Ramona Dadu

Efficacy and Tolerability of Vemurafenib in Patients with BRAFV600E -Positive Papillary Thyroid Cancer: M.D. Anderson Cancer Center Off Label Experience

CONTEXT Vemurafenib, a selective BRAF inhibitor, appears to have promising clinical activity in patients with papillary thyroid cancer (PTC) harboring the BRAF(V600E) mutation. OBJECTIVE To determine the efficacy and safety of vemurafenib when used outside of a clinical trial. DESIGN A retrospective review at MD Anderson Cancer Center. METHODS The best responses were evaluated using RECIST v1.1. A single radiologist reviewed all images. Adverse events (AEs) were evaluated using CTCAE v.4.0. RESULTS We identified 17 patients with advanced PTC harboring the BRAF(V600E) mutation who were treated with vemurafenib outside of a clinical trial. Median age at diagnosis was 63 years, and 53% were male. At vemurafenib start, 3 (18%) patients had disease confined to the neck, and 14 (72%) had distant metastases. Tyrosine kinase inhibitors had been previously administered to 4 (24%) patients. Two (12%) patients discontinued vemurafenib because of AEs before restaging. Best response: partial response (PR) in 7/15 (47%) and stable disease (SD) in 8/15(53%) patients. The rate of durable response (PR plus SD ≥ 6 months) was 67%. Median time to treatment failure was 13 months. There was no association between change in thyroglobulin and tumor size. Drug discontinuation, drug interruptions, and dose reductions were needed in 5 (29%), 13 (76%), and 10 (59%) patients, respectively. Most common AEs were fatigue (71%), weight loss (71%), anorexia (65%), arthralgias (59%), hair loss (59%), rash (59%), hand-foot syndrome (53%), calluses (47%), diarrhea (47%), fever (41%), dry mouth (35%), nausea (35%), and verrucous keratosis (35%). Grade ≥ 3 AEs were present in 8 (47%) patients. CONCLUSIONS Vemurafenib is a potentially effective and well-tolerated treatment strategy in patients with advanced PTC harboring the BRAF(V600E) mutation. Our results are similar to those reported in a phase II clinical trial and support the potential role of vemurafenib in this patient population.

Role of Salvage Targeted Therapy in Differentiated Thyroid Cancer Patients Who Failed First-Line Sorafenib

CONTEXT Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES Progression-free survival, best response, and median OS were measured. RESULTS Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Sorafenib in Metastatic Thyroid Cancer: A Systematic Review

BACKGROUND Sorafenib was recently approved by the U.S. Food and Drug Administration for radioiodine-resistant metastatic differentiated thyroid cancer (DTC). In addition, two drugs (vandetanib and cabozantinib) have received U.S. Food and Drug Administration approval for use in medullary thyroid cancer (MTC). Several published phase II trials have investigated the efficacy of sorafenib in thyroid cancers, but to date, results from those studies have not been compared. METHODS A systematic review of the literature was performed to assess response rate, median progression-free survival, and adverse events associated with sorafenib therapy for metastatic thyroid cancers. RESULTS This review included seven trials involving 219 patients: 159 with DTC (papillary, follicular, and poorly differentiated), 52 with MTC, and 8 with anaplastic thyroid cancer. No study reported complete responses to treatment. Overall partial response, stable disease, and progressive disease rates were 21%, 60%, and 20%, respectively. The median progression-free survival was 18 months for patients with all subtypes of thyroid cancer. Drug was discontinued in 16% of patients because of toxicities or intolerance, and the dose was reduced in a further 56%. Side effects with an incidence ≥ 50% were hand-foot syndrome (74%), diarrhea (70%), skin rash (67%), fatigue (61%), and weight loss (57%). Deaths not related to progressive disease occurred in nearly 4% of patients. CONCLUSION Treatment with sorafenib in patients with progressive DTC and MTC is a promising strategy, but the adverse event rate is high, leading to a high rate of dose reduction or discontinuation. Consequently, sorafenib use in patients with metastatic thyroid cancer requires careful selection of patients and careful management of side effects.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs’ therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer

BACKGROUND In the past decade, targeted therapy with antiangiogenic drugs has become standard of care for most types of metastatic, progressive thyroid cancer. While these drugs were thought initially to be less toxic than traditional chemotherapy, they can have rare but serious and fatal toxicities. Once such toxicity that has been reported in other tumor types is upper airway fistula formation, which can be life-threatening. SUMMARY Here, we describe three patients treated with antiangiogenic tyrosine kinase inhibitors at two academic institutions who developed aerodigestive fistula. All three patients had risk factors for fistula formation, which included external beam radiation and/or large tumor with invasion of the tracheal wall. CONCLUSIONS Fistula formation is a known but rare side effect of antiangiogenic tyrosine kinase inhibitors. Knowledge of the risk factors that may predispose thyroid cancer patients to this serious adverse event is vital prior to prescribing antiangiogenics. Particular caution should be observed when using these drugs in patients undergoing radiation therapy or surgery, or in patients whose tumor is invading vital structures of the neck, as they may be at higher risk of developing this rare complication. In these patients, antiangiogenic tyrosine kinase inhibitors should be used cautiously, patients should be aware of the risk, and physicians should monitor patients for symptoms of fistula.

Efficacy and Tolerability of Different Starting Doses of Sorafenib in Patients With Differentiated Thyroid Cancer

Sorafenib has proven efficacy in advanced differentiated thyroid cancer (DTC), but many patients must reduce the dose or discontinue treatment because of toxicity. The tolerability and efficacy of lower starting doses of sorafenib for DTC remain largely unstudied. Methods. We retrospectively examined overall survival, time to treatment failure, time to progression, discontinuation rates, and dose-reduction and interruption rates in patients with metastatic DTC treated with first-line sorafenib outside of a clinical trial. Two patient groups were compared; group 1 received the standard starting dose of 800 mg/day, and group 2 received any dose lower than 800 mg/day. Results. We included 75 adult patients, with 51 in group 1 and 24 in group 2. Mean age at diagnosis was 54 years, and 56% were male. The most common histologies included 43% papillary thyroid cancer of the conventional type, 15% papillary thyroid cancer of the follicular variant, and 15% Hürthle cell carcinoma. Time to treatment failure was 10 months (95% confidence interval [CI]: 5.6-14.3) in group 1 and 8 months (95% CI: 3.4-12.5) in group 2 (p = .56). Median overall survival was 56 months (95% CI: 30.6-81.3) in group 1 and 30 months (95% CI: 16.1-43.8) in group 2 (p = .08). Rates of discontinuation due to disease progression were 79% in group 1 and 91% in group 2, and 21% in group 1 and 9% in group 2 (p = .304) stopped treatment because of toxicity. Dose-reduction rates were 59% and 43% (p = .29), and interruption rates were 65% and 67% (p = .908) in group 1 and group 2, respectively. Conclusion. Efficacy and tolerability of sorafenib in treatment-naïve DTC patients does not appear to be negatively influenced by lower starting daily doses.

Patterns of Treatment Failure in Anaplastic Thyroid Carcinoma

BACKGROUND Anaplastic thyroid cancer (ATC) is one of the most lethal forms of cancer with a high mortality rate. Current guidelines support surgery for resectable ATC followed by external beam radiation therapy (EBRT) with or without chemotherapy. Treatment for those who are unresectable is palliative. Our goal was to examine first-line therapies as well as the role of genomic profiling in an effort better understand how to approach ATC. METHODS This is a retrospective study of ATC patients who were seen at our institution from January 2013 to October 2015. Median overall survival (OS) and time to treatment failure (TTF) were calculated by the Kaplan-Meier method. RESULTS Fifty-four patients were included. Median age at diagnosis was 63 years and 29/54 (54%) were women. The majority had stage IVC disease at diagnosis (50%), followed by IVB (32%), and IVA (18%). Approximately 93% had somatic gene testing. Initial treatment was surgery in 23 patients, EBRT with or without radiosensitizing chemotherapy in 29 patients, and systemic chemotherapy in 2 patients. Nineteen patients had all three treatment modalities. For the entire cohort, median OS was 11.9 months with 39% survival at 1 year and median TTF was 3.8 months. The majority of patients (74%) developed new distant metastasis or progression of existing metastatic disease. Patients who received trimodal therapy consisting of surgery, EBRT, and chemotherapy had a median OS of 22.1 months versus 6.5 months in those who received dual therapy with EBRT and chemotherapy (p = 0.0008). The TTF was the same in the two groups (7.0 and 6.5 months, respectively). Men were three times more likely to die from ATC than women (p = 0.0024). No differences in OS or TTF were noted based on tumor size (5 cm cutoff), age (60 years cutoff), or presence of any mutation. There was a trend toward shorter TTF in patients with somatic mutations in TP53. CONCLUSION Patients with ATC amenable to aggressive tri-modal therapy demonstrate improved survival. The short TTF, due primarily to distant metastatic disease, highlights the potential opportunity for improved outcomes with earlier initiation of systemic therapy including adjuvant or neoadjuvant therapy.

Use of Tyrosine Kinase Inhibitors for Treatment of Medullary Thyroid Carcinoma.

Two independent events--the identification of activating mutations of the RET proto-oncogene, a receptor tyrosine kinase, in medullary thyroid carcinoma, and the recognition that small organic molecules could bind to and inhibit phosphorylation of signaling molecules, thereby inactivating the pathway-led to the recognition that kinase inhibitors could be used to treat medullary thyroid carcinoma (MTC). The introduction of these compounds into clinical practice has transformed the treatment of metastatic MTC and provided insight into the mechanisms by which RET causes C-cell transformation. This chapter will review the progress in this field over the past 7 years.

Thyroid Gland Malignancies

Surgery remains the most important effective treatment for differentiated (DTC) and medullary thyroid cancer (MTC). Radioactive iodine (RAI) is another important treatment but is reserved only for DTC whose disease captures RAI. Once patients fail primary therapy, observation is often recommended, as most DTC and MTC patients will have indolent disease. However, in a fraction of patients, systemic therapy must be considered. In recent decades 4 systemic therapies have been approved by the United States FDA for DTC and MTC. Sorafenib and lenvatinib are approved for DTC and vandetanib and cabozantinib for MTC. Anaplastic thyroid cancer (ATC) is a rare and rapidly progressive form of thyroid cancer with a very high mortality rate. Treatment of ATC remains a challenge. Most patients are not surgical candidates at diagnosis due to advanced disease. External beam radiation and radiosensitizing radiation are the mainstay of therapy at this time. However, exciting new drugs and approaches to therapy are on the horizon but it will take a concerted, worldwide effort to complete clinical trials in order to find effective therapies that will improve the overall survival for this devastating disease.

Efficacy of the Natural Clay, Calcium Aluminosilicate Anti-Diarrheal, in Reducing Medullary Thyroid Cancer-Related Diarrhea and Its Effects on Quality of Life: A Pilot Study.

INTRODUCTION Medullary thyroid cancer (MTC)-related diarrhea can be debilitating, reduces quality of life (QOL), and may be the only indication for initiating systemic therapy. Conventional antidiarrheal drugs are not always helpful and may have side effects. Calcium aluminosilicate antidiarrheal (CASAD), a natural calcium montmorrilonite clay, safely adsorbs toxins and inflammatory proteins associated with diarrhea. It was hypothesized that CASAD would reduce the severity of diarrhea and improve QOL in MTC patients. METHODS This was a prospective pilot trial (NCT01739634) of MTC patients not on systemic therapy with self-reported diarrhea of three or more bowel movements (BMs) per day for a week or more. The study design included a one-week run-in period followed by one week of CASAD ± a two-week optional continuation period. The primary endpoint was efficacy of one week of CASAD treatment in decreasing the number of BMs per day by ≥20% when compared with the baseline run-in period. Secondary objectives included tolerability and safety and the impact on QOL using the MD Anderson Symptom Inventory-Thyroid questionnaire (MDASI-THY). RESULTS Ten MTC patients (median age = 52 years, 70% female, 80% white) were enrolled. All had distant metastases, and median calcitonin was 5088 ng/mL (range 1817-42,007 ng/mL). Ninety percent had received prior antidiarrheals, and 40% of these had used two or more drugs, including tincture of opium (30%), loperamide (50%), diphenoxylate/atropine (20%), colestipol (10%), or cholestyramine (10%). Of seven evaluable patients, four (56%) had ≥20% reduction in BMs per day. Six out of seven patients discontinued their prior antidiarrheals. Best response ranged from 7% to 99% reduction in mean BMs/day from baseline. Five out of seven patients considered CASAD a success, and they opted for the two-week continuation period. Improvements in diarrhea and all six interference items assessed by MDASI-THY were noted at weeks 1 and 3. Total interference score was significantly improved at three weeks compared with baseline (p = 0.05). An oral levothyroxine absorption test was performed in one patient; malabsorption of levothyroxine was not observed. Adverse events included flatulence (40%), bloating (10%), heartburn (10%), and constipation (10%). CONCLUSIONS CASAD is a promising strategy for treatment of MTC-related diarrhea. In this small pilot study, improvements in frequency and quality of diarrhea as well as QOL were noted. Further studies in this population are warranted.