CALGB 80802 (Alliance): Impact of Sorafenib with and without Doxorubicin on Hepatitis C Infection in Patients with Advanced Hepatocellular Carcinoma.

Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf-mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58-7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. SIGNIFICANCE: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.

Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study.

BACKGROUND: Although immunotherapy has emerged as a therapeutic strategy for many cancers, there are limited studies establishing the safety and efficacy in people living with HIV (PLWH) and cancer. METHODS: PLWH and solid tumors or Kaposi sarcoma (KS) receiving antiretroviral therapy and a suppressed HIV viral load received nivolumab at 3 mg/kg every 2 weeks, in two dose deescalation cohorts stratified by CD4 count (stratum 1: CD4 count > 200/µL and stratum 2: CD4 count 100-199/µL). An expansion cohort of 24 participants with a CD4 count > 200/µL was then enrolled. RESULTS: A total of 36 PLWH received nivolumab, including 15 with KS and 21 with a variety of other solid tumors. None of the first 12 participants had dose-limiting toxicity in both CD4 strata, and five patients (14%) overall had grade 3 or higher immune related adverse events. Objective partial response occurred in nine PLWH and cancer (25%), including in six of 15 with KS (40%; 95% CI, 16.3-64.7). The median duration of response was 9.0 months overall and 12.5 months in KS. Responses were observed regardless of PDL1 expression. There were no significant changes in CD4 count or HIV viral load. CONCLUSIONS: Nivolumab has a safety profile in PLWH similar to HIV-negative subjects with cancer, and also efficacy in KS. Plasma HIV remained suppressed and CD4 counts remained stable during treatment and antiretroviral therapy, indicating no adverse impact on immune function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02408861.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline.

PURPOSE: To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: For human epidermal growth factor receptor 2 (HER2)-negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

A phase II study of sapanisertib (TAK-228) a mTORC1/2 inhibitor in rapalog-resistant advanced pancreatic neuroendocrine tumors (PNET): ECOG-ACRIN EA2161.

This was a two-stage phase II trial of a mTORC1/2 inhibitor (mTORC: mammalian target of rapamycin complex) Sapanisertib (TAK228) in patients with rapalog-resistant pancreatic neuroendocrine tumors (PNETs) (NCT02893930). Approved rapalogs such as everolimus inhibit mTORC1 and have limited clinical activity, possibly due to compensatory feedback loops. Sapanisertib addresses the potential for incomplete inhibition of the mTOR pathway through targeting of both mTORC1 and mTORC2, and thus to reverse resistance to earlier rapamycin analogues. In stage 1, patients received sapanisertib 3 mg by mouth once daily on a continuous dosing schedule in 28-day cycle. This trial adopted a two-stage design with the primary objective of evaluating objective tumor response. The first stage would recruit 13 patients in order to accrue 12 eligible and treated patients. If among the 12 eligible patients at least 1 patient had an objective response to therapy, the study would move to the second stage of accrual where 25 eligible and treated patients would be enrolled. This study activated on February 1, 2017, the required pre-determined number of patients (n = 13) had entered by November 5, 2018 for the first stage response evaluation. The accrual of this trial was formally terminated on December 27, 2019 as no response had been observed after the first stage accrual. Treatment-related grade 3 adverse events were reported in eight (61%) patients with hyperglycemia being the most frequent, in three patients (23%). Other toxicities noted in the trial included fatigue, rash diarrhea, nausea, and vomiting. The median PFS was 5.19 months (95% CI [3.84, 9.30]) and the median OS was 20.44 months (95% CI [5.65, 22.54]). Due to the lack of responses in Stage 1 of the study, the study did not proceed to stage 2. Thus the potential to reverse resistance was not evident.

Anal Cancer: Emerging Standards in a Rare Disease.

The social stigma surrounding an anal cancer diagnosis has traditionally prevented open discussions about this disease. However, as recent treatment options and an increasing rate of diagnoses are made worldwide, awareness is growing. In the United States alone, 9,090 individuals were expected to be diagnosed with anal cancer in 2021. The US annual incidence of squamous cell carcinoma of the anus continues to increase by 2.7% yearly, whereas the mortality rate increases by 3.1%. The main risk factor for anal cancer is a human papillomavirus infection; those with chronic immunosuppression are also at risk. Patients with HIV are 19 times more likely to develop anal cancer compared with the general population. In this review, we have provided an overview of the carcinoma of the anal canal, the role of screening, advancements in radiation therapy, and current trials investigating acute and chronic treatment-related toxicities. This article is a comprehensive approach to presenting the existing data in an effort to encourage continuous international interest in anal cancer.

Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.

BACKGROUND: Trastuzumab is a monoclonal antibody against HER2 (also known as ERBB2). The primary objective of the NRG Oncology/RTOG-1010 trial was to establish whether trastuzumab improves disease-free survival when combined with trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) for patients with untreated HER2-overexpressing oesophageal adenocarcinoma. METHODS: NRG Oncology/RTOG-1010 was an open label, randomised, phase 3 trial for which patients were accrued from 111 NRG-affiliated institutions in the USA. Eligible patients were adults (aged ≥18 years) with newly diagnosed pathologically confirmed oesophageal adenocarcinoma, American Joint Committee on Cancer 7th edition T1N1-2 or T2-3N0-2 stage disease, and a Zubrod performance status of 0-2. Patients were stratified by adenopathy (no vs yes [coeliac absent] vs yes [coeliac present ≤2 cm]) and randomly assigned (1:1) to receive weekly intravenous paclitaxel (50 mg/m2 intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30-60 min) for 6 weeks with radiotherapy 50·4 Gy in 28 fractions (chemoradiotherapy) followed by surgery, with or without intravenous trastuzumab (4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21-56 days after surgery). The primary endpoint, disease-free survival, was defined as the time from randomisation to death or first of locoregional disease persistence or recurrence, distant metastases, or second primary malignancy. Analyses were done by modified intention to treat. This study is registered with Clinicaltrials.gov, NCT01196390; it is now closed and in follow-up. FINDINGS: 606 patients were entered for HER2 assessment from Dec 30, 2010 to Nov 10, 2015, and 203 eligible patients who were HER2-positive were enrolled and randomly assigned to chemoradiotherapy plus trastuzumab (n=102) or chemoradiotherapy alone (n=101). Median duration of follow-up was 2·8 years (IQR 1·4-5·7). Median disease-free survival was 19·6 months (95% CI 13·5-26·2) with chemoradiotherapy plus trastuzumab compared with 14·2 months (10·5-23·0) for chemoradiotherapy alone (hazard ratio 0·99 [95% CI 0·71-1·39], log-rank p=0·97). Grade 3 treatment-related adverse events occurred in 41 (43%) of 95 patients in the chemoradiotherapy plus trastuzumab group versus 52 (54%) of 96 in the chemoradiotherapy group and grade 4 events occurred in 20 (21%) versus 21 (22%). The most common grade 3 or worse treatment-related adverse events for both groups were haematological (53 [56%] of 95 patients in the chemoradiotherapy plus trastuzumab group vs 55 [57%] of 96 patients in the chemotherapy group) or gastrointestinal disorders (28 [29%] vs 20 [21 %]). 34 (36%) of 95 patients in the chemoradiotherapy plus trastuzumab group and 27 (28%) of 96 patients in the chemoradiotherapy only group had treatment-related serious adverse events. There were eight treatment-related deaths: five (5%) of 95 patients in the chemoradiotherapy plus trastuzumab group (bronchopleural fistula, oesophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three (3%) of 96 in the chemoradiotherapy group (two multiorgan failure and one sepsis). INTERPRETATION: The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing oesophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in oesophageal cancer are warranted. FUNDING: National Cancer Institute and Genentech.

Impact of Anti-PD-1 and Anti-CTLA-4 on the Human Immunodeficiency Virus (HIV) Reservoir in People Living With HIV With Cancer on Antiretroviral Therapy: The AIDS Malignancy Consortium 095 Study.

BACKGROUND: Antibodies to programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) may perturb human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) by reversing HIV latency and/or boosting HIV-specific immunity, leading to clearance of infected cells. We tested this hypothesis in a clinical trial of anti-PD-1 alone or in combination with anti-CTLA-4 in people living with HIV (PLWH) and cancer. METHODS: This was a substudy of the AIDS Malignancy Consortium 095 Study. ART-suppressed PLWH with advanced malignancies were assigned to nivolumab (anti-PD-1) with or without ipilimumab (anti-CTLA-4). In samples obtained preinfusion and 1 and 7 days after the first and fourth doses of immune checkpoint blockade (ICB), we quantified cell-associated unspliced (CA-US) HIV RNA and HIV DNA. Plasma HIV RNA was quantified during the first treatment cycle. Quantitative viral outgrowth assay (QVOA) to estimate the frequency of replication-competent HIV was performed before and after ICB for participants with samples available. RESULTS: Of 40 participants, 33 received nivolumab and 7 nivolumab plus ipilimumab. Whereas CA-US HIV RNA did not change with nivolumab monotherapy, we detected a median 1.44-fold increase (interquartile range, 1.16-1.89) after the first dose of nivolumab and ipilimumab combination therapy (P = .031). There was no decrease in the frequency of cells containing replication-competent HIV, but in the 2 individuals on combination ICB for whom we had longitudinal QVOA, we detected decreases of 97% and 64% compared to baseline. CONCLUSIONS: Anti-PD-1 alone showed no effect on HIV latency or the latent HIV reservoir, but the combination of anti-PD-1 and anti-CTL-4 induced a modest increase in CA-US HIV RNA and may potentially eliminate cells containing replication-competent HIV. CLINICAL TRIALS REGISTRATION: NCT02408861.

COVID-19 Clinical Research.

INTRODUCTION: While the global COVID-19 pandemic has challenged the entire humanity and health systems, it also triggered researchers to urgently perform clinical trials to assess the safety and efficacy of many agents and modalities to combat COVID-19. As of April 22, over 650 clinical studies have been registered both in USA and internationally. Results from these studies are also coming at a brisk pace in this unprecedented emergency. AREAS COVERED: We searched the NCI website and Medline and summarize various national and international clinical trials and summarize few of the pivotal ones in this paper, including those specific to oncology population. Two hundred and eighty four studies are actively recruiting adults and children with confirmed COVID-19, including 25 are early-phase I/phase I, 72 phase II, 58 phase III, 12 phase IV, and 31 other trials. They can be categorized into four groups: drugs that combat SARS-CoV-2, immunomodulatory agents to counteract cytokine storm, convalescence plasma therapies and vaccines trials. EXPERT OPINION: It is hoped that these efforts will results in a successful treatment to COVID-19, especially in a timely fashion before the second pandemic expected in fall. It is essential to acknowledge the devotion and hard work of the clinical research team and clinical research volunteers.

Immunotherapy in Anal Cancer.

PURPOSE OF REVIEW: Standard treatment for early-stage squamous cell cancer of the anal canal (SCCA) includes concurrent chemotherapy and radiation to achieve curative intent. Treatment options are limited, however, especially with locoregional disease relapse occurring in 20-30% of patients and about 10-30% of patients presenting with metastatic disease. With more than 90% of SCCAs occurring in the setting of HPV, immune-based therapies are now the target of possible new treatments for this rare disease. This review highlights the role of immunotherapy in HPV-associated SCCA. RECENT FINDINGS: Immunotherapy has been shown to extend progression-free survival and overall survival in various solid malignancies, including SCCA. So far, single-agent monotherapy with either nivolumab or pembrolizumab has shown durable clinical response with a tolerable side effect profile. The 2018 NCCN guidelines now advise nivolumab or pembrolizumab monotherapy as second-line treatment in the management of metastatic SCCA. Further investigation with immunotherapy continues to be critical for such a rare malignancy with few treatment options.

Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice.

PURPOSE: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. METHODS: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). RESULTS: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. CONCLUSION: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset.

The Neutrophil-to-Lymphocyte Ratio is a Prognostic Biomarker in An Ethnically Diverse Patient Population with Advanced Pancreatic Cancer.

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is associated with decreased overall survival in patients with pancreatic adenocarcinoma (PAC) in studies including few minority patients. We investigated the association between NLR and survival in patients with advanced PAC in an ethnically diverse population. METHODS: We retrospectively evaluated 226 patients with advanced PAC treated at Montefiore Medical Center between 2006 and 2015. Adjusted Cox proportion hazard regression models were utilized to derive effect estimates for survival duration. RESULTS: Patients with a NLR ≤ 5 (126 patients, median age 66 years) were more likely to be non-Hispanic Black (30.8% vs. 20%), while patients with a NLR > 5 (70 patients, median age 66 years) were more likely to be non-Hispanic White (21.4% vs. 12.2%) or Hispanic (44.3% vs. 34%). A NLR > 5 compared with a NLR ≤ 5 was significantly associated with a worse overall survival when adjusted for a priori and exploratory variables from the univariate analysis (median survival 7.4 vs. 12 months, HR 1.650, 95% CI 1.139, 2.390). CONCLUSIONS: In an ethnically diverse population, elevated NLR is an independent marker of poor prognosis and a potentially valuable factor in driving therapeutic decisions and defining prognosis for patients in the locally advanced or metastatic for PAC setting, meriting investigation in prospective clinical trials.

Comparing outcomes following total neoadjuvant therapy and following neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer.

BACKGROUND: There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database. METHODS: LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM). FINDINGS: Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT (p = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% (p = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT (p = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p = 0•13) or negative CRM (OR = 1•77, p = 0•19) in multivariable logistic regression modelling. INTERPRETATION: With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.

Excision repair cross-complementing group-1 (ERCC1) induction kinetics and polymorphism are markers of inferior outcome in patients with colorectal cancer treated with oxaliplatin.

BACKGROUND: ERCC1, a component of nucleotide excision repair pathway, is known to repair DNA breaks induced by platinum drugs. We sought to ascertain if ERCC1 expression dynamics and a single nucleotide polymorphism (SNP) rs11615 are biomarkers of sensitivity to oxaliplatin therapy in patients with colorectal cancer (CRC). METHODS: Western blot and qPCR for ERCC1 expression was performed from PBMCs isolated from patients receiving oxaliplatin-based therapy at specified timepoints. DNA was also isolated from 59 biorepository specimens for SNP analysis. Clinical benefit was determined using progression free survival (PFS) for metastatic CRC. RESULTS: ERCC1 was induced in PBMC in response to oxaliplatin in 13/25 patients with mCRC (52%). Median PFS with ERCC1 induction was 190d compared to 237d in non-induced patients (HR 2.35, CI 1.005-5.479; p=0.0182). ERCC1 rs11615 SNP analysis revealed that 43.3% harbored C/C, 41.2%-T/C and 15.5%-T/T genotype. Median PFS was significantly lower with C/C or T/C (211 and 196d) compared to T/T (590d; p=0.0310). CONCLUSIONS: ERCC1 was induced in a sub-population of patients undergoing oxaliplatin treatment, which was associated with poorer outcome, suggesting this could serve as a marker of oxaliplatin response. C/C or C/T genotype in ERCC1 rs11615 locus decreased benefit from oxaliplatin.

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial.

IMPORTANCE: Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC). OBJECTIVE: To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS. INTERVENTIONS OR EXPOSURES: Patients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL. MAIN OUTCOMES AND MEASURES: The primary end point was OS, and progression-free survival (PFS) was a secondary end point. RESULTS: Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib. CONCLUSIONS AND RELEVANCE: This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01015833.

Human papillomavirus, radiation dose and survival of patients with anal cancer.

Purpose: To determine if anal cancer patients with HPV positive disease have different overall survival (OS) compared to those with HPV negative disease, and to elucidate differences in the association between radiation dose and OS.Patients and methods: We utilized the National Cancer Database (NCDB) registry to identify a cohort of non-metastatic anal cancer patients treated with curative intent between 2008 and 2014. Propensity score matching was used to account for potential selection bias between patients with HPV positive and negative disease. Multivariable Cox regression was used to determine the association between HPV status and OS. Kaplan-Meier methods were used to compare actuarial survival estimates.Results: We identified 5927 patients with tumor HPV status for this analysis, 3523 (59.4%) had HPV positive disease and 2404 (40.6%) had HPV negative disease. Propensity-matched analysis demonstrated that patients with HPV positive locally advanced (T3-4 or node positive) anal cancer had better OS (HR = 0.81 (95%CI: 0.68-0.96), p=.018). For patients with early stage disease (T1-2 and node negative) there was no difference in OS (HR = 1.11 (95%CI: 0.86-1.43), p=.43). In the unmatched cohort, we found a significant improvement in OS with increasing radiation dose only for patients with locally advanced, HPV negative disease (p<.001). In those patients, significant improvement in OS compared to the group receiving 30-45 Gy was seen for increasing doses up to 55-60 Gy, but not beyond 60 Gy.Conclusion: We found HPV to be a significant prognostic marker in anal tumors, especially for locally advanced disease. We further found that higher radiation dose up to 55-60 Gy was associated with better OS, but only for patients with locally advanced, HPV negative disease.

Multimodality Management of Localized Biliary Cancer.

OPINION STATEMENT: Biliary tract cancers (BTCs) are a diverse group of malignancies arising from the biliary tree, including cholangiocarcinoma and gallbladder carcinoma. Patients that are candidates for surgical resection should also have lymphadenectomy. Since recurrence rates are high, after surgical resection, patients should be considered for adjuvant therapy in a multidiscipline setting. The limited availability of randomized clinical trial data makes the optimal treatment option unclear; however, chemotherapy or chemoradiation has been shown to have benefits especially in patients with R1 or R2 resections or lymph node involvement. Patients with unresectable disease should be considered for neoadjuvant therapy with chemotherapy or chemoradiation. Patients that are unable to tolerate chemotherapy should also be considered for locoregional therapies. Clinical trial enrollment is strongly recommended for all patients. Trials involving targeted or immunotherapy are currently ongoing in patients with advanced disease.

Survival outcome and prognostic model of patients with colorectal cancer on phase 1 trials.

Background Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results There were 187 enrollments on 37 phase I trials. Median age was: 59 (29-83) years and number of prior therapies: 3 (0-8). The clinical benefit rate (CBR): response (5.6%) + stable disease, was 43.1%. Median progression free survival (PFS) and overall survival (OS) was 7.7 weeks and 43.7 weeks, respectively. The MVA identified age > 60 years (HR 1.63, p < 0.004), albumin<3.5 g/dL (HR 3.69, p < 0.001), direct bilirubin>ULN (HR1.69, p < 0.01), and WBC ≥ 5.2 k/uL (HR 1.97, p < 0.001) as negative prognostic factors. A risk score based on the MVA revealed that patients with a score of 0-1 had an improved OS (58.7 weeks) compared to a score of 2 (49.9 weeks, p < 0.01) and 3 (14.1 weeks, p < 0.001). Conclusions Phase 1 trials may offer similar or better clinical outcome for mCRC patients than standard third line therapies; the prognostic model could assist in selecting appropriate patients.

Biomarker-driven targeted therapies for gastric/gastro-esophageal junction malignancies.

Gastroesophageal malignancies often contain high amounts of genetic and molecular alterations that result in an aggressive disease capable of rapidly metastasizing to distant organs and early development of drug resistance. Most patients in the Western hemisphere present with locally advanced or metastatic disease that is treated with systemic chemotherapy used either in the neoadjuvant or palliative setting, respectively. This article will review the various recent advances in the development of targeted therapies for the treatment of advanced gastric and gastroesophageal cancer.

Evolving Paradigms in HIV Malignancies: Review of Ongoing Clinical Trials.

This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non-AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy-naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.