Erin M. Bertino

Consensus guidelines for the management and treatment of neuroendocrine tumors.

Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.

Pulmonary neuroendocrine/carcinoid tumors: a review article.

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well‐differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors. Cancer 2009.

Romidepsin: a novel histone deacetylase inhibitor for cancer

Introduction: Romidepsin is a novel histone deacetylase (HDAC) inhibitor, with a recent approval for treatment of cutaneous T-cell lymphoma (CTCL). HDAC inhibitors represent a novel approach to anti-tumor therapy. In contrast to traditional cytotoxic chemotherapy, HDAC inhibitors target underlying epigenetic changes leading to malignant transformation. Further study of romidepsin and similar agents in solid and hematologic malignancies is ongoing. Areas covered: This review discusses the development of romidepsin, its mechanism of action, pivotal clinical trials, drug toxicity and its recent approval for CTCL treatment. Key clinical trials covered include Phase I/II testing of romidepsin in solid and hematologic malignancies. In addition, the Phase II trial in CTCL leading to FDA approval of romidepsin is reviewed in detail. Literature search was performed using PubMed; keywords and concepts used included romidepsin, T-cell lymphoma and HDAC inhibitors. Expert opinion: Romidepsin is a potent HDAC inhibitor with demonstrable activity in T-cell lymphoma. In contrast to vorinostat, romidepsin is approved as second-line therapy. Current approval only includes CTCL; promising results have been demonstrated in Phase II testing of peripheral T-cell lymphoma subtypes. Future directions include expanded indications in T-cell lymphomas as well as novel combinations with other HDAC inhibitors and other therapeutic agents.

Benefits and limitations of antiangiogenic agents in patients with non-small cell lung cancer

Lung cancer is one of the most common cancers and, unfortunately, the most deadly. Most patients present either with locally advanced or metastatic disease or develop disease recurrence after local therapies. For these patients, chemotherapy has been the primary treatment but often yields less than optimal results. Recent advances in targeted therapies have raised the promise of improved outcomes for patients. In particular, angiogenesis has been identified as a viable target. Several approaches have been developed, including monoclonal antibodies and tyrosine kinase inhibitors against angiogenic growth factors, particularly vascular endothelial growth factor, and novel vascular disrupting agents. In this review, the role of these antiangiogenic agents in patients with non-small cell lung cancer will be discussed, with an emphasis on bevacizumab and other agents under development and clinical testing (i.e., tyrosine kinase inhibitors and vascular disrupting agents).

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS-activated tumors

The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras‐activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents.

Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients

UNLABELLED In this phase II trial, carboplatin with nanoparticle albumin-bound (nab)-paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC) was evaluated. Most patients had squamous cell histology. Tumor-associated stromal caveolin-1 (Cav-1) expression was correlated with improved response rate and survival in NSCLC patients who received nab-paclitaxel in this phase II trial. These results suggest Cav-1 might serve as a potential biomarker in this patient population. BACKGROUND The combination of bevacizumab with platinum-based chemotherapy results in greater response rate (RR) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Bevacizumab is contraindicated in patients with squamous histology or hemoptysis. Nanoparticle albumin-bound (nab)-paclitaxel is a novel formulation of paclitaxel with greater dose tolerance and improved efficacy. We hypothesized that nab-paclitaxel and carboplatin would be superior to alternative doublets in advanced NSCLC patients ineligible for bevacizumab. PATIENTS AND METHODS We conducted a single-arm phase II trial (NCT00729612) with carboplatin and nab-paclitaxel on day 1 of a 21-day cycle to evaluate RR (primary end point), safety, toxicity, and OS. Eligibility included: squamous histology, hemoptysis, or ongoing anticoagulation. Correlative studies included immunohistochemistry for secreted protein acid rich in cysteine (SPARC) and caveolin-1 (Cav-1). RESULTS Sixty-three patients were enrolled. Most patients had squamous cell carcinoma (n = 48); other reasons for eligibility included hemoptysis (n = 11) and anticoagulation (n = 2). Toxicity Grade ≥ 3/4 included neuropathy, cytopenias, and fatigue. RR was 38% (24 partial response/0 complete response); 20 patients had stable disease (32%). Median progression-free survival was 5 months and median OS was 9.7 months. Immunohistochemistry for SPARC and Cav-1 was performed in 38 and 37 patients respectively. Although no association was found for SPARC expression in tumor or stroma with RR or OS, we found that higher Cav-1 levels in tumor-associated stroma was associated with improved RR and OS. CONCLUSION Carboplatin and nab-paclitaxel every 21 days demonstrated promising efficacy with tolerable toxicity in NSCLC patients ineligible for bevacizumab therapy. Further analysis and validation of Cav-1 and SPARC expression in tumor and stromal compartments as prognostic and/or predictive biomarkers of NSCLC or nab-paclitaxel treatment is warranted.

Relationship between Overall Survival and Response or Progression-Free Survival in Advanced Non–Small Cell Lung Cancer Patients Treated with Anti–PD-1/PD-L1 Antibodies

Introduction Alternative predictive end points for overall survival (OS), such as tumor response and progression‐free survival (PFS), are useful in the early detection of drug efficacy; however, they have not been fully investigated in patients with advanced NSCLC treated with anti–programmed death protein 1 (PD‐1)/programmed death ligand 1 (PD‐L1) antibodies. Methods In a systematic review of the reported prospective clinical trials, data for response rate, median PFS, and median OS were extracted from 12 arms in 10 reported clinical trials using anti–PD‐1/PD‐L1 antibody, and their correlation was investigated. In a retrospective analysis at our institution, OS was compared according to tumor response on 5‐ to 9‐week computed tomography scans and status of being progression‐free at 8, 16, and 24 weeks by landmark analysis in 71 patients with advanced NSCLC treated with anti–PD‐1/PD‐L1 antibodies between 2013 and 2015. Results In a systematic review, moderate correlations between median OS and median PFS (p = 0.120, r = 0.473) and between median OS and response rate (p = 0.141, r = 0.452) were identified using the Spearman correlation coefficient, although these correlations were not statistically significant. In a retrospective analysis of patients treated at our institution, disease control (partial response [PR]/stable disease versus progressive disease/not evaluable), and progression‐free status at 8, 16, and 24 weeks significantly predicted OS (Cox proportional hazards model, PR/stable disease versus progressive disease/not evaluable, p = 0.0104, HR = 3.041; 8‐week progression‐free yes versus no, p = 0.0183, HR = 2.684; 16‐week progression‐free yes versus no, p = 0.0036, HR = 4.009; and 24‐week progression‐free yes versus no, p = 0.0002, HR = 12.726). Conclusions Both disease control (PR plus stable disease status) and landmark progression‐free survival were correlated with OS, with the longer interval landmark PFS being the best predictor of survival in patients with NSCLC treated with anti–PD‐1/PD‐L1 antibodies.

Phase III Randomized, Placebo-Controlled, Double-Blind Trial of Celecoxib in Addition to Standard Chemotherapy for Advanced Non–Small-Cell Lung Cancer With Cyclooxygenase-2 Overexpression: CALGB 30801 (Alliance)

Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non-small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ≥ 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ≥ 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ≥ 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ≥ 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.

Preoperative Bevacizumab in Combination With Paclitaxel and Carboplatin in Surgically Resectable Non-Small Cell Lung Cancer

Preoperative chemotherapy is established for stage III (N2 positive) non-small cell lung cancer (NSCLC) and has demonstrated benefit in two studies. In both studies, survival was improved for patients who received chemotherapy (5-year survival 53% vs 24% [1], and median survival 26 vs 8 months [2]). Recently, Pisters and colleagues [3] reported the results of S9900, a trial of preoperative chemotherapy, followed by surgical resection, compared with surgical resection alone in earlier stage NSCLC [3]. Although this trial was stopped before full accrual, it showed a trend toward improved survival in the preoperative chemotherapy arm. Bevacizumab, an antibody directed to vascular endothelial growth factor, has improved response rates and overall survival when combined with chemotherapy for patients with metastatic lung cancer and is being tested in the adjuvant setting with chemotherapy [4]. Several important toxicities, including bleeding, tracheoesophageal fistulas, and wound healing complications, affect the utility of bevacizumab in the perioperative setting [5]. We designed a trial of induction chemotherapy and bevacizumab for patients with surgically resectable NSCLC. Unfortunately, this National Cancer Institute-sponsored protocol was terminated early due to poor accrual. Although conclusions about the efficacy of this approach cannot be established, we wish to communicate that thoracic operations can be performed safely after bevacizumab-containing chemotherapy. The trial enrolled 6 men, and most were white. Patients with squamous cell carcinoma were not excluded from treatment; however, patients with central tumors (within the inner onethird of the chest) and hemoptysis were excluded. Four patients had squamous cell cancers. Planned treatment included two preoperative cycles of carboplatin AUC 6, paclitaxel (200 mg/ m 2 ), and bevacizumab (15 mg/kg) on day 1 of a 21-day cycle. Five patients received two cycles of chemotherapy with bevacizumab; 1 patient received two cycles of chemotherapy, but bevacizumab was discontinued before cycle 2 due to hypertension. Treatment-related toxicity was minimal. There were no significant bleeding events—1 patient had grade 1 epistaxis and another had grade 1 hematuria. The only grade 3 or 4 toxicity observed was neutropenia. Four of the enrolled patients underwent planned surgical resection: three lobectomies and one bilobectomy. The average time between the last dose of bevacizumab and the operation was 48 days (range, 35 to 75 days). Progressive disease was discovered in 2 patients during the preoperative evaluation, and they did not undergo resection. No postoperative complications attributable to bevacizumab were observed. One patient had atelectasis due to secretions and a persistent air leak. Despite receiving bevacizumab, no significant perioperative bleeding complications were observed. Similarly, none of the patients had wound-healing complications, and there were no fistulas. Furthermore, no perioperative thromboembolic events occurred. Partial pathologic responses were discovered in 2 patients at the time of the operation, as demonstrated by smaller tumors with necrosis. Improved survival remains the goal of perioperative therapy for early-stage NSCLC. Our limited data provide early signals that bevacizumab can safely be added to preoperative chemotherapy and supports the ongoing Bevacizumab and Chemo

A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer

mAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune systems ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m2 i.v. every two weeks with lenalidomide given orally days 1–21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily, days 1–21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244–50. ©2016 AACR.