Overall Survival Benefit In Patients Research Articles

Metastatic location of extensive stage small-cell lung cancer: implications for thoracic radiation.

This study was designed to evaluate the role of thoracic radiotherapy (TRT) in a selected patient population with oligometastatic extensive stage small-cell lung cancer (ES-SCLC) without brain or liver involved. The underlying hypothesis was that TRT will improve outcomes in this favorable patient population. 305 patients were included in an institutional review board (IRB)-approved study, of which 105 received TRT after chemotherapy (ChT) and 200 received ChT alone. The survival outcomes were compared between ChT+TRT group and ChT-alone group in patients with oligometastasis without brain or liver involved and patients with brain/liver/multimetastasis, respectively. The 1-year, 2-year and 5-year overall survival (OS) for all patients were 60.3%, 23.9% and 1.6%, respectively. The addition of TRT significantly improved PFS in total patients than ChT alone (14.5months vs. 10.1months, p = 0.006), but the OS benefit was not significant (17.8months vs. 16.5months, p = 0.061). For patients with oligometastasis (n = 118), TRT offered significant progression free survival (PFS) (16.5months vs. 9.1months, p = 0.005) and OS (19.2months vs. 15.6months, p = 0.039) benefits. However, for patients with brain/liver/multimetastasis, the PFS and OS were not improved with TRT (p = 0.49, p = 0.811). TRT provided significant PFS and OS benefits in patients with oligometastatic ES-SCLC without brain or liver involved. The consolidative TRT is a reasonable treatment option for this favorable patient population.

Accumulation of active metabolite M-2 predicts overall survival (OS) of chemorefractory metastatic colorectal cancer patients treated with regorafenib (REGO).

3121 Background: TEXCAN, a prospective phase II GERCOR study of treatment with REGO in chemorefractory metastatic colorectal cancer (mCRC) patients (NCT02699073) included a prospective pharmacokinetic (PK) ancillary study aiming to investigate correlations between OS and concentrations (C) of REGO and its active metabolites M-2 and M-5. Methods: 55 patients were included, with the same inclusion/exclusion criteria as CORRECT (NCT01103323), and treated orally with 160 mg REGO daily for 3 weeks on and 1 week off. 34 patients had PK samples at C1D15 and 26 at C2D15 for Cmin. REGO, M-2 and M-5 Cmin were measured by LC-MS/MS. PK analyses studied the link between OS and PK parameters: Cmin of REGO, M-2 and M-5 at C1 and accumulation of pharmacological active metabolites between C1 and C2, assessed by the C2/C1 ratio of M-2 or M-5 Cmin concentrations. Results: REGO, M-2 and M-5 Cmin [median (Q1-Q3)] were respectively 1.99 (1.03-2.73), 1.44 (0.89-2.49) and 1.61 (0.79-2.37) mg/L at C1D15 and 1.90 (1.10-2.76), 1.29 (0.77-2.24) and 1.17 (0.45-2.42) mg/L at C2D15. C2/C1 M-2 ratio and M-5 ratio medians were 0.82 (0.50-1.78) and 0.75 (0.41-1.93), respectively. Univariate analyses showed a major OS benefit in patients with C2/C1 M-2 ratio ≥median vs < median (12.6 vs 4.0 months respectively, hazard ratio = 0.35, 95% confidence interval 0.14-0.86, p-value = 0.023) but not for C2/C1 M-5 ratio ≥median. Multivariate analyses, including the CORRECT REGOSCORE groups, showedan independent 66% reduction in death risk in the group of patients with C2/C1 M-2 ratio ≥median. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum) (0.53, p-value = 0.006). Restricted Cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio rises and when C1 Csum ranged between 2.5 and 5.5 mg/L. PK parameters were not associated with toxicities. Conclusions: M-2 accumulation between C1 and C2 is independently associated with improved OS in mCRC patients treated by REGO. M-2 accumulates and OS is favorable when C1 REGO+M-2+M-5 sum ranged between 2.5 and 5.5 mg/L. These results may lead to develop individual REGO dosage modification strategies based on PK monitoring. Clinical trial information: NCT02699073.

Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC.

114 Background: Evidence from randomized clinical trials and retrospective studies has shown that tumors with specific driver mutations may be less likely to respond to ICI; the optimal timing of ICI is unknown in this population. In this analysis, we evaluated the characteristics of responders to ICI compared to non-responders, with emphasis on the role of driver mutations. Methods: We retrospectively collected clinical characteristics and outcomes for patients who received ICI for NSCLC at Stanford University between April 2015 and August 2016. Patients were classified as responders if time on ICI was 180 days or more, and as non-responders if less than 180 days. Outcomes included radiographic improvement while on ICI, survival from diagnosis, and survival from ICI initiation. Results: Data were available for 84 patients, with median follow-up of 31 months. 18 patients were deemed responders (21%); 66 were deemed non-responders (79%). Of the patients who underwent genomic testing, 13% (2/15) of responders had mutations in EGFR/ALK/ROS1, compared to 32% (17/49) of non-responders (p = 0.195). Within the responders, 89% (16/18) had an associated radiographic improvement, compared to 11% (7/66) of non-responders (p < 0.0001). Patients with mutations in EGFR/ALK/ROS1 had a median overall survival of 46 months from diagnosis, compared to 26 months in those without these mutations (p = 0.08). Patients with mutations in EGFR/ALK/ROS1 had a median survival of 4.9 months from ICI initiation, compared to 7.0 months in those without (p = 0.45). Conclusions: Patients receiving ICI for 180 days or more had a significantly higher rate of radiographic improvement, suggesting that time on therapy appears to be a surrogate endpoint of clinical benefit. While there was not a statistically significant smaller number of responders with EGFR/ALK/ROS1, there appeared to be clinically meaningful lower response rate in these patients. This was likely limited by sample size; expansion of the sample size is planned. There was a trend to overall survival benefit in patients with driver mutations, likely driven by targeted therapy as there were no statistical differences in survival from time of ICI initiation.

A systematic review of contemporary management of oligometastatic prostate cancer: fighting a challenge or tilting at windmills?

Amongst the unanswered questions regarding prostate cancer (PCa), the optimal management of oligometastatic disease remains one of the major concerns of the scientific community. The very existence of this category is still subject to controversy. Aim of this systematic review is to summarize current available data on the most appropriate management of oligometastatic PCa. All relevant studies published in English up to November the 1st were identified through systematic searches in PubMed, EMBASE, Cochrane Library, CINAHL, Google Scholar and Ovid database. A search was performed including the combination of following words: (prostate cancer) and (metastatic) and [(oligo) or (PSMA) or (cytoreductive) or (stereotaxic radiotherapy) or (prostatectomy)]. 3335 articles were reviewed. After title screening and abstract reading, 118 papers were considered for full reading, leaving a total of 36 articles for the systematic review. There is still no consensus on the definition of oligometastatic disease, nor on the imaging modalities used for its detection. While retrospective studies suggest an added benefit with the treatment the primitive tumor by cytoreductive prostatectomy (55% survival rate vs 21%, p < 0.001), prospective studies do not validate the same outcome. Nonetheless, most studies have reported a reduction in local complications after cytoreductive prostatectomy (< 10%) compared to the best systemic treatment (25-30%). Concerning radiotherapy, an overall survival benefit for patients with a low metastatic burden was found in STAMPEDE (HR 0.68, 95% CI 0.52-0.90; p = 0.007) and suggested in subgroup analysis of the HORRAD trial. Regarding the impact of metastases-directed therapy (MDT), the STOMP and ORIOLE trials suggested that metastatic disease control might improve androgen deprivation therapy-free survival (in STOMP: 21 vs 13months for MDT vs standard of care). Nonetheless, the impact of MDT on long-term oncologic results remains unclear. Finally, oligometastatic disease appears to be a biologically different entity compared to high-burden metastatic disease. New findings on exosomes appear to make them intriguing biomarkers in the early phases of oligometastatic PCa. Oligometastatic PCa is today a poorly understood disease. The implementation of new imaging techniques as whole-body MRI and PSMA PET/CT has increased exponentially the number of oligometastatic patients detected. Data of available trials suggest a benefit from cytoreductive prostatectomy to reduce local complication, though its impact on survival remains unknown. Radiotherapy may be beneficial for patients with low-burden metastatic PCa, while MDT may delay the need for androgen deprivation therapy. Results from ongoing trials data are eagerly awaited to draw reliable recommendations.

Outcomes of salvage surgery for the oropharynx and larynx: a contemporary experience in a UK Cancer Centre.

The purpose of this study was to review our recent experience of salvage surgery, comparing larynx and oropharynx recurrence patterns. A single centre, retrospective review of salvage surgery for recurrent head and neck cancer including patients between 2008 and 2016. 61 patients were identified, 36 underwent salvage laryngectomy and 25 received oropharyngeal resections. The median overall survival of oropharyngeal recurrent tumors was 26 months (95% CI 15-118 months) and for laryngeal tumors was 23 months (95% CI 11-38 months), p = 0.1008. There was a significant overall survival benefit in patients with negative resection margin. The median survival in the negative margin group was 38 months (95% CI 25-108 months) compared to the positive margin group, 9 months (95% CI 5-15 months), p < 0.0001. Survival results following surgical salvage in the larynx and oropharynx appear to be similarly poor. Those patients with clear margins appear to have a significantly better prognosis.

Regional Lymph Node Metastases in Groin Sarcomas: A Diagnostic and Therapeutic Challenge.

The evaluation of lymph nodes and the role of groin dissection for groin sarcomas has been controversial where there have not been previous studies or guidelines published. In this study, we aim to first formulate a clinical approach in the evaluation of regional lymph nodal metastases. Second, we aim to also evaluate the role of regional lymphadenectomy in the setting of pathologically involved regional lymph nodes for groin sarcomas. In total, 43 consecutive patients with groin sarcomas underwent treatment at the National Cancer Centre Singapore between 2002 and 2015. Univariate comparisons were performed using the log-rank test. A Cox multivariate analysis was performed for disease-specific survival to identify independent prognostic factors. The median disease-free survival was 18 months (range, 1 to 180 mo). The median overall survival (OS) was 28 months (range, 3 to 180 mo). In total, 28 patients underwent a groin dissection. Of the 28 patients who underwent groin dissections, 15 had negative lymph node involvement, 7 had positive lymph node involvement and 6 had lymphovascular invasion.On univariate analysis, grade (P=0.047) and clinical and/or radiological involvement (P=0.039) were significant for regional lymph nodal metastases.The 5-year OS for patients with positive lymph nodes was 31%. Our study suggests that the evaluation of lymph nodes via groin dissections in groin sarcomas in the Asian population should be based primarily on clinical and radiologic evidence. Regional lymph node dissection seems to confer OS benefit in patients with these high-risk tumors and can improve local control of disease.

Outcome of Patients with Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Beyond First Complete Remission (CR1)

Abstract Introduction Despite substantial progress in the treatment of newly diagnosed AML, 20% to 40% of patients do not achieve remission with conventional induction chemotherapy. In addition, 50% to 70% of patients with CR1 are expected to relapse within 3 years. Currently, allogeneic HSCT is thought to be the most reliable curative option for patients with relapsed and/or refractory (r/r) disease. Compared to HSCT in CR1 allogeneic HSCT beyond CR1 is associated with lower survival rates. So far, different predictive factors influencing survival in r/r AML have been identified. However, pretransplantation variables delineating prognostic subgroups after allogeneic HSCT beyond CR1 are less well known and the total number of patients in trials addressing this issue has been limited. Methods We analyzed the outcome after allogeneic HSCT in non-APL-AML patients transplanted with either subsequent 2nd complete remission (CR2), r/r AML or with persisting cytopenia (PC, including patients with hematologic complete remission with incomplete hematologic recovery and patients with persisting bone marrow hypoplasia) after induction or salvage therapy. Of 3989 patients who enrolled into a multicenter clinical trial (AMLCG1999; NCT00266136) of the German Acute Myeloid leukemia Cooperative Group (AMLCG) we identified 498 subjects aged 17 to 74 years who underwent allogeneic HSCT beyond first CR. Before transplantation, all patients received first line treatment either with 6-Thioguanine, cyararabine, daunorubicin (TAD) and high-dose cytarabine, mitoxantrone (HAM) or HAM/HAM. After induction failure (n=97) or relapse (n=401) patients either received salvage chemotherapy (n=299) or directly underwent allogeneic HSCT (n=199). Overall survival (OS) and relapse free survival (RFS) after allogeneic HSCT were the main endpoints for this analysis. Kaplan-Meier analysis was performed to estimate survival probabilities in subgroups. Log-rank tests were used to compare survival groups. Relative hazard rates and differences in subgroups were calculated using cox regression analysis. Results At a median follow-up of 6.5 years for surviving patients, OS and RFS rates were 32% (95% CI 28-36%) and 30% (95% CI 26-34%), respectively. Subgroup analysis revealed an OS of 49% in 128 patients with allogeneic HSCT in CR2. In comparison, 73 patients who underwent allogeneic HSCT with PC after induction (n = 42) / salvage treatment (n = 31) and 297 patients with refractory disease (RD) exhibited an OS of 39% and 23%, respectively (Figure 1). The corresponding cumulative incidences (CI) at 1/6.5 years for death in remission after allogeneic HSCT were 25%/31% for patients transplanted in CR2, 29%/41% for patients transplanted with PC and 30%/46% for patients transplanted with RD, respectively. The cumulative incidence of relapse (CIR) after 6.5 years was 58% for patients transplanted with RD compared to 34% for patients transplanted in CR2 and 31% for patients with PC. Main prognostic factors for survival outcome were remission status prior to allogeneic HSCT and cytogenetic risk category at diagnosis. By contrast, patient age, donor, graft source, remission status after induction therapy and CMV status had no significant impact on survival outcome. Conclusions Long-term OS rates after allogeneic HSCT for patients with r/r AML are considered to range between 20 and 40%. Our analysis indicates that a substantial fraction of patients who received similar first line treatment within one prospective trial is able to achieve long term survival when transplanted beyond CR1. In addition, remission upon salvage therapy prior to allogeneic HSCT might be a relevant prognostic factor for patients with r/r AML. However, whether remission induction prior to HSCT can provide an overall survival benefit in patients with r/r disease is still elusive and is currently being evaluated in a prospective randomized clinical trial (ETAL3-ASAP; NCT02461537). Disclosures Beelen: Medac: Consultancy, Other: Travel Support. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Lenz:Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Research Funding; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria. Hiddemann:Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stelljes:MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding.

Receiving treatment at a specialist centre confers an overall survival benefit for patients with mantle cell lymphoma.

Receiving treatment at a specialist centre confers an overall survival benefit for patients with mantle cell lymphoma.

Safety and Efficacy of Oxaliplatin Doublet Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer

BackgroundColon cancer is common in the elderly, but owing to under representation in clinical trials, the benefit of standard therapies is uncertain in this age group. We aimed to clarify the efficacy and complications of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for patients 70 years and older with stage III colon cancer. Patients and MethodsAll patients with stage III colon adenocarcinoma were identified from an Australian cancer registry (2006-2013). Multivariable Cox hazard regression was used to determine prognostic factors for all-cause mortality. Chemotherapy complications were quantified using discontinuation rates, hospital admissions, and mortality for 12 months after starting chemotherapy. ResultsA total of 2164 patients fulfilled our inclusion criteria, including 1080 (49.9%) patients ≥ 70 years. Patients ≥ 70 years were less likely to receive adjuvant chemotherapy (60.7% vs. 89.6%) or oxaliplatin doublet chemotherapy (18.8% vs. 71.2%). Older patients receiving oxaliplatin were more likely to cease treatment early (18.7% vs. 7.6%) and require hospital admission (67.0% vs. 53.5%). The addition of oxaliplatin provided an overall survival benefit for patients < 70 years (hazard ratio, 0.44; 95% confidence interval, 0.3-0.6; P < .0001) and for patients ≥ 70 years (hazard ratio, 0.64; 95% confidence interval, 0.5-0.9; P = .005). ConclusionsDespite a modestly increased rate of hospital admission and early chemotherapy cessation, we demonstrate a persistent survival benefit for the addition of oxaliplatin to a fluoropyrimidine as adjuvant treatment for stage III colon cancer in elderly patients.

The Overall Survival Benefit for Patients with T1 Renal Cell Carcinoma after Nephron-Sparing Surgery Depends on Gender and Age

Due to the recommendations in the urological guidelines to perform nephron-sparing surgery in patients with organ-confined renal cell carcinoma (RCC), the customary therapy regimen changed, but it is not well studied yet whether partial nephrectomy (PN) especially in the elderly is beneficial. From 2000 to 2015, 3,592 patients from 7 clinics undergoing surgery in RCC were identified; 2,323 had T1 tumours. We retrospectively compared the overall survival benefit of patients with T1 RCC who underwent either PN or radical nephrectomy (RN) and studied effects of age and gender. Results: In T1 RCC, PN was beneficial in male patients (p = 0.0006) independent of age, especially in those men ≤75 years of age (p = 0.0005); but PN was not beneficial for female patients (p = 0.0629) regardless of age and male patients older than 75 years (p = 0.736). The OS of female patients after RN and male patients after PN is the same, regardless of age. A life expectancy of more than 45 months at least is necessary to experience an overall survival benefit after PN. Conclusions: There should be harder proven indications for PN in female patients and especially in all patients older than 75 years, particularly with regard to perioperative risk factors.

Abstract B108: Antitumor efficacy of EGFR antibody necitumumab and dual PI3K/mTOR inhibitor (LY3023414) in preclinical tumor models

Abstract Necitumumab (Nmab) in combination with chemotherapy has demonstrated overall survival benefit in patients with advanced or metastatic squamous non-small cell lung cancer (SqNSCLC). The PI3K/ mTOR pathway shows aberrant activity in multiple tumor types and is implicated in the development of intrinsic and acquired resistance to anti-EGFR therapy. LY3023414, a potent dual PI3K/mTOR inhibitor, is currently undergoing clinical evaluation. The objective of this study was to evaluate the combination effects of Nmab and LY3023414 in multiple tumor models. Nmab and/or LY3023414 were evaluated using Cancer Cell Sensitivity Profiling (CCSP) using a panel of ~500 genetically and histologically diverse human tumor cell lines. The combination treatment showed greater inhibition of tumor cell growth as compared to single-agent treatments in a large fraction of the cell lines tested. The combination effect was further assessed in 21 patient-derived xenograft (PDX) models across multiple tumor types with and without genetic alterations in the PI3K pathway. Compared to both monotherapies, the combination treatment demonstrated greater efficacy in 16 of 21 models, and reached statistical significance in 6 models. Nmab -/+ LY3023414 was also evaluated in a panel of 40 SqNSCLC PDX models using a single-mouse trial format. Combination therapy exhibited significant benefit over either monotherapy as exemplified by disease control (61% for combination vs 17.5% and 34.3% for Nmab and LY3023414, respectively) and overall response rate (22% for combination vs 10% and 5.7% for Nmab and LY3023414, respectively). Median time to tumor doubling or event-free survival (mEFS) was also in favor of the combination therapy (mEFS = 38.9 days for combination vs 14.2 and 32.4 days for Nmab and LY3023414, respectively). To gain mechanistic insights into the combinatorial effect observed, we employed a high-content gene/protein expression assay (nCounter Vantage 3D RNA:Protein Solid Tumor Signaling Pathways Panel) in a SqNSCLC PDX model harboring PIK3CA mutation that was highly sensitive to the combination therapy. nCounter Vantage 3D analysis confirmed inhibition of the PI3K/mTOR pathway in LY3023414-treated tumors. A more robust effect on signaling events downstream of mTOR was observed in the combination group. Furthermore, pathway analysis of the gene expression data suggested alterations in cell cycle/apoptosis, DNA repair, Notch, TGFb, and Wnt signaling in the combination group. Collectively, these data indicate that the Nmab/LY3023414 combination provides a benefit over both monotherapies. A more profound blockade of the PI3K/ mTOR pathway accompanied by inhibition of tumor cell cycle, survival, and DNA repair mechanisms may underlie this effect. Citation Format: Maxine A. Melchior, Xuemei Guo, Gregory P. Donoho, Philip W. Iversen, Thompson N. Doman, Manisha Brahmachary, Xueqian Gong, Gerald E. Hall, Jason R. Manro, Yung-mae M. Yao, Sean Buchanan, Tod Smeal, Michael D. Kalos, Ruslan D. Novosiadly. Antitumor efficacy of EGFR antibody necitumumab and dual PI3K/mTOR inhibitor (LY3023414) in preclinical tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B108.

Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non–Small Cell Lung Carcinoma

Checkpoint inhibitors have replaced docetaxel as the new standard second-line therapy in advanced non-small cell lung carcinoma (NSCLC), but little is known about the potential predictive value of clinical and molecular characteristics. To estimate the relative efficacy of checkpoint inhibitor vs docetaxel overall and in subgroups defined by clinicopathological characteristics. This systematic review and meta-analysis searched MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials for randomized clinical trials published in the English language between January 1, 1996, and January 30, 2017. Randomized clinical trials that compared a checkpoint inhibitor (nivolumab, pembrolizumab, or atezolizumab) with docetaxel. For each trial included in this study, the trial name, year of publication or conference presentation, patients' clinicopathological characteristics, type of chemotherapy, and type of checkpoint inhibitor were extracted. Data collection for this study took place from February 1 to March 31, 2017. Two reviewers performed study selection, data abstraction, and risk of bias assessment. Hazard ratios (HR) and 95% CIs for the overall population and subgroups were extracted. Pooled treatment estimates were calculated using the inverse-variance-weighted method. In total, 5 trials involving 3025 patients with advanced NSCLC were included in this meta-analysis. These patients were randomized to receive a checkpoint inhibitor (nivolumab, 427 [14.1%]; pembrolizumab, 691 [22.8%]; or atezolizumab, 569 [18.8%]) or docetaxel (1338 [44.2%]). Checkpoint inhibitors were associated with prolonged overall survival, compared with docetaxel (HR, 0.69; 95% CI, 0.63-0.75; P < .001). They prolonged overall survival in the EGFR wild-type subgroup (HR, 0.67; 95% CI, 0.60-0.75; P < .001), but not in the EGFR mutant subgroup (HR, 1.11; 95% CI, 0.80-1.53; P = .54; interaction, P = .005), and they prolonged overall survival in the KRAS mutant subgroup (HR, 0.65; 95% CI, 0.44-0.97; P = .03) but not in the KRAS wild-type subgroup (HR, 0.86; 95% CI, 0.67-1.11; P = .24; interaction, P = .24). The relative treatment benefits were similar according to smoking status (never smokers [HR, 0.79] vs ever smokers [HR, 0.69]; interaction, P = .40), performance status (0 [HR, 0.69] vs 1 [HR, 0.68]; interaction, P = .85), age (<65 years [HR, 0.71] vs ≥65 years [HR, 0.69]; interaction, P = .74), histology (squamous [HR, 0.67] vs nonsquamous [HR, 0.70]; interaction, P = .71), or sex (male [HR, 0.69] vs female [HR, 0.70]; interaction, P = .82). Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second-line therapy in NSCLC. The finding of no overall survival benefit for patients with EGFR mutant tumors suggests that checkpoint inhibitors should be considered only after other effective therapies have been exhausted. The findings of this meta-analysis could also assist in the design and interpretation of future trials and in economic analyses.

Is fertility-preservation safe for adult non-metastatic gynecologic rhabdomyosarcoma patients? Systematic review and pooled survival analysis of 137 patients.

Recently, conservative approaches such as wide local excisions and neoadjuvant chemotherapy are being considered to select young adult females with gynecologic RMS who have strong desire to preserve fertility. This analysis aims to identify prognosticators affecting survival outcomes and defining potential candidacy for fertility-preservation. Another focus is to explore the role of chemotherapy in reducing the need for aggressive surgery and the role of radiotherapy in decreasing rates of local failure. A comprehensive database search identified 137 females > 16 years old with primary non-metastatic gynecologic RMS, who were included in a multivariate survival analysis. 5-year overall survival rate was 65%. Patients < 50 years old, with cervix uteri primaries, well-defined/polypoid presentations, embryonal histology and superficial tumors were more likely to survive. Deeply invasive disease and alveolar/pleomorphic histology significantly increased risks of treatment failure and tumor recurrence. Chemotherapy use was a significant multivariate predictor of better overall and metastasis-free survival. Radical surgery did not add local control or overall survival benefit for patients with superficial lesions (minimal/no cervical stromal invasion and no myometrial invasion). While high-quality clinical trial evidence is missing, existing evidence seems to support holding back on radical surgery for selected candidates with well-defined, polypoid, superficial, embryonal cervical/endometrial RMS lesions that could be completely excised with conservative surgery; further local resections with/without radiotherapy are then warranted based on margin status. Experience on the use of neoadjuvant chemotherapy in the conservative management of uterine RMS in adults is very limited, though this approach is golden-standard in pediatrics. A suggested scheme is introduced for the management of uterine RMS.

World Health Organization Grade II Meningiomas: The Role of Adjuvant/Salvage Gamma Knife Surgery After Initial Surgery and Prognostic Factor Assessment.

This study was performed to evaluate the efficiency of Gamma Knife surgery (GKS) on reducing recurrence of World Health Organization (WHO) grade II meningiomas after surgery and to define the risk factors associated with tumor recurrence/progression and patient's death. This retrospective study included 75 patients who were diagnosed with WHO grade II meningiomas after initial surgery. The Kaplan-Meier method with a log-rank test was used to calculate the survival curves. Univariate and multivariate Cox proportional hazards model were used to identify the risk factors associated with tumor recurrence/progression and patient's death. The median follow-up period was 70 months. The overall survival (OS) was 97.2% at 2 years and 89.8% at 5 years. The progression-free survival (PFS) at 1, 3, and 5 years was 89.3%, 72.6%, and 59.3%, respectively. Comparing the effects on PFS and OS between different groups, there were no statistically significant differences between the surgery-alone group and the surgery with adjuvant/salvage GKS group (P= 0.512; P= 0.949). In multivariate Cox proportional hazards model analysis, extent of resection (P= 0.001) and tumor location (P= 0.015) were associated with tumor recurrence; only histologic subtypes (P= 0.005) were associated with patient's death. There was no significant PFS or OS benefit for patients with WHO grade II meningiomas treated with adjuvant/salvage GKS postoperatively. Convexity meningiomas with gross total resection tended to benefit PFS. We suggest trying to achieve maximum safe gross total resection for patients with WHO grade II meningiomas, then following up closely.

Clinical Potential of Statins in Prostate Cancer Radiation Therapy.

Statins are cholesterol- lowering drugs that have been shown to possess anti-tumour properties. Observational studies have shown that 3-hydroxy-3-methlyglutaryl coenzyme A reductase inhibitor (statin) use may be associated with reduced prostate cancer risk. Preclinical studies suggest that statins possess anticancer and radiosensitising properties. This review aims to determine the impact of statin use in the efficacy of radiation therapy and the therapeutic window in prostate cancer. The scientific databases PubMed, Science Direct, EMBASE, Cochrane Collaboration, and Google Scholar were searched for articles identifying statin use in histologically confirmed prostate cancer treated with external beam radiation therapy. Improvement was observed in freedom from biochemical failure (91% vs. 79%), relapse free survival (72% vs. 69%), distant metastasis free survival (96% vs. 94%), and prostate-specific antigen (PSA) relapse free survival (89% vs. 83%) with statin use, however this did not translate into an overall survival benefit for patients. Conflicting data concerning clinical outcomes reduce the integrity of these findings. The literature supports the radiosensitising properties of statins and their potential antitumor effects in prostate cancer. Statin use in prostate cancer presents many obstacles yet to be overcome, which warrant attention prior to the routine implementation of statins in treatment regimes. However, there is evidence to support their beneficial use.

Real-World Utilization Of Blinatumomab In Acute Lymphoblastic Leukemia In The US

Blinatumomab is the first bispecific CD19 directed CD3 T-cell engager immunotherapy to demonstrate overall survival benefit in patients with Philadelphia chromosome-negative (Ph-) relapsed/refractory acute lymphoblastic leukemia (ALL). In December 2014 the FDA granted an accelerated approval to blinatumomab in patients with Ph- relapsed/refractory B-precursor ALL based on findings from a phase II trial in 185 adults followed by the supplemental BLA approval to include new data in pediatric patients. Approved on 12/3/2014, blinatumomab is the first CD19 targeting bi-specific T-cell engagers (Bites) in the immuno-oncology arsenal. As it will likely compete with CD19 targeted CAR-T therapeutics, its uptake since approval may predict CAR-T potential in a similar clinical setting. Patients diagnosed with ALL on systemic therapy (ST) between 12/2014 and 12/2016 were identified from the Symphony Health claims database. Market share and time to treatment discontinuation (TTD) were examined. TTD was defined as time from ST initiation to switch or last administration date plus 90 days if no other ST was administered. TTD was described with Kaplan-Meier curves. Of the 18,162 ALL patients on ST since blinatumomab approval, 218 (1.2%) were treated with blinatumomab; of them 29 (13.3%) appeared to be Ph+ (indicated by utilization of nilotinib, ponatinib, dasatinib, imatinib, or bosutinib). The most common regimen was blinatumomab monotherapy followed by combination with methotrexate and/or cytarabine. Of the 218 patients treated with blinatumomab, 123 (56.4%) were male, 83 (38.1%) received blinatumomab in the first-line, and mean (SD) age was 43.9 (18.0) years. The mean (SD) number of prior antineoplastic regimens was 3.2 (3.6). Mean (median) TTD was 122.5 (110.0) days. This is the first real-world evidence study of blinatumomab and it demonstrates the uniqueness of the patient population for which it is currently indicated. CAR T-cell economic modeling should be informed by this research.

Salvage Re-Irradiation for Recurrent High-Grade Glioma and Comparison to Bevacizumab Alone

High-grade gliomas (HGGs) are the most common lethal primary brain tumor in adults and almost always recur after initial treatment. Despite this, there is little evidence arguing superiority of a single treatment strategy at time of recurrence, with options including supportive care, re-resection, systemic therapy, or re-irradiation. While bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is now commonly used for recurrent HGG, there has been longstanding interest in re-irradiation for patients with local-only recurrence. The purpose of this study is to examine outcomes of patients with recurrent HGG treated with re-irradiation. This is a retrospective analysis of patients with recurrent HGG who received salvage re-irradiation at a major academic institution from 2010-2014, as well as those who received bevacizumab alone. Progression-free survival (PFS) and overall survival (OS) were calculated from date of re-irradiation completion, or date of bevacizumab initiation in the bevaciumab alone cohort. Cox proportional hazards modeling was used to examine factors associated with OS. Propensity score modeling was used to compare survival after re-irradiation vs. bevacizumab alone. Sixty-seven patients received re-irradiation for recurrence, and 177 patients received bevacizumab alone. Among the re-irradiation cohort, 51% received concurrent bevacizumab. Median time in the re-irradiation cohort from initial diagnosis to re-irradiation was 31.4 months. The most common re-irradiation dose/fractionation regimens were 6 Gy x 5 (36%), 3.5 Gy x 10 (21%), 2.67 Gy x 15 (15%), and 18-20 Gy x 1 (15%). No early or late toxicities > grade 2 were observed. Median PFS and OS after re-irradiation were 4.8 months 10.7 months, respectively. Number of progressions prior to re-irradiation (adjusted hazard ratio [AHR], 1.6; 95% CI, 1.1-2.3; P = .007), and recurrence in a new brain location (vs. local-only; AHR, 7.4; 95% CI, 2.4-23.1; P < .001) were associated with OS; dose/fractionation regimen was not. Compared to bevacizumab alone, patients who received re-irradiation had a non-significant increase in OS (HR, 0.80; 95% CI, 0.53-1.23; P = .31). Among patients with local-only recurrence, there was a trend towards longer median OS after re-irradiation compared to bevacizumab alone (12.4 vs. 8.0 months; P = .12). Re-irradiation for recurrent HGG appears safe and was associated with reasonable PFS and OS even as many patients received bevacizumab and had >2 prior progressions. Number of progressions prior to re-irradiation and recurrence location were associated with OS, while dose/fractionation regimen was not. While re-irradiation was not associated with OS benefit in propensity score adjusted analysis compared with bevacizumab alone, there was a trend towards OS benefit in patients with local-only recurrence.

The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer.

Radium-223 dichloride (radium-223) was approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases in the United States and Europe in 2013. This followed a reported overall survival benefit for patients treated with radium-223 and best standard of care (BSoC) when compared with placebo and BSoC in the ALpharadin in SYMptomatic Prostate CAncer (ALSYMPCA) trial. At that time, docetaxel was the standard first-line choice for patients with metastatic CRPC (mCRPC). Since then, the treatment landscape has changed dramatically with new hormonal agents (abiraterone and enzalutamide) considered to be the first-line choice for many patients. The optimal patient profile for radium-223 in the modern setting, and its best use either in sequence or in combination with other approved agents are unclear, with few definitive guidelines available. This article reports on the views of a group of urologists and medical oncologists experienced in treating patients with mCRPC with radium-223 in routine clinical practice. The aim is to provide an overview of the current use of radium-223 in the treatment of patients with mCRPC, and to discuss best practices for patient selection and on-treatment monitoring. Where agreement was reached, guidance on the optimal use of radium-223 is provided.

Factors Influencing Disease Progression in Patients with Head and Neck Melanoma.

Histological parameters as well as the status of sentinel lymph node are known to be strong prognostic factors in patients with melanoma. In this study, we retrospectively analyzed 1,384 patients who were diagnosed with head and neck melanoma between 1976 and 2010 regarding prognostic factors [tumor thickness, level of invasion, sentinel lymph node (SLN) status, ulceration, histological subtype, localization, and gender], overall survival, and disease-free survival. Patients who developed metastases had a significantly thicker tumor than patients without metastases. Additionally, a thicker tumor was often associated with a higher level of invasion (Clark level). There was no overall survival benefit in patients who underwent SLN dissection when compared to patients who did not (p=0.07). Compared to SLN-negative patients, patients with SLN involvement had a significantly shorter disease-free period (p<0.001) and shorter overall survival time (p<0.001). In summary, tumor thickness is the most important prognostic factor. SLN dissection does not affect the overall survival of patients with melanoma. However, a positive SLN is a marker for a worse outcome in these patients.

Abstract 5648: Combined immune checkpoint targeting with anti-PD-1 plus anti-CD40 antibodies as the most effective approach to eradicate head and neck squamous cell carcinomas (HNSCCs) in mouse models

Abstract Introduction: Immunotherapy with single agent anti-PD-1 antibody confers modest overall survival benefits in patients with recurrent/metastatic HNSCCs. Combined immune checkpoint targeting has shown promising results for melanomas and other solid tumors. Thus, evaluation of combination immunotherapy in animal models specific to HNSCCs could inform prioritization and design of human clinical trials for this disease. We conducted this pre-clinical study to test the hypothesis that combining anti-PD-1 with either anti-CTLA-4 or co-stimulatory immune checkpoint agonist antibodies would be more effective than anti-PD-1 monotherapy in a mouse model of oral carcinoma. We also aimed at identifying the combination regimen with highest anti-tumor activity. Methods: C57BL/6 mice were subcutaneously grafted with 2x106 mouse oral cancer 1 (MOC1) cells derived from a carcinogen-induced tumor molecularly similar to human HNSCC. After 25 days, mice were randomized into one of 12 treatment groups (IgG, or antibodies targeting PD-1, CTLA-4, CD40, OX-40, GITR, 4-1BB, PD-1+CTLA-4, PD1+CD40, PD-1+OX-40, PD-1+GITR, or PD-1+4-1BB), N=8-9 mice/group. Antibodies were administered every 4 days for 3 doses. Tumors were measured twice per week. The primary endpoint was overall survival. Mice were sacrificed when tumor diameter was &amp;gt;2 cm or tumor ulceration was &amp;gt;5 mm. Survival curves were computed using the Kaplan-Meier method and compared using the log-rank (Mantel-Cox) test. Results: In analogy to human clinical trials, anti-PD-1 therapy led to a modest improvement in survival compared to IgG [HR=0.41; 95%CI 0.06-0.53; P=0.015], indicating that this model recapitulates, in part, the effects of immunotherapy in HNSCC patients; none of the animals survived long term. Monotherapy with anti-CTLA-4, anti-CD40, anti-OX-40, or anti-4-1BB also improved survival compared to IgG (P=0.0001, 0.003, 0.02, and 0.003, respectively), but were not more effective than anti-PD-1 alone (P=0.09, 0.12, 0.72, and 0.77, respectively). Combination therapy did not prolong survival compared to anti-PD-1 alone, with the exception of anti-PD-1+ anti-CTLA4 [HR=0.36; 95% CI 0.07-0.6; P=0.016], and anti-PD-1+ anti-CD40 [HR=0.125, 95% CI 0.02-0.24; P=0.0003]. Notably, 50% of mice receiving anti-PD-1+ anti-CD40 antibodies had complete tumor eradication and are alive and disease-free 120 days after tumor grafting. Conclusions: Single agent immunotherapy targeting PD-1, CTLA-4, CD40, OX-40 and 4-1BB modestly improved survival in a mouse model of oral cancer. Combination with anti-PD-1+ anti-CTLA4 and anti-PD-1+ anti-CD40 antibodies outperformed anti-PD-1 monotherapy. Complete responses were exclusively seen with PD-1+CD40 dual targeting. This regimen should be prioritized for evaluation in HNSCC clinical trials. Citation Format: Jose Augusto Monteiro de Oliveira Novaes, Alissa R. Poteete, Marlese A. Pisegna, Uma Giri, Fahao Zhang, Patrick Hwu, John V. Heymach, William N. William. Combined immune checkpoint targeting with anti-PD-1 plus anti-CD40 antibodies as the most effective approach to eradicate head and neck squamous cell carcinomas (HNSCCs) in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5648. doi:10.1158/1538-7445.AM2017-5648