Ana O. Hoff

Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer

BACKGROUND Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131). METHODS In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety. RESULTS The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related. CONCLUSIONS Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Epidemiology and risk factors for osteonecrosis of the jaw in cancer patients

Osteonecrosis of the jaw (ONJ), previously an entity associated with radiation therapy to the head and neck, has been observed in patients treated with bisphosphonates. Patients with metastatic breast cancer and myelomatous bone disease, commonly treated with high‐potency nitrogen‐containing bisphosphonates for a prolonged period of time, have the greatest risk of ONJ development. The reported frequency of ONJ ranges from 0.6% to 6.2% in breast cancer and from 1.7% to 15% in patients with multiple myeloma. Osteonecrosis of the jaw has also been observed in patients with other cancers such as prostate cancer and in benign bone disorders such as osteoporosis and Pagets disease in which the incidence is low. Risk factors associated with the development of ONJ include dental extractions, length of bisphosphonate treatment, and the type of bisphosphonate used. In this review, we summarize the reported incidence and risk factors associated with ONJ.

Relationship between GH response and glycemic fluctuations in the glucagon stimulation test.

OBJECTIVE Verifying the association between glycemic fluctuation and GH response in the glucagon stimulation test. Basal evaluation of growth hormone (GH) has poor diagnostic accuracy due to its pulsatile secretion. GH-stimulation tests are used for an adequate evaluation of somatotrophic axis. Various stimuli can be employed, among them glucagon, which has an elusive mechanism of action. Since hypoglycemia reportedly occurs during the test, investigation of its role as a stimulus to GH release is granted. DESIGN Retrospective analysis of glucagon-stimulated GH tests performed in 128 children (36.7% female; age 12.4+3.3 years), at Fleury Functional Tests Facility from July 2000 to 2006. GH and blood glucose (BG) curves, IGF-1, and IGFBP-3 have been assessed. Positive GH response was defined by a peak GH value >or=3.3 microg/L. Normal IGF-1 levels were defined as those between 2.5th and 97.5th percentiles for age and gender. RESULTS Hypoglycemia under 2.2 mmol/L did not occur during the test. BG decrease occurred with lower magnitude and was not associated to GH response. Comparison between patients with negative and positive GH response showed, respectively, BG nadir 3.74 vs. 3.62 mmol/L, glucose AUC 23.3 vs. 22.4, and glycemic decrease (below 3.3 mmol/L) 19% vs. 35.5% (with P non-significant for all comparisons). CONCLUSION Hypoglycemia was not seen after glucagon stimulation and decrease in BG occurred above levels physiologically expected to stimulate GH release, being apparently not associated to GH response.

Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma

OBJECTIVE The p.V600E BRAF and RAS mutations are found in 30-80% of differentiated thyroid carcinoma (DTC). BRAF mutation has been associated with poor prognosis. This study investigated the role of molecular studies in preoperative diagnosis of DTC and the association of p.V600E mutation with prognostic factors. DESIGN Prospective study. METHODS A total of 202 patients with cytological diagnosis of Bethesda III-VI underwent preoperative molecular studies and subsequent thyroidectomy. p.V600E and RAS mutations were studied in the cytology smears, using real-time PCR genotyping technique. The BRAF mutation (BRAF(+) or BRAF(-)) was correlated with histological and clinical findings. RESULTS Molecular study of 172 nodules with Bethesda III-V cytology improved negative predictive value and accuracy of Bethesda III and IV diagnosis. BRAF mutation was present in 65% of 94 DTC and p.Q61R NRAS in one. Except for age, BRAF(+) and BRAF(-) did not differ in sex, tumor size, histological subtype, multifocality, vascular invasion, extrathyroidal extension, or prognostic staging. Among papillary carcinomas, lymph node (LN) metastasis was diagnosed in 23% BRAF(+) and 37% BRAF(-). Distant metastasis occurred in four BRAF(-). Recurrent or persistent disease was more frequent in BRAF(-) (26.7 vs 3.3% BRAF(+), P=0.002) along follow-up of 29.8±10 months. BRAF(+) patients without LN metastasis by pre-operative evaluation submitted to thyroidectomy with central neck dissection (CND) had more frequent LN metastasis (45 vs 5% no CND, P=0.002), but no difference in clinical outcome was observed. CONCLUSIONS Pre-operative identification of BRAF mutation improved cytological diagnosis of DTC, but it was not associated with poor prognostic factors. Prophylactic CND did not guarantee better outcome in BRAF(+) patients.

Endocrine side effects of cancer immunotherapy

Immune checkpoint inhibitors have recently become a cornerstone for the treatment of different advanced cancers. These drugs, represented mainly by monoclonal antibodies anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) and anti-PD-1 ligand molecules (PD-L1 and L2), have the ability to reactivate the immune system against tumor cells, but can also trigger a myriad of autoimmune side effects, termed immune-related adverse events (irAEs). In particular, there are a number of endocrine-related irAEs. Current data from clinical trials show increased incidence of hypophysitis with CTLA4 inhibition and thyroid dysfunction with PD-(L)1 blockade. In addition, a few cases of type 1 diabetes mellitus and primary adrenal insufficiency have been reported. We discuss the incidence, clinical manifestations, diagnosis and management of immune-related endocrinopathies in this highly complex context of oncological patients in need of immunotherapies.

Symptomatic Hypoglycemia Related to Inappropriately High IGF-II Serum Levels in a Patient with Desmoplastic Small Round Cell Tumor

A 45-year old man was diagnosed with desmoplastic small round cell tumor (DSRCT) with involvement of the peritoneum and pelvis. Disease progression was observed despite systemic chemotherapy. Six months after diagnosis, he developed severe hypoglycemia presented with seizures. He received intravenous glucose infusion and hydrocortisone with poor glycemic control, but with seizures resolution. The investigation excluded insulinoma, adrenal, liver and GH deficiencies. Laboratory showed slight rise of IGF-II and significant increase of the ratio IGF-II : IGF-I, which is pathognomonic of non-islet cell tumor hypoglycemia (NICTH). He received the diagnoses of NICTH related to IGF-II inappropriate production by DSRCT. Despite the attempt to control tumor mass and hypoglycemia, the patient died 9 months after diagnosis. NICTH related to inappropriate IGF-II secretion should be investigated in all cancer patients with refractory hypoglycemia whom insulinoma and other metabolic abnormalities were excluded from.

A ten‐year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives

Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision‐making.

25-Hydroxyvitamin D and TSH as Risk Factors or Prognostic Markers in Thyroid Carcinoma

Objective The increasing incidence of thyroid nodules demands identification of risk factors for malignant disease. Several studies suggested the association of higher TSH levels with cancer, but influence of 25-hydroxyvitamin D (25OHD) is controversial. This study aimed to identify the relationship of thyroid cancer with higher TSH levels and hypovitaminosis D and to evaluate their influence on prognostic characteristics of papillary thyroid carcinomas (PTC). Methods We retrospectively evaluated 433 patients submitted to thyroidectomy for thyroid nodules. Patients were categorized according to quartiles of TSH and 25OHD levels. Clinicopathological features were analyzed. Results Subjects with thyroid carcinomas were more frequently male and younger compared to those with benign disease. Their median TSH levels were higher and adjusted odds-ratio (OR) for cancer in the highest-quartile of TSH (> 2.4 mUI/mL) was 2.36 (1.36–4.09). Although vitamin D deficiency/insufficiency was prevalent in our cohort (84%), no significant differences in 25OHD levels or quartile distribution were observed between benign and malignant cases. Among 187 patients with PTC, analyses of prognostic features revealed increased risk of lymph nodes metastases for subjects with highest-quartile TSH levels (OR = 3.7, p = 0.029). Decreased 25OHD levels were not overtly associated with poor prognosis in PTC. Conclusions In this cross-sectional cohort, higher TSH levels increased the risk of cancer in thyroid nodules and influenced its prognosis, particularly favoring lymph nodes metastases. On the other hand, no association was found between 25OHD levels and thyroid carcinoma risk or prognosis, suggesting that serum 25OHD determination may not contribute to risk assessment workup of thyroid nodules.

Vitamin D and cancer: does it really matter?

Purpose of review This article provides a background for an evidence-based decision regarding the prescription of vitamin D for cancer prevention and improvement of outcomes in oncology. Recent findings In 2014, Feldman and colleagues published a review suggesting a beneficial role for vitamin D in cancer development. In the same year, a Cochrane meta-analysis that included 18 randomized clinical trials comparing vitamin D administration versus no intervention in healthy population found no difference regarding cancer incidence between the groups. One year later, a phase III trial published in the New England Journal of Medicine did not show any protective effect of vitamin D against adenoma development. Summary Vitamin D is well known for its importance in calcium and phosphate homeostasis, being essential for bone mineralization. However, calcitriol, or 1,25-dyhydroxy-vitamin D3, is a multifunctional steroid hormone with many extra skeletal actions and may regulate signaling pathways related to cancer development and progression. In preclinical studies, it was shown that vitamin D can promote cell differentiation and inhibit proliferation, angiogenesis, and cell migration. Inconsistent results are found in epidemiological studies and early trials regarding clinical effects of vitamin D supplementation and cancer in terms of prevention and impact in cancer-related mortality.

Preventive medicine for von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.