Hari Anant Deshpande

Novel chemotherapy options for advanced thyroid tumors: small molecules offer great hope.

Purpose of review Endocrine tumors are often overlooked in medical oncology discussions, as many of them are effectively cured by surgery alone or surgery plus an ablative radiation therapy. For the rare aggressive endocrine cancers that are widely metastatic or rapidly progressive, however, the role of the medical oncologist becomes more important. To date, conventional chemotherapy has not had a significant impact on the natural history of these malignancies. This has led to the evaluation of novel compounds; some of which have already entered into randomized clinical trials. This review will focus on the advances made in the treatment of advanced thyroid cancer, the commonest of endocrine malignancies. Recent findings A growing understanding of molecular oncology has allowed the development of targeted agents in different types of thyroid cancer. Some agents presently being evaluated in clinical trials include inhibitors of angiogenesis (sorafenib, CA4P, axitinib and vandetanib), the epidermal growth factor receptor (gefitinib, vandetanib) and RET protein (vandetanib). Preliminary results from these studies will be reviewed in this paper. Summary The recent explosion of targeted agents available for study has generated enthusiasm for oncologists treating thyroid cancer. Antiangiogenesis strategies in particular appear promising. RET inhibition in medullary thyroid cancer is also being explored. Further clinical trials will determine which of these will enter the clinic in the near future.

Vandetanib (ZD6474) in the Treatment of Medullary Thyroid Cancer

Vandetanib (ZD6474) is an orally bioavailable small molecule tyrosine kinase inhibitor of multiple growth factor receptors, including RET (Rearrange during transfection), vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR). The activity against RET and VEGF made it a good choice in the treatment of medullary thyroid cancer (MTC). As there is considerable cross talk between growth factor pathways, dual inhibition with such agents has become an attractive strategy, in the treatment of many malignancies with encouraging Phase II clinical trial data to date. Vandetanib was tested in two Phase II trials in the treatment of patients with medullary thyroid cancer at doses of 100 mg and 300 mg daily respectively. The encouraging results of these 2 trials led to a randomized phase II trial comparing this medication to placebo using a crossover design. More than 300 patients were included in this study, which ultimately showed a significant improvement in progression-free survival in patients taking vandetanib. Based on these results, the Oncology Drug Advisory Committee (ODAC) of the Food and Drug Administration (FDA) recommended that vandetanib be approved for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer.

Management of patients with advanced non-small cell lung cancer: current and emerging options.

Systemic therapy for advanced non-small cell lung cancer (NSCLC) has evolved over the last two decades, with modest improvements in quality of life and overall survival. A plateau has been reached with traditional chemotherapy, and efforts are now being directed at developing molecularly targeted agents. To date, three such agents have been found to improve overall survival in advanced NSCLC. Erlotinib, a small-molecule inhibitor of the epidermal growth factor receptor, was approved by the US FDA in 2004 as second- or third-line treatment for advanced NSCLC. Bevacizumab, an antibody to vascular endothelial growth factor, a key mediator of angio-genesis, received approval in 2006, after a randomized trial reported a median survival of 1 year when bevacizumab was added to first-line chemotherapy. More recently, cetuximab, an antibody to the epidermal growth factor receptor, was found to improve outcome when added to chemotherapy, and FDA approval is anticipated. Several additional agents are currently being evaluated in randomized trials, with encouraging results from early studies. These and other studies are prospectively investigating predictive clinical and molecular characteristics, with the ultimate goal of individualizing therapy in advanced NSCLC.

Vandetanib for the treatment of metastatic medullary thyroid cancer.

Medullary thyroid cancer (MTC) represents an aggressive form of thyroid malignancy. Some may occur spontaneously or can be associated with Multiple Endocrine Neoplasia syndromes, or Familial Medullary Thyroid Cancer syndrome. In these patients, the protooncogene RET (rearranged during transfection) is mutated. In patients who have unresectable or metastatic disease, the long term prognosis is poor. New treatments for this disease have focused on the use of targeted agents that inhibit the receptor tyrosine kinase of RET. One of these treatments, Vandetanib (Caprelsa, Astra Zeneca), recently has received approval from the Food and Drug Administration for the treatment of patients with progressive locally advanced and/or metastatic disease. This review highlights the studies that led to the drugs approval, and discusses on the potential financial costs of treatment and side effects of this therapy. The main clinical studies evaluating Vandetanib for the treatment of other solid tumors will also be reviewed.

A Comparison of Prognostic Ability of Staging Systems for Human Papillomavirus-Related Oropharyngeal Squamous Cell Carcinoma.

Importance The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system, developed for human papillomavirus (HPV)-unrelated disease, discriminates poorly when applied to HPV-related oropharyngeal squamous cell cancer (OPSCC), leading to calls for a new staging system. Objective To compare the prognostic ability of the AJCC/UICC seventh edition staging system; a recently proposed system, the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S); and a novel objectively derived system for HPV-related OPSCC using a national database of patients primarily treated with either radiation or surgery. Design, Setting, and Participants In this observational study, patients with HPV-related nonmetastatic OPSCC were identified in the National Cancer Database between 2010 and 2012. Recursive partitioning analysis (RPA) was used to derive the proposed-RPA staging system. The data were analyzed from March to May 2016. Main Outcomes and Measures Overall survival was calculated using the Kaplan-Meier method. The performance of the 3 systems was compared using published criteria, and internal validation using bootstrap methods was performed. Survival differences between stage groups were evaluated using the log-rank test. Results A total of 5626 patients (86.0% male; median [range] age, 58 [21-90] years) were identified. The median (range) follow-up was 28.5 (0.1-58.8) months. A novel staging system (proposed-RPA) consisting of stage IA, T1-2N0-2a; stage IB, T1-2N2b-3; stage II, T3N0-3; stage III, T4a-bN0-3 resulted in 3-year overall survival rates of 91%, 87%, 81%, and 70%, respectively. This system, as well as the ICON-S, significantly prognosticated for survival when either primary surgery or primary radiation subgroups were examined (log-rank P < .001 for all). The AJCC/UICC system, ICON-S, and proposed-RPA all significantly predicted survival outcomes when analyzed globally (log-rank P < .001 for all). The AJCC/UICC system could not differentiate between survival when stages I and IVA were compared, however (log-rank P = .17). On comparative performance evaluation for survival prediction, the proposed-RPA provided superior prognostication compared with the other systems. Conclusions and Relevance We validated the ICON-S staging as prognostic, overall, and in primary radiation therapy and surgery subgroups, but ultimately found that a staging system consisting of stage IA, T1-2N0-2a; stage IB, T1-2N2b-3; stage II, T3N0-3; and stage III, T4a-bN0-3 (with stage IV representing M1 disease) outperformed the others. The proposed-RPA is an alternative staging system that should be evaluated for potential adoption as part of the next AJCC/UICC staging system.

New targeted therapies and other advances in the management of anaplastic thyroid cancer.

Purpose of review Anaplastic thyroid cancer is the most aggressive solid tumor known to humans. Even when found in a localized form, the prognosis is grave. For metastatic disease, there has been little effect on survival using traditional chemotherapy. Recent findings Over a five-decade interval, there has been little progress in the treatment of this malignancy. However, targeted agents represent a new mode of treatment, and some studies have shown encouraging preclinical results. Combretastatin has shown activity in phase 1 and phase II trials; although the registration phase III study failed to meet its accrual goals, it did appear to show some benefit, especially in younger patients. Summary Combinations of this compound and other targeted agents may prove to be a breakthrough in an otherwise untreatable cancer.

Current status of vandetanib (ZD6474) in the treatment of non-small cell lung cancer

Vandetanib (ZD6474) is an oral small molecule inhibitor of multiple intracellular receptor kinases, including the vascular endothelial growth factor receptor (VEGFR) -2 and epidermal growth factor receptor (EGFR). Both VEGFR and EGFR pathways have emerged as instrumental in the growth and metastasis of multiple malignancies, including non-small cell lung cancer (NSCLC). Indeed, inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC. As there is considerable cross talk between these pathways, dual inhibition with such agents has become an attractive strategy, with encouraging Phase II clinical trial data to date. The convenience of one oral agent targeting both pathways is clear, and clinical trials have established the maximum tolerated daily dose of vandetanib, with data from randomized Phase III trials emerging. This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib, and speculate on the future of this agent in NSCLC.

Axitinib: The evidence of its potential in the treatment of advanced thyroid cancer

Introduction: Thyroid cancer is a rare disease with an incidence of around 37,000 cases per year. However, its incidence is rising faster than many other cancers and for men this disease ranks highest overall in the rate of increase (2.4% annual increase) in cancer deaths. As the number of radioactive iodine-resistant thyroid cancers increases, the need for newer treatments has become more important. Axitinib is one of many new small molecule inhibitors of growth factor receptors that have shown promise in the treatment of many cancers. It targets the vascular endothelial growth factor receptors 1, 2 and 3. Aims: The goal of this article is to review the published evidence for the use of axitinib in the treatment of thyroid cancer and define its therapeutic potential. Evidence review: The major evidence of axitinib activity has appeared in meeting report abstracts. One phase II study has been published. This included patients with any histological type of thyroid cancer that was not amenable to treatment with radioactive iodine. Clinical potential: To date, in phase II clinical studies axitinib has demonstrated antitumor activity in advanced refractory thyroid cancer. As a monotherapy it resulted in a 30% response rate with another 38% of patients having stable disease. Axitinib appears to have a good tolerability profile, with hypertension being the most common grade 3 or greater side effect.

Demethylation therapy as a targeted treatment for human papilloma virus-associated head and neck cancer

Purpose: DNA methylation in human papillomavirus–associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC. Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC. Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels. Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276–87. ©2017 AACR.

Clinical utility of vandetanib in the treatment of patients with advanced medullary thyroid cancer

Vandetanib (ZD6474) became the first systemic agent to be approved for the treatment of metastatic or locally advanced medullary thyroid cancer. It was a proof of principle, because it is an orally bioavailable medication that targets the growth factors felt to be important in the pathogenesis of this disease, ie, the rearranged during transfection proto-oncogene and vascular endothelial growth factor receptor. It was tested initially in two Phase II studies at doses of 100 mg and 300 mg daily. Although activity was seen at both doses, the higher dose was chosen for a randomized, placebo-controlled Phase II study. This trial, which accrued more than 300 patients, showed a statistically significant benefit for the group taking vandetanib compared with those taking placebo medication. Progression-free survival for the vandetanib arm has not been reached, compared with 19 months for the placebo arm. The main toxicity appears to be diarrhea, although some patients experienced significant side effects, including torsades de pointes and sudden cardiac death. Therefore, it is now necessary for practitioners to enroll in a Risk Evaluation Mitigation Strategy before being allowed to prescribe this medication, to reduce the risk of serious side effects occurring.