benefit in the form of disease reduction and improved survival, patients with low PD-L1 (< 50%) sometimes benefit from treatment. Since the PD-L1/PD-1 pathway is dynamic, monitoring PD-L1 levels during treatment may be more accurate than a static baseline tumor biopsy; however, rebiopsying the primary or metastatic disease is rarely feasible. Liquid biopsies that measure the upregulation of PD-L1 on tumor-associated cells (TACs), ie, cancer-associated macrophage-like cells and circulating tumor cells, have been performed, but their predictive value for ICI therapy efficacy is unknown. MATERIALS AND METHODS: We initiated a single-blind prospective study to evaluate TAC PD-L1 expression changes in rmNSCLC from blood samples before (T0) and after (T1) treatment with ICI (ICI, n = 41) or without ICI (no ICI, n = 41). Anonymized blood was filtered to isolate TACs, which were then quantified for high/low PD-L1 expression. Progression-free survival (PFS) or overall survival (OS) hazard ratios (HRs) were evaluated at 18 and 24 months by censored univariate analysis. RESULTS: Increased TAC PD-L1 expression between T0 and T1 in patients who were not treated with ICI had no relationship with PFS or OS. However, increased TAC PD-L1 expression between T0 and T1 in patients treated with ICI had significantly better PFS (HR, 3.49; 95% CI, 1.5 to 8.3; P =.0091) and OS (HR, 3.058; 95% CI, 1.2 to 7.9; P =.0410). CONCLUSION: Blood-based monitoring of dynamic changes in PD-L1 in TACs appears to identify patients with rmNSCLC who may benefit from ICI. Monitoring programmed death 1 receptor and its ligand on circulating tumor-associated cells in recurrent or metastatic non–small-cell lung cancer predicts response to immunotherapy and radiation. [ABSTRACT FROM AUTHOR]

Background: Cryptophycin 52 is a novel antitubulin drug with in vitro and in vivo activity in non-small cell lung cancer. Based upon promising Phase 1 data, a multicenter trial was performed to evaluate the drug in previously treated non-small cell lung cancer (NSCLC). Methods: Patients with Stage IIIb (pleural effusion) or Stage IV NSCLC and performance status 0–1 with adequate organ function who had received at least one and no more than two prior chemotherapy regimens (one of which must have contained a platinum agent) were eligible. Cryptophycin 52 was administered at a dose of 1.5 mg/m2 day 1 and 8 every 3 weeks. Patients were reassessed every two cycles. Results: Twenty-six patients were enrolled of whom 25 are evaluable for toxicity and response. There were no responders, toxicity was predominantly neurologic in the form of peripheral neuropathy and constipation. After the first 12 patients were enrolled, the dose was lowered to 1.125 mg/m2 day 1 and 8. Toxicity was substantially reduced with this maneuver. Median survival was 4.1 months. The median number of cycles was two, however ten patients received four or more courses of therapy. Conclusion: Cryptophycin 52 failed to produce measurable responses utilizing this schedule. In 40% of patients there was evidence of disease stabilization. Toxicity at 1.5 mg/m2 was unacceptable. Since activity and toxicity may be dose and schedule dependent, other schedules of cryptophycin 52 should be considered. [Copyright &y& Elsevier]

Purpose: Delays initiating cancer therapy are increasingly common, impact outcomes, and have implications for health equity. However, it remains unclear (1) whether patients’ beliefs regarding acceptable diagnostic to treatment intervals align with current guidelines, and (2) to what degree psychological factors contribute to longer intervals. We conducted a qualitative study with patients and cancer care team members (“providers”). Methods: We interviewed patients with several common solid tumors as well as providers. Interviews were analyzed using an interpretive approach, guided by modified grounded theory. Results: Twenty-two patients and 12 providers participated. Half of patients had breast cancer; 27% waited >60 days between diagnosis and treatment. Several themes emerged. (1) Patients felt treatment should begin immediately following diagnosis, while providers’ opinion on the goal timeframe to start treatment varied. (2) Patients experienced psychological distress while waiting for treatment. (3) Participants identified logistical, social, and psychological sources of delay. Fear related to multiple aspects of cancer care was common. Emotion-driven barriers could manifest as not taking steps to move ahead, or as actions that delayed care. (4) Besides addressing logistical challenges, patients believed that education and anticipatory guidance, from their care team and from peers, may help overcome psychological barriers to treatment and facilitate the start of therapy. Conclusions: Patients feel an urgency to start cancer therapy, desiring time frames shorter than those included in guidelines. Psychological distress is frequently both a contributor to, and a consequence of, treatment delays. Addressing multilevel barriers, including psychological ones, may facilitate timely treatment and reduce distress. [ABSTRACT FROM AUTHOR]

A modified version of the PGDx elioTM Plasma Resolve assay was validated as a laboratory-developed test (LDT) for clinical use in the Molecular Diagnostics Laboratory at Fox Chase Cancer Center. The test detects single nucleotide variants (SNVs) and small insertions and deletions (indels) in 33 target genes using fragmented genomic DNA extracted from plasma. The analytical performance of this assay was assessed with reference standard DNA and 29 samples from cancer patients and detected 66 SNVs and 23 indels. Using 50 ng of input DNA, the sensitivity was 95.5% to detect SNVs at 0.5% allele frequency, and the specificity was 92.3%. The sensitivity to detect indels at 1% allele frequency was 70.4%. A cutoff of 0.25% variant allele frequency (VAF) was set up for diagnostic reporting. An inter-laboratory study of concordance with an orthologous test resulted in a positive percent agreement (PPA) of 91.7%. [ABSTRACT FROM AUTHOR]

• Largest experience to date of the results of follow-up testing stage III NSCLC. • No survival difference between relapse detected by symptoms vs. routine CT chest. • Favorable outcomes seen in symptomatic patients with only CNS relapse. • The CNS results obscured potential benefits from chest CT. • Routine CNS and chest imaging may improve outcomes. The majority of patients with locally advanced non-small cell lung cancer (LANSCLC) will recur after receiving multimodal treatment with curative intent. Current guidelines recommend routine follow-up with computerized tomography (CT) scans, though minimal data exist on the utility of this approach nor has an optimal follow-up strategy to detect recurrence been defined. This study examined whether survival varied if relapse was detected with scheduled follow-up CT versus symptoms, and whether the pattern of recurrence affected these outcomes. Single institution retrospective review of patients who had undergone definitive management of LANSCLC with chemoradiotherapy +/- surgical resection. Standard follow-up testing consisted of routine exam and chest CT beginning at every 3 months in the first year and decreasing to annually after the fifth year. 311 patients were assessed, of which 167 patients recurred and were evaluable. 104 progressions were detected by follow-up and 63 by symptoms. For the entire group, there was no difference in overall survival (OS) for those detected by scans vs. symptoms (7.6 vs. 6.1 months, p = 0.797). After excluding patients with oligometastatic (1–3) brain metastases (OBM), OS was superior in patients with scan detected relapse (7.5 vs. 3.4 months, p = 0.013). Routine surveillance by CT chest detects more localized disease than symptom driven follow-up, though OS does not differ. This null result is largely driven by the favorable outcomes for patients with OBM who present symptomatically. A strategy of both chest and brain imaging could be considered and warrants further investigation. [ABSTRACT FROM AUTHOR]

Supplemental digital content is available in the text. Background: Therapies targeting the epidermal growth factor receptor (EGFR) result in a painful rash, the most common and debilitating toxicity among patients with non-small cell lung cancer (NSCLC) who take EGFR tyrosine kinase inhibitor (TKI) therapy; however, predicting the development and the severity of the rash is difficult. Objective: The aim of this study was to examine how erlotinib—an EGFR TKI that NSCLC patients take to stop or slow tumor growth—altered the transcriptome of dermal fibroblasts. Methods: Dermal fibroblasts (ATCC PCS-201-012) were seeded in cell culture flasks, grown under standard conditions, and transferred to cell culture dishes. Cells were treated once daily for 3 days with erlotinib 100 nM (n = 5), erlotinib 1 μM (n = 5), vehicle 1 μM (dimethyl sulfoxide) (n = 5), or no treatment (n = 5). Total RNA was extracted using a standard TRIzol method and hybridized using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Raw intensities generated from the arrays were normalized using a Robust Multiarray Average method and analyzed using analysis of variance in Limma R software. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis to identify canonical or noncanonical signaling pathways enriched in this dataset. Results: We selected genes for investigation based on their potential role in wound healing (AQP3), rash development (CCL2), fibroblast activation (PALLD), cancer and cancer progression (GDF-15 , SLC7A11 , MMP12 , and DIRAS3), and cell cycle control (CDC6). We were able to validate four of these genes by both Western blot analysis and quantitative polymerase chain reaction (MMP12 , CCL2 , CDC6 , and SLC7A11). Discussion: If found predictive of rash in future studies using patient samples, our findings may help to identify those at risk for severe rash so that (a) the dose of EGFR TKI therapy may be adjusted; (b) additional treatments for the rash can be developed; and/or (c) precise, patient-centered interventions can be developed so that patients with cancer can better self-manage their rash and adhere to EGFR TKI treatment. [ABSTRACT FROM AUTHOR]

Summary: The incidence of malignancy associated with pregnancy is rising. This issue is of increasing importance in lung cancer given the rising number of cases of lung cancer in women, many of childbearing age. Treatment with chemotherapy in patients who are pregnant is indicated in scenarios where the malignancy is aggressive and the risk of death of the mother outweighs the risk of fetal effects from chemotherapy. We report a case of a pregnant female with limited stage small cell lung carcinoma treated at 27 weeks gestation with cisplatin and etoposide and subsequent delivery of a healthy child. [Copyright &y& Elsevier]

PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non–small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access. METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of.01 were used for all comparisons. RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P <.0001), from rural areas (17.3% v 14.4%; P =.004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P <.0001), but less likely to be female (38.6% v 47.2%; P <.0001), Asian (2.8% v 5.1%; P <.0001), or Hispanic (2.4% v 3.8%; P =.003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P <.0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P <.0001), females (38.6% v 46.0%; P <.0001), and racial or ethnic minorities (14.8% v 21.5%; P <.0001). CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted. Precision medicine master protocols conducted as a public-private partnership may improve trial access for patients. [ABSTRACT FROM AUTHOR]

As the COVID-19 pandemic accelerates in the United States, this commentary asks how oncology specialists and allied providers are balancing a delay in cancer diagnosis or treatment against the risk for potential COVID-19 exposure, mitigating the risks for significant care disruptions associated with social distancing behaviors, and managing the appropriate allocation of limited health care resources during this unprecedented health care crisis. [ABSTRACT FROM AUTHOR]

As the COVID-19 pandemic accelerates in the United States, this commentary asks how oncology specialists and allied providers are balancing a delay in cancer diagnosis or treatment against the risk for potential COVID-19 exposure, mitigating the risks for significant care disruptions associated with social distancing behaviors, and managing the appropriate allocation of limited health care resources during this unprecedented health care crisis. [ABSTRACT FROM AUTHOR]

Purpose The primary goal of Phase II clinical trials is to understand better a treatment's safety and efficacy to inform a Phase III go/no-go decision. Many Phase II designs have been proposed, incorporating randomization, interim analyses, adaptation, and patient selection. The Phase II design with an option for direct assignment (i.e. stop randomization and assign all patients to the experimental arm based on a single interim analysis (IA) at 50% accrual) was recently proposed [An et al., 2012]. We discuss this design in the context of existing designs, and extend it from a single-IA to a two-IA design. Methods We compared the statistical properties and clinical relevance of the direct assignment design with two IA (DAD-2) versus a balanced randomized design with two IA (BRD-2) and a direct assignment design with one IA (DAD-1), over a range of response rate ratios (2.0-3.0). Results The DAD-2 has minimal loss in power (< 2.2%) and minimal increase in T1ER (< 1.6%) compared to a BRD-2. As many as 80% more patients were treated with experimental vs. control in the DAD-2 than with the BRD-2 (experimental vs. control ratio: 1.8 vs. 1.0), and as many as 64% more in the DAD-2 than with the DAD-1 (1.8 vs. 1.1). We illustrate the DAD-2 using a case study in lung cancer. Conclusion In the spectrum of Phase II designs, the direct assignment design, especially with two IA, provides a middle ground with desirable statistical properties and likely appeal to both clinicians and patients. [ABSTRACT FROM AUTHOR]

Purpose: Recent randomized studies have suggested improvements in progression-free and overall survival with the addition of stereotactic body radiation therapy (SBRT, also known as SABR) in patients with oligometastatic non-small cell lung cancer. Given the novelty and complexity of incorporating SBRT in the oligometastatic setting, the multidisciplinary American Radium Society Lung Cancer Panel was assigned to create appropriate use criteria on SBRT as part of consolidative local therapy for patients with oligometastatic and oligoprogressive non-small cell lung cancer.Methods and Materials: A review of the current literature was conducted from January 1, 2008, to December 25, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to systematically search the PubMed database to retrieve a comprehensive set of relevant articles.Results: Based on representation in existing randomized trials, the panel defined the term "oligometastasis" as ≤3 metastatic deposits (not including the primary tumor) in the previously untreated setting or after first-line systemic therapy after the initial diagnosis. "Oligoprogression" also referred to ≤3 discrete areas of progression in the setting of prior or ongoing receipt of systemic therapy. In all appropriate patients, the panel strongly recommends enrollment in a clinical trial whenever available. For oligometastatic disease, administering first-line systemic therapy followed by consolidative radiation therapy (to all sites plus the primary/nodal disease) is preferred over up-front radiation therapy. Owing to a dearth of data, the panel recommended that consolidative radiation therapy be considered on a case-by-case basis for 4 to 5 sites of oligometastatic disease, driver mutation-positive oligometastatic disease without progression on up-front targeted therapy, and oligoprogressive cases.Conclusions: Although SBRT/SABR appears to be both safe and effective in treating patients with limited metastatic sites of disease, many clinical circumstances require individualized management and strong multidisciplinary discussion on account of the limited existing data. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate mediastinal nodal clearance (MNC) rates after induction chemotherapy and concurrent, full-dose radiation therapy (RT) in a phase II trimodality trial (Radiation Therapy Oncology Group protocol 0229). Patients and Methods: Patients (n=57) with stage III non-small cell lung cancer (pathologically proven N2 or N3) were eligible. Induction chemotherapy consisted of weekly carboplatin (AUC = 2.0) and paclitaxel 50 mg/m2. Concurrent RT was prescribed, with 50.4 Gy to the mediastinum and primary tumor and a boost of 10.8 Gy to all gross disease. The mediastinum was pathologically reassessed after completion of chemoradiation. The primary endpoint of the study was MNC, with secondary endpoints of 2-year overall survival and postoperative morbidity/mortality. Results: The grade 3/4 toxicities included hematologic 35%, gastrointestinal 14%, and pulmonary 23%. Forty-three patients (75%) were evaluable for the primary endpoint. Twenty-seven patients achieved the primary endpoint of MNC (63%). Thirty-seven patients underwent resection. There was a 14% incidence of grade 3 postoperative pulmonary complications and 1 30-day, postoperative grade 5 toxicity (3%). With a median follow-up of 24 months for all patients, the 2-year overall survival rate was 54%, and the 2-year progression-free survival rate was 33%. The 2-year overall survival rate was 75% for those who achieved nodal clearance, 52% for those with residual nodal disease, and 23% for those who were not evaluable for the primary endpoint (P=.0002). Conclusions: This multi-institutional trial confirms the ability of neoadjuvant concurrent chemoradiation with full-dose RT to sterilize known mediastinal nodal disease. [Copyright &y& Elsevier]

Abstract: Purpose: Sufficient data are currently unavailable to assist in defining suitable regimens for patients ≥70 years with advanced non-small cell lung cancer (NSCLC). Methods: Chemonaïve patients with a performance status (PS) of 0 or 1 and stage IIIB or IV NSCLC were randomized to gemcitabine 1000mg/m2 on days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 on day 1; the same schedule of gemcitabine plus paclitaxel 200mg/m2 on day 1; or paclitaxel 225mg/m2 on day 1 plus carboplatin AUC 6.0 on day 1. Cycles were every 21 days up to 6. Efficacy and toxicity results were compared by age groups. Results: Overall survival (OS) between patients <70 years (8.6 months, 95% CI: 7.9, 9.5) and ≥70 years (7.9 months, 95% CI: 7.1, 9.5) was similar. OS was 8.8 months (95% CI: 7.5, 10.3) among patients 70–74 years, 6.5 months (95% CI: 5.6, 9.3) among patients 75–79 years, and 7.9 months (95% CI: 6.3, 10.3) among patients ≥80 years. OS was lower among patients 75–79 years compared with patients 70–74 years (P =0.04). Compared with patients <70 years, patients ≥70 years experienced similar rates of myelosuppresion, but younger patients experienced more vomiting and nausea. There was no clear pattern with respect to differences in efficacy by treatments across age groups. Conclusions: Based on the similarity of patient outcomes across age groups, doublet chemotherapy is feasible among carefully selected elderly patients with good PS. [Copyright &y& Elsevier]

The present study was designed to investigate the ability of N-[4-(5-bromo-2-pyrimidyloxy)-3-methylphenyl]-(dimemethylamino)-benzoylphenylurea (dimemethylamino benzoylphenylurea; BPU) to sensitize cells to radiation and to examine the relationship between phenotype versus survival, DNA damage, apoptosis, or cell cycle progression in non-small cell lung cancer (NSCLC) cell lines. Asynchronous cultures of three NSCLC (phenotype) lines, A549 (adenocarcinoma), NCI-H226 (squamous) and NCI-H596 (adenosquamous) were used. Cells were treated for 24 h with BPU at various concentrations (0–10 μM) to obtain drug doses for inhibiting cell survival by ∼50% (IC50). Cells were X-irradiated without BPU or after 24 h BPU treatment at IC50. Radiation doses ranged from 0 to10 Gy. Cell survival was determined by a colony-forming ability assay. The effect of BPU on the cell cycle distribution and induction of apoptosis were measured by flow cytometry-based assays. The effect of BPU on radiation-induced DNA damage and repair was analyzed according to nuclear γH2AX immunofluorescence of cells exposed to X-rays alone or after BPU. Anti-γH2AX antibody staining, a surrogate determinant of double stranded DNA breaks, was measured using flow cytometry. BPU (1.5 μM) for 24 h produced ∼50% cell survival. BPU and X-irradiation were synergistic in the three cell lines at survival levels of 20–50%. Flow cytometry analysis of replicate experiments with BPU (1.5 μM for 24 h) showed that BPU blocked cell progression at S and/or G2/M. The incidence of apoptosis in BPU-treated versus control cells ranged from ∼0.3 to ∼8%. Twenty-four hour after X-irradiation cells pre-treated with BPU and X-irradiated after drug exposure showed γH2AX levels approximately two times higher than did the cells exposed to X-rays only. The study identified BPU as a novel radiation sensitizer. The analysis of phosphorylated histone H2AX as a surrogate marker of DNA double strand breaks suggested a positive association between radiosensitization and the inhibition of X-irradiation-induced DNA damage repair by BPU. [ABSTRACT FROM AUTHOR]

The article discusses the differences in epidemiology, biology and therapy of lung cancer in women in the U.S. Emerging literature shows a biological basis for the differences in the pathogenesis and possibly increased susceptibility to lung cancer in women. There are also considerable data which supports small but important differences favoring women in terms of response to therapy and long-term survival after the diagnosis of lung cancer, regardless of histology or age.

Background: Tamoxifen has been reported to enhance the antitumor activity of cisplatin in preclinical models by modulation of protein kinase C signal transduction and apoptosis-related pathways.Methods: We conducted a phase I study of high-dose oral tamoxifen in combination with intravenous cisplatin, with two objectives: 1) to determine tolerability, and 2) to determine the daily tamoxifen dose required to achieve serum levels equivalent to in vitro concentrations reported to enhance cisplatin cytotoxicity in preclinical models. Tamoxifen was administered days one through seven at escalating daily doses of 160 mg/m2 (n = 5), 200 mg/m2 (n = 6), and 250 mg/m2 (n = 4) by patient cohort, followed by cisplatin at 100 mg/m2 on day eight. Serum concentrations of tamoxifen and its hydroxylated metabolite N-desmethyltamoxifen were determined by high-performance liquid chromatography (HPLC) on day eight of the first treatment cycle in seven patients.Results: Fifteen patients with advanced malignancies received treatment with tamoxifen at 160 mg/m2, 200 mg/m2, and 250 mg/m2 per cycle, respectively. Serum concentrations of tamoxifen and N-desmethyltamoxifen on day eight of the first cycle ranged from 1.75-8.22 microM (mean 4.72 microM) and 3.62-10.85 microM (mean 3.87 microM), respectively. Toxicity analysis demonstrated that grade 3/4 nonhematological toxicity occurred in 0/5 at a tamoxifen dose of 160 mg/m2, 1/6 at a tamoxifen dose of 200 mg/m2, and in 1/4 patients at the 250 mg/m2 dose level. No grade 4 hematological toxicity occurred. Classic dose-limiting toxicity was not observed; the trial was closed to further accrual after documentation that targeted tamoxifen levels (around 5 microM) were achieved with daily tamoxifen doses > or = 160 mg/m2 in combination with cisplatin.Conclusions: This regimen of high-dose tamoxifen in combination with cisplatin can be safely administered. Serum tamoxifen levels comparable to concentrations required for enhancement of cisplatin sensitivity in vitro are clinically achievable with acceptable toxicity. The level of antitumor activity in nonsmall cell lung cancer NSCLC is encouraging (partial response in 4/10 patients). Based on these data, a Phase II study of high-dose tamoxifen in combination with cisplatin in patients with metastatic NSCLC is being conducted through the Southwest Oncology Group. [ABSTRACT FROM AUTHOR]

The advent of immunotherapy has ushered in a new era in both cancer research and cancer treatment strategies. Published reviews have described potential mechanisms for therapeutic synergisms from the combination of radiation therapy and immunotherapy, largely overlooking the role of humoral immunity by only focusing on cellular immunity. Given that these 2 branches of the immune system are highly interdependent, in this review we detail both what has already been established regarding the role of humoral immunity in cancer and propose potential avenues that are ripe for further investigation and potential clinical applications. [ABSTRACT FROM AUTHOR]

Purpose: Cross-sectional research suggests that thinking about multiple ways to reach goals (hope pathways) and the belief that one can reach them (hope agency) may be adaptive for lung cancer patients. We examined the between-person and within-person associations among aspects of hope agency and pathways thinking, daily fatigue, pain, and functional concerns (e.g., sense of independence, usefulness) among lung cancer patients during active treatment. Methods: Data from a daily diary study were used to examine relations among hope agency, hope pathways, fatigue, pain, and functional concern in 50 patients with advanced lung cancer. Participants were accrued from one outpatient cancer center and completed the study between 2014 and 2015. Results: Adjusting for covariates and the previous day's symptoms or concern, patients who engaged in higher pathways thinking reported lower daily symptoms, whereas those who engaged in higher agency thinking reported less functional concern. Within-person increases in pathways thinking were associated with less daily fatigue, pain, and functional concern; within-person increases in agency thinking were associated with less daily fatigue and pain. Models examining symptoms and concerns as predictors of hope suggested within-person increases in functional concern and fatigue and pain were related to lower agency and pathways thinking the same day. Patients with higher fatigue and pain did not report lower agency or pathways thinking, but patients with more functional concern did. Conclusions: Increases in hope pathways thinking may be associated with lower symptoms and better functioning in lung cancer patients. This suggests that it is important to determine the efficacy of interventions that emphasize the pathways the component of hope. [ABSTRACT FROM AUTHOR]

Background: Platinum and etoposide with thoracic radiation followed by prophylactic cranial irradiation constitute the standard treatment for limited-stage small cell lung cancer (LS-SCLC). Many patients with LS-SCLC are elderly with comorbidities.Methods: Individual patient data were collected from 11 phase 2 or 3 trials for LS-SCLC conducted by the National Clinical Trials Network and activated from 1990 to 2010. The primary endpoint was overall survival (OS); the secondary endpoints were progression-free survival (PFS), the rate of severe adverse events, and off-treatment reasons. The outcomes were compared for patients 70 years old or older (elderly patients) and patients younger than 70 years (younger patients).Results: Individual patient data from 1049 younger patients (81%) and 254 elderly patients (19%) were analyzed. In the multivariate model, elderly patients, in comparison with younger patients, had worse OS (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.18-1.63; median OS for elderly patients, 17.8 months; OS for younger patients, 23.5 months) and worse PFS (HR, 1.19; 95% CI, 1.03-1.39; median PFS for elderly patients, 10.6 months; median PFS for younger patients, 12.3 months). Elderly patients, in comparison with younger patients, experienced more grade 5 adverse events (8% vs 3%; P < .01) and more grade 3 or higher dyspnea (11% vs 7%; P = .03) but less grade 3 or higher esophagitis/dysphagia (14% vs 19%; P = .04) and less grade 3 or higher vomiting (11% vs 17%; P = .01). Elderly patients completed treatment less often, discontinued treatment because of adverse events and patient refusal more frequently, and died during treatment more frequently.Conclusions: Elderly patients with LS-SCLC have worse PFS and OS and more difficulty in tolerating therapy. Future trials should incorporate assessments of elderly patients, novel monitoring of adverse events, and more tolerable radiation and systemic therapies. [ABSTRACT FROM AUTHOR]

Objective Co-signaling molecules PD-L1, B7-H3, and PD-1 play a key role in cancer immunology. There are limited but emerging data on expression of these molecules in HIV-infected lung cancer patients. Materials and Methods We reviewed archived lung cancer tissue samples from HIV-infected cases (n = 13) and HIV-uninfected controls (n = 13) from 2001-2015. Cases and controls were matched by histology and stage. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 and B7-H3, and percent of tumor infiltrating immune cells (TII) expressing PD-1 and PD-L1. Positive expression was defined as >5%. Statistical analysis was performed using the non-parametric Mann-Whitney test and the chi-square test. Results PD-L1 expression on tumor cells was positive in 23% of cases and 46% of controls. B7-H3 expression on tumor cells was positive in 92% of cases and 69% of controls. PD-1 expression on TII was positive in 69% of cases and 54% of controls. PD-L1 expression on TII was positive in 31% of cases and 69% of controls. B7-H3 percent expression on tumor cells was significantly higher in cases vs. controls (median 90% vs 20%, p = 0.005), but there were no significant differences in percent expression of PD-L1 on tumor cells, PD-1 on TII or PD-L1 on TII. Conclusion HIV-infected lung cancer patients had significantly higher B7-H3 tumor expression compared to HIV-uninfected controls, with similar rates of tumor PD-L1 expression, as well as PD-1 and PD-L1 expression on TII. These results support inclusion of HIV-infected lung cancer patients in future immunotherapy trials. [ABSTRACT FROM AUTHOR]

Purpose: To determine, in a retrospective analysis of a large cohort of stage III non-small cell lung cancer patients treated with curative intent at our institution, whether having a pathologic complete response (pCR) influenced overall survival (OS) or freedom from recurrence (FFR) in patients who underwent definitive (≥60 Gy) neoadjuvant doses of chemoradiation (CRT).Methods and Materials: At our institution, 355 patients with locally advanced non-small cell lung cancer were treated with curative intent with definitive CRT (January 2000-December 2013), of whom 111 underwent mediastinal reassessment for possible surgical resection. Ultimately 88 patients received trimodality therapy. Chi-squared analysis was used to compare categorical variables. The Kaplan-Meier analysis was performed to estimate OS and FFR, with Cox regression used to determine the absolute hazards.Results: Using high-dose neoadjuvant CRT, we observed a mediastinal nodal clearance (MNC) rate of 74% (82 of 111 patients) and pCR rate of 48% (37 of 77 patients). With a median follow-up of 34.2 months (range, 3-177 months), MNC resulted in improved OS and FFR on both univariate (OS: hazard ratio [HR] 0.455, 95% confidence interval [CI] 0.272-0.763, P = .004; FFR: HR 0.426, 95% CI 0.250-0.726, P = .002) and multivariate analysis (OS: HR 0.460, 95% CI 0.239-0.699, P = .001; FFR: HR 0.455, 95% CI 0.266-0.778, P = .004). However, pCR did not independently impact OS (P = .918) or FFR (P = .474).Conclusions: Mediastinal nodal clearance after CRT continues to be predictive of improved survival for patients undergoing trimodality therapy. However, a pCR at both the primary and mediastinum did not further improve survival outcomes. Future therapies should focus on improving MNC to encourage more frequent use of surgery and might justify use of preoperative CRT over chemotherapy alone. [ABSTRACT FROM AUTHOR]

Objectives To determine the prognostic effect of Body Mass Index (BMI) in definitively treated locally advanced NSCLC patients. Materials and methods In this single institution retrospective cohort study, we evaluated 291 patients who were treated for locally advanced NSCLC from 2000 to 2010. They were stratified into four BMI groups based on World Health Organization criteria: underweight (<18.5 kg/m2), normal weight (18.5 to <25 kg/m2), overweight (25 to <30 kg/m2), and obese (≧30 kg/m2). Overall survival was analyzed by BMI group. Results Baseline patient characteristics and treatment parameters were similar between obese and normal weight patients. Increasing BMI was associated with improved overall survival (P = 0.011), even when underweight cases were excluded. There was a sustained 31%–58% reduction in mortality of obese relative to normal weight patients (HR 0.68 ± 0.21, 0.61 ± 0.19, and 0.42 ± 0.19, for each year post-treatment respectively). Statin use after diagnosis was highly associated with increasing BMI (P < 0.001) and predicted improved survival in a multivariate analysis (HR 0.60, 95% CI 0.41–0.89, P = 0.011). Conclusion Obese patients in this retrospective study had significantly improved survival relative to normal weight patients. Our data suggest that the protective effect of obesity in locally advanced NSCLC is not solely due to short-term treatment effects, decreased smoking exposure, or poor prognostic factors from underweight patients. Notably, statin use was also associated with improved survival. Additional studies are needed to clarify the mechanisms and possible concomitant factors underlying the obesity paradox in NSCLC. [ABSTRACT FROM AUTHOR]

Background Elevated COX-2 expression has been correlated with inferior outcome in NSCLC. COX-2 catalyzes the transformation of arachidonate to PGE 2 . We and others have demonstrated that PGE 2 induces proliferation and metastatic spread and immunosuppression through the G protein-coupled EP4 receptor. We hypothesized that EP4 expression on malignant cells would correlate with outcome and patterns of relapse after treatment of LANSCLC stage IIIA (7th edition, N2+). Methods Tissue specimens from 41 pts treated for LANSC at UMGCC were obtained. A tissue microarray was prepared and examined for EP4 expression. Intensity of staining was scored semi-quantitatively as 0–4 in both the nuclear and cytoplasmic compartments by a pathologist blinded to the clinical data. Results EP4 nuclear staining 0–1 vs. 2+ was associated with overall survival, (OS) (44.3 vs. 18 mo; HR = 0.41, p = 0.024) and numerically superior progression free survival (PFS) (16.4 vs. 10.2 mo, p =0.16). EP4 cytoplasmic staining did not correlate with OS (0–1 vs. 2+, 23.8 vs. 28.8 mo; HR = 1.2, p = 0.81). Relapse pattern (no relapse or local vs. systemic) did not correlate with EP nuclear staining (p = 1.0, X 2 ). Conclusions This is the first clinical study of EP4 expression in lung cancer. There was a significant correlation between OS and nuclear EP4 expression, indicating that this is a potential therapeutic target. Studies with AT-007, a specific inhibitor of EP4, are planned to commence this year. [ABSTRACT FROM AUTHOR]

Purpose: KML-001 (sodium metaarsenite) displaces hTERT from the nucleus and is synergistic with cisplatin. This phase I trial tested the tolerability, activity and pharmacology of this combination.Methods: Patients with advanced solid tumors that were "platinum sensitive," PS 0-1, normal renal and hepatic function were eligible. Treatment was with cisplatin 75 mg/m2 day 1 and KML-001 p.o. daily days 1-14 on a 21-day cycle. A standard 3 + 3 design was employed. Blood specimens for arsenic and platinum pharmacokinetics were obtained at 0, 1, 2, 3, 4, 5, 6, 24 h and days 8, 15 and 22.Results: Eighteen patients (7 M, 11 F) were evaluable for the primary endpoint of toxicity. Patients were heavily pretreated for a variety of malignancies (mean number of prior regimens = 3). Sixteen had prior platinum therapy. The dose-limiting toxicity was prolongation of the QTc interval, seen in three patients in cohort 3 (20 mg) (two during cycle 1, one during cycle 2). A documented response was seen in a patient with heavily pretreated SCLC in cohort one. Several other patients had reduction in tumor burden. In addition to the dose-limiting toxicity of QTc prolongation, the most common toxicities observed were nausea and vomiting and cytopenias. Myelosuppression was primarily seen in patients who had undergone prior radiotherapy.Conclusions: The combination of KML-001 and cisplatin was technically feasible and active. However, the occurrence of significant QTc prolongation led to discontinuation of the trial. This prolongation was likely a result of electrolyte abnormalities resulting from cisplatin superimposed on the known risks of arsenicals and QTc prolongation. Combinations with other platinum agents (e.g., carboplatin) should be considered. This is the first fully reported human trial of KML-001. [ABSTRACT FROM AUTHOR]

Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle ( 1 ), containing the 4,6,8-triaminoimidazo[4,5- e ][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N 6 -positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N 6 -position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N 6 -positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N 6 and no attachment at N-1, or a combined C-10 at N 6 and a CH 2 Ph at N-1. Any alkyl chain shorter or longer than C-10 at N 6 with a CH 2 Ph attached at N-1, would result in decrease of biological activity. [ABSTRACT FROM AUTHOR]

Activating mutations in the epidermal growth factor receptor ( EGFR ) gene are exceedingly rare in small cell lung cancer (SCLC). We present two cases of SCLC harboring EGFR mutations, one in an 82 year-old male smoker with a combined SCLC and adenocarcinoma with a novel D855H point mutation in exon 21, and the second in a 68 year-old female never smoker with the L858R point mutation in exon 21. The cases, accompanied by a review of the literature, highlight the importance of integration of clinicopathologic considerations and adherence to recently promulgated Guideline recommendations for molecular testing in lung cancer. [ABSTRACT FROM AUTHOR]

Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G1/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications. [ABSTRACT FROM AUTHOR]

Objectives Borderline or poor performance status (PS) patients comprise a significant proportion of those diagnosed with advanced non-small cell lung cancer (AdvNSCLC), but are often excluded from clinical trials. It is difficult to draw conclusions about the benefit of therapy in borderline PS patients due to lack of reliable PS assessments, and small clinical trial samples. Retrospective population-based secondary analyses may allow investigators to study under-represented populations in clinical trials. We hypothesized that patients with poor functional status derive benefit from chemotherapy compared good functional status, but that the magnitude of the benefit is lower compared to patients with good functional status. By utilizing a “disability status” (DS) measure as a proxy for PS, we offer a reliable mechanism for patient stratification that can be implemented in administrative claims data. Methods Medicare beneficiaries diagnosed with AdvNSCLC between 2001 and 2005 were selected from the Surveillance, Epidemiology and End Results database linked to Medicare claims. Disability status, a previously developed and validated claims-based proxy for baseline PS, was implemented. Patients were assigned to good versus poor DS. Cox proportional hazard models were used to examine the differential effects of chemotherapy for the two DS groups on all-cause mortality, controlling for tumor and patient characteristics. Results Most patients in the cohort ( n = 21,019) were ≥75 years of age (59%), and non-Hispanic white (85%); 91% were assigned to good DS; 38% received chemotherapy. Chemotherapy had a strong protective effect among good DS patients (hazard ratio, 0.43; CI 0.42–0.45; p < 0.001), with a slightly smaller effect for poor DS (hazard ratio, 0.50; CI 0.44–0.57). Conclusions Chemotherapy improves survival for advanced NSCLC patients with poor DS but to a lower magnitude than for good DS patients. The DS measure opens the door to assess outcomes for cancer patients with poor functional status using insurance claims data. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Dinaciclib (MK-7965, formerly SCH 727965), a novel, small-molecule inhibitor of cyclin-dependent kinases, has been shown to induce apoptosis in preclinical studies of human tumor cell lines, including non-small cell lung cancer (NSCLC) cells. Erlotinib, an epidermal growth factor receptor inhibitor, is approved for the treatment of advanced NSCLC as second- or third-line therapy. This phase 2, randomized, multicenter, open-label study compared dinaciclib with erlotinib in patients with previously treated NSCLC. Materials and methods: The study was comprised of 2 parts: in part 1, patients were randomized to either intravenous (IV) dinaciclib (50mg/m2) or oral erlotinib (150mg) using an adaptive Bayesian design that adjusted the randomization ratio in favor of the more active arm, and in part 2, patients who had progressed on erlotinib were permitted to cross over to receive dinaciclib at the same dosage as in part 1. Patients were followed until disease progression or death, initiation of nonstudy cancer treatment, discontinuation, or withdrawal of consent. The primary efficacy end point was time-to-progression (TTP) in part 1 and objective response rate (ORR) in part 2. Results: Based on Kaplan–Meier estimates, the median TTP was 1.49 months (95% confidence interval [CI]: 1.31, 2.63) following initial treatment with dinaciclib, compared with 1.58 months (95% CI: 1.38, 2.83) with erlotinib. No objective responses were observed following initial treatment with dinaciclib. Common severe (grade 3 or 4) drug-related adverse effects included neutropenia, leukopenia, vomiting, and diarrhea. Conclusions: Dinaciclib, administered IV, was well tolerated at the 50mg/m2 dose, but does not have activity as monotherapy in previously treated NSCLC. Evaluation of dinaciclib in combination with other agents for other indications including breast cancer and multiple myeloma is in progress. [Copyright &y& Elsevier]

The first annual workshop for preclinical and clinical development of radiosensitizers took place at the National Cancer Institute on August 8-9, 2012. Radiotherapy is one of the most commonly applied and effective oncologic treatments for solid tumors. It is well recognized that improved clinical efficacy of radiotherapy would make a substantive impact in clinical practice and patient outcomes. Advances in genomic technologies and high-throughput drug discovery platforms have brought a revolution in cancer treatment by providing molecularly targeted agents for various cancers. Development of predictive biomarkers directed toward specific subsets of cancers has ushered in a new era of personalized therapeutics. The field of radiation oncology stands to gain substantial benefit from these advances given the concerted effort to integrate this progress into radiation therapy. This workshop brought together expert clinicians and scientists working in various disease sites to identify the exciting opportunities and expected challenges in the development of molecularly targeted agents in combination with radiation therapy. [ABSTRACT FROM AUTHOR]

Abstract: Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure–activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4′,5′-f][1,3]diazepine structural skeleton of the lead compound 1. [Copyright &y& Elsevier]

Objective: Lung cancer remains number one cause of cancer related deaths worldwide. Cell cycle deregulation plays a major role in the pathogenesis of Non-Small Cell Lung Cancer (NSCLC). CDC25A represents a critical cell cycle regulator that enhances cell cycle progression. In this study we aimed to investigate the role of a novel CDC25A transcriptional variant, CDC25AQ110del, on the regulation of the CDC25A protein, and its impact on prognosis of NSCLC patients. Methodology/Principal Findings: Here we report a novel CDC25A transcript variant with codon 110 (Glutamine) deletion, that we termed CDC25AQ110del in NSCLC cells. In 9 (75%) of the 12 NSCLC cell lines, CDC25AQ110del expression accounted for more than 20% of the CDC25A transcripts. Biological effects of CDC25AQ110del were investigated in H1299 and HEK-293F cells using UV radiation, flowcytometry, cyclohexamide treatment, and confocal microscopy. Compared to CDC25Awt, CDC25AQ110del protein had longer half-life; cells expressing CDC25AQ110del were more resistant to UV irradiation and showed more mitotic activity. Taqman-PCR was used to quantify CDC25AQ110del expression levels in 88 primary NSCLC tumor/normal tissue pairs. In patients with NSCLC, Kaplan Meier curves showed tumors expressing higher levels of CDC25AQ110del relative to the adjacent lung tissues to have significantly inferior overall survival (P = .0018). Significance: Here we identified CDC25A as a novel transcriptional variant of CDC25AQ110del in NSCLC. The sequence-specific nature of the abnormality could be a prognostic indicator in NSCLC patients as well as a candidate target for future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract: Synthesis and broad-spectrum anticancer activity of a novel heterocyclic compound 1 containing the title imidazo[4,5-e][1,3]diazepine ring system have been reported. The compound shows potent in vitro antitumor activity with low micromolar IC50’s against prostate, lung, breast, and ovarian cancer cell lines tested. The long alkyl chain attached to the six-position of the heterocyclic ring of 1 appears to be necessary for the observed biological activity. [Copyright &y& Elsevier]

The article presents the results of a study on the impact of pre- and postoperative chemotherapy on the pulmonary function tests (PFT) in patients with stage I or II non-small cell lung cancer. According to the authors, the baseline scores of PFT varied with smoking status of patients. They add that 2 out of 85 patients did not undergo surgery because of PFT reduction after chemotherapy. They indicate that the diffusing capacity of the lung for carbon monoxide did not affect the ability to undergo surgical resection.

Background: The assessment of the impact of neoadjuvant therapy on quality of life (QL) has rarely been prospectively planned and evaluated, although validated QL instruments are available-such as the Lung Cancer Symptom Scale (LCSS) used in this study. The modest but significant survival gains reported with neoadjuvant and adjuvant approaches need to be viewed in terms of the added risks and toxicities associated with two or three modalities of treatment.Materials and Methods: The objective was to compare patient-determined QL ratings from baseline (prior to neoadjuvant chemotherapy) with those in subsequent months of follow-up. All patients had clinical stage I or II non-small cell lung cancer (NSCLC) and participated in one of two similar randomized protocols. Patients received preoperative chemotherapy (three cycles) of gemcitabine plus carboplatin or paclitaxel in one trial or gemcitabine plus carboplatin or cisplatin in the second. Patients completed the LCSS at baseline, every 3 weeks preoperatively, and every 3 months postoperatively up to 12 months.Results: Full QL data are available for 43 patients with at least one postsurgical evaluation and for 23 patients with evaluation at 1-year postsurgery. In patients with at least one postsurgical evaluation, 84% had an ECOG performance status of 0, 93% had a complete resection, and 67% (95% CI = 52, 81) of patients experienced improved or stable symptoms. A subgroup of patients (14 of 43) reported worsening of QL (33%). These patients experienced a mean worsening of 66% in individual symptom parameters, with an average of seven of nine LCSS symptom parameters declining.Conclusions: Most patients reported improved or stable QL. Prospectively planned QL assessment is feasible with neoadjuvant trials and adds useful information not otherwise attainable. [ABSTRACT FROM AUTHOR]

Advanced non-small cell lung cancer (NSCLC) remains an incurable disease. Immunotherapies that activate patients’ T cells against resident tumor cells are being developed; however, these approaches may not be effective in NSCLC patients due to tumor-induced immune suppression. A major cause of immune suppression is myeloid-derived suppressor cells (MDSC). Because of the strategic role of CD4+ T lymphocytes in the activation of cytotoxic CD8+ T cells and immune memory, we are developing cell-based vaccines that activate tumor-specific CD4+ T cells in the presence of MDSC. The vaccines are NSCLC cell lines transfected with costimulatory (CD80) plus major histocompatibility complex class II (MHC II) genes that are syngeneic to the recipient. The absence of invariant chain promotes the presentation of endogenously synthesized tumor antigens, and the activation of MHC II-restricted, tumor-antigen-specific CD4+ T cells. Potential vaccine efficacy was tested in vitro by priming and boosting peripheral blood mononuclear cells from ten NSCLC patients who had varying levels of MDSC. CD4+ T cell activation was quantified by measuring Type 1 and Type 2 cytokine release. The vaccines activated CD4+ T cells from all ten patients, despite the presence of CD33+CD11b+ MDSC. Activated CD4+ T cells were specific for NSCLC and did not cross-react with tumor cells derived from non-lung tissue or normal lung fibroblasts. The NSCLC vaccines activate tumor-specific CD4+ T cells in the presence of potent immune suppression, and may be useful for the treatment of patients with NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: To report the outcome of patients with synchronous, solitary brain metastasis from non–small-cell lung cancer (NSCLC) treated with gamma knife stereotactic radiosurgery (GKSRS). Patients and Methods: Forty-two patients diagnosed with synchronous, solitary brain metastasis from NSCLC were treated with GKSRS between 1993 and 2006. The median Karnofsky performance status (KPS) was 90. Patients had thoracic Stage I-III disease (American Joint Committee on Cancer 2002 guidelines). Definitive thoracic therapy was delivered to 26/42 (62%) patients; 9 patients underwent chemotherapy and radiation, 12 patients had surgical resection, and 5 patients underwent preoperative chemoradiation and surgical resection. Results: The median overall survival (OS) was 18 months. The 1-, 2-, and 5-year actuarial OS rates were 71.3%, 34.1%, and 21%, respectively. For patients who underwent definitive thoracic therapy, the median OS was 26.4 months compared with 13.1 months for those who had nondefinitive therapy, and the 5-year actuarial OS was 34.6% vs. 0% (p < 0.0001). Median OS was significantly longer for patients with a KPS ≥90 vs. KPS < 90 (27.8 months vs. 13.1 months, p < 0.0001). The prognostic factors significant on multivariate analysis were definitive thoracic therapy (p = 0.020) and KPS (p = 0.001). Conclusions: This is one of the largest series of patients diagnosed with synchronous, solitary brain metastasis from NSCLC treated with GKSRS. Definitive thoracic therapy and KPS significantly impacted OS. The 5-year OS of 21% demonstrates the potential for long-term survival in patients treated with GKSRS; therefore, patients with good KPS should be considered for definitive thoracic therapy. [Copyright &y& Elsevier]

Summary: Introduction: The role of chemotherapy in patients with advanced non-small cell lung cancer and poor performance status or who have HIV disease or organ transplantation is unclear. While survival appears to be enhanced, serious toxicity may occur. We evaluated the efficacy of sequential, dose attenuated carboplatin/gemcitabine followed by paclitaxel in patients with PS=2,3, HIV infection or after solid organ transplantation. Patients and methods: Chemotherapy naive patients with PS 2,3 or who were HIV positive or post solid organ transplantation were eligible. Treatment consisted of gemcitabine: 1000mg/m2 d 1,8 carboplatin: AUC=5 d 1 q 21d×2 followed by paclitaxel 80mg/m2 q wk×6 followed by a 2 week break and then repeated until progression. Results: 47 patients were entered. Stage IIIb/IV: 8/39, PS 2/3=26/19, HIV infection=2, solid organ transplantation=2. 12 (25%) had brain metastases. Thirty-nine patients completed two cycles of carboplatin/gemcitabine and 29 pts received at least one cycle of paclitaxel. Overall response rate was 19% (95% CI 1.2–31.7%). Median event free, overall and 1-year survivals were 3.3 months, 5.8 months and 8.4%. Toxicity was moderate with 19% experiencing grade 4 neutropenia (11% with febrile neutropenia). Conclusions: Sequential carboplatin/gemcitabine to paclitaxel is well tolerated and active in this population. The survival seen is comparable to that of other regimens utilized in PS=2 patients with superior tolerability however, the prognosis for these patients is very poor even with treatment. This is the first trial to prospectively evaluate chemotherapy for patients with HIV disease or organ transplantation and NSCLC. [Copyright &y& Elsevier]

Summary: The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-α. This study evaluated the response rate of the combination therapy of aprinocarsen, gemcitabine, and carboplatin in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N3 and/or pleural/pericardial effusion) were treated with gemcitabine 1250mg/m2 on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2–7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients. [Copyright &y& Elsevier]

Purpose. We evaluated the combination of UCN-01 plus cisplatin and sought to determine how the cell cycle effects of each agent affected the combined response. Cisplatin-induced DNA damage results in cell cycle arrest, primarily at the S and G2 checkpoints, providing the opportunity for DNA damage repair prior to mitosis. Thus, strategies to enhance cisplatin cytotoxicity include attenuation of DNA damage-induced checkpoints. The cyclin-dependent kinase inhibitor 7-hydroxystaurosporine (UCN-01) can potentiate cisplatin activity, likely via abrogation of the S and G2 checkpoints. UCN-01 has additional effects on cell cycling, including induction of an RB-associated G1 arrest. Methods. NSCLC cell lines A549 (wt p53, wt RB), Calu1 (p53-null, wt RB) and H596 (mt p53, RB-null) were treated with UCN-01 and/or cisplatin with two-drug treatments delivered in alternate sequences. Effects of drug treatment on cell growth, cell cycling, apoptosis and levels and phosphorylation of cell cycle-associated proteins were evaluated. The interaction between the two drugs was assessed using median effect analysis. Results. When UCN-01 preceded cisplatin, growth inhibition was additive or less than additive, as assessed by median effect analysis. In contrast, when NSCLC cells were treated with cisplatin followed by UCN-01, the combination was synergistic. In this treatment sequence, a decrease in the proportion of cells at the G2 checkpoint was confirmed by reduced expression of cyclins A and B and activation of Cdk1. Abrogation of the G2 DNA damage checkpoint and apoptosis were prevalent only in cell populations treated with cisplatin followed by UCN-01 and was markedly enhanced in the cell lines with disrupted p53. Conclusions. These studies indicate that timing of drug administration strongly influences response to cisplatin plus UCN-01 in NSCLC cells, and this is related to the cell cycle-modulatory effects of these agents. Furthermore, this sequence combination was more effective in cell lines with dysfunctional p53. These findings support the hypothesis that checkpoint abrogation is the major mechanism of UCN-01-mediated potentiation of cisplatin cytotoxicity. [ABSTRACT FROM AUTHOR]