Alcohol intake and risk of thyroid cancer in the NIH-AARP Diet and Health Study

Background:

Certain studies suggest that alcohol may reduce the risk of thyroid cancer in women, but the effect in men remains unclear.

Methods:

We analysed the association between alcohol and thyroid cancer in a large (n=490 159) prospective NIH-AARP Diet and Health Study with self-reported beer, wine, and liquor intakes.

Results:

Over 7.5 years of follow-up (median), 170 men and 200 women developed thyroid cancer. Overall, the thyroid cancer risk decreased with greater alcohol consumption (⩾2 drinks per day vs none, relative risk=0.57, 95% CI 0.36–0.89, P-trend=0.01).

Conclusions:

These results suggest a potential protective role for alcohol consumption in thyroid cancer.     

Thyroid cancer following nuclear tests in French Polynesia

Background:

Between 1966 and 1974, France conducted 41 atmospheric nuclear tests in Polynesia, but their potential health effects have not previously been investigated.

Methods:

In a case–control study, we compared the radiation exposure of almost all the French Polynesians diagnosed with differentiated thyroid carcinoma between 1981 and 2003 (n=229) to the exposure of 373 French Polynesian control individuals without cancer from the general population. Radiation exposures were estimated using measurements after the nuclear tests, age at time of each test, residential and dietary information.

Results:

The average thyroid dose before 15 years of age was about 1.8 mGy, and 5% of the cases and 3% of the controls received a dose above 10 mGy. Despite this low level of dose, and after adjusting for ethnic group, level of education, body surface area, family history of thyroid cancer and number of pregnancies for women, we observed an increasing risk (P=0.04) of thyroid cancer with increasing thyroid dose received before age of 15 years, which remained after excluding non-aggressive differentiated thyroid micro-carcinomas. This increase of risk per unit of thyroid radiation dose was higher (P=0.03) in women who later experienced four or more pregnancies than among other women.

Conclusion:

The risk estimate is low, but is based on limited exposure data. The release of information on exposure, currently classified, would greatly improve the reliability of the risk estimation.     

Clinical Efficacy of Targeted Biologic Agents as Second‐Line Therapy of Advanced Thyroid Cancer

Introduction.

Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established.

Methods.

We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant.

Results.

We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6–8.2), and median PFS (4.6 months; 95% confidence interval: 3.2–8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months).

Conclusion.

Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted 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.     

Personal history of rosacea and risk of incident cancer among women in the US

Background:

Rosacea is an inflammatory skin disease. We examined the association between personal history of rosacea and risk of incident cancers.

Methods:

A total of 75 088 whites were included from the Nurses'' Health Study II (1991–2011). Information on clinician-diagnosed rosacea and diagnosis year was collected in 2005. All cancers other than basal cell carcinoma (BCC) were confirmed.

Results:

During 1 447 205 person-years, we identified 5194 cases with internal malignancies and 5788 with skin cancers. We did not observe significant associations between personal history of rosacea and internal malignancies, except for thyroid cancer (hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.07–2.36). Among skin cancers, personal history of rosacea was associated with an elevated risk of BCC (HR=1.50, 95% CI=1.35–1.67).

Conclusions:

We suggest possible associations between personal history of rosacea and an increased risk of thyroid cancer and BCC. Further studies are warranted to replicate our findings and to explore the underlying mechanisms.     

Tyrosine kinase inhibitors rechallenge in solid tumors: a review of literature and a case description with lenvatinib in thyroid cancer

Introduction: In the last decade tyrosine kinase inhibitors (TKIs) have been employed for a wide range of hematological and solid tumors and today they represent a valid therapeutic option for different neoplasms. Among them, both sorafenib and lenvatinib were approved for the treatment of radioactive iodine (RAI) refractory differentiated thyroid carcinoma (DTC). Unfortunately, in some cases the efficacy of TKIs is limited by the onset of drug resistance after the initial response.

Areas covered: We report the case of a patient with a RAI refractory advanced DTC, treated with lenvatinib after surgery, multiple RAI administrations, traditional chemotherapy, and sorafenib. During treatment with lenvatinib, a noticeable response was detected by sequential computed tomography scans but, after 27 months, tumor progression became evident and led to lenvatinib interruption. In absence of any active treatment, a further disease progression was documented, and lenvatinib was re-administered obtaining a new objective response. Starting from this case report, we review available reports about the rechallenge with TKIs in solid tumors, discussing the possible mechanisms underlying the efficacy of this approach.

Expert commentary: Rechallenge with TKIs in solid tumors could be a therapeutic option in subjects with advanced and metastatic DTC who experience a progressive disease after initial response to lenvatinib.     

Baseline and lifetime alcohol consumption and risk of differentiated thyroid carcinoma in the EPIC study

Background:

Results from several cohort and case–control studies suggest a protective association between current alcohol intake and risk of thyroid carcinoma, but the epidemiological evidence is not completely consistent and several questions remain unanswered.

Methods:

The association between alcohol consumption at recruitment and over the lifetime and risk of differentiated thyroid carcinoma was examined in the European Prospective Investigation into Cancer and Nutrition. Among 477 263 eligible participants (70% women), 556 (90% women) were diagnosed with differentiated thyroid carcinoma over a mean follow-up of 11 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models.

Results:

Compared with participants consuming 0.1–4.9 g of alcohol per day at recruitment, participants consuming 15 or more grams (approximately 1–1.5 drinks) had a 23% lower risk of differentiated thyroid carcinoma (HR=0.77; 95% CI=0.60–0.98). These findings did not differ greatly when analyses were conducted for lifetime alcohol consumption, although the risk estimates were attenuated and not statistically significant anymore. Similar results were observed by type of alcoholic beverage, by differentiated thyroid carcinoma histology or according to age, sex, smoking status, body mass index and diabetes.

Conclusions:

Our study provides some support to the hypothesis that moderate alcohol consumption may be associated with a lower risk of papillary and follicular thyroid carcinomas.     

Gefitinib and Erlotinib in Metastatic Non‐Small Cell Lung Cancer: A Meta‐Analysis of Toxicity and Efficacy of Randomized Clinical Trials

Background.

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with metastatic and advanced non-small cell lung cancer (NSCLC). The U.S. Food and Drug Administration initially granted accelerated approval to gefitinib but subsequently rescinded the authorization. Erlotinib and afatinib are similar compounds approved for the treatment of metastatic NSCLC. The objective of this study was to compare the efficacy and toxicity of erlotinib, gefitinib, and afatinib in NSCLC.

Methods.

We tabulated efficacy variables including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) and quantitated toxicities and rates of dose reductions and discontinuation. Summary odds ratios were calculated using random and fixed-effects models. An odds ratio was the summary measure used for pooling of studies.

Results.

We examined 28 studies including three randomized trials with afatinib. Clinical toxicities, including pruritus, rash, anorexia, diarrhea, nausea, fatigue, mucositis, paronychia, and anemia, were similar between erlotinib and gefitinib, although some statistical differences were observed. Afatinib treatment resulted in more diarrhea, rash, and paronychia compared with erlotinib and gefitinib. Regarding efficacy, similar outcomes were recorded for ORR, PFS, or OS in the total population and in specific subgroups of patients between erlotinib and gefitinib. All three TKIs demonstrated higher ORRs in first line in tumors harboring EGFR mutations.

Conclusion.

Gefitinib has similar activity and toxicity compared with erlotinib and offers a valuable alternative to patients with NSCLC. Afatinib has similar efficacy compared with erlotinib and gefitinib in first-line treatment of tumors harboring EGFR mutations but may be associated with more toxicity, although further studies are needed. Gefitinib deserves consideration for U.S. marketing as a primary treatment for EGFR-mutant NSCLC.     

Preparation with recombinant humanized thyroid-stimulating hormone before radioiodine ablation after thyroidectomy: a systematic review

Background

Standard treatment for differentiated thyroid cancer is thyroidectomy followed in selected cases by radioiodine ablation (ra). Recombinant humanized thyroid-stimulating hormone (rhtsh) is an exogenous source of tsh that can be administered to obviate the need for hormone withdrawal. In this systematic review, we analysed the evidence for the therapeutic use of rhtsh for ra preparation.

Method

A systematic review of the medline and embase databases from 1996 through January 2008 selected articles reporting randomized controlled trials, cohort studies, and retrospective studies published in English that compared ra using rhtsh with standard hormone withdrawal.

Results and Interpretation

Stimulation by rhtsh is equivalent to thyroid hormone withdrawal in achieving ablation while avoiding detrimental symptoms of hypothyroidism and significantly lowering the whole-body radiation dose. Furthermore, rhtsh may be the only option for patients who either cannot raise endogenous tsh or who would be at risk from the morbidity of hypothyroidism. Based on the results of validated instruments of physical and mental performance, there is agreement that rhtsh maintains a better quality of life. Studies of cost-effectiveness found that rhtsh-prepared patients lost less time from work and required fewer encounters with health care providers.     

The role of fluorine-18-fluorodeoxyglucose positron emission tomography in evaluating the response to tyrosine-kinase inhibitors in patients with metastatic primary renal cell carcinoma

Background

Positron emission tomography-computed tomography (PET-CT) using fluorodeoxyglucose (FDG) is increasingly used in the evaluation of patients with advanced renal cell carcinoma (RCC), primarily for staging purposes. The aim of this paper is to perform a systematic review about the usefulness of PET-CT using FDG in response assessment after treatment with tyrosine-kinase inhibitors (TKIs) in patients with advanced RCC.

Materials and methods.

The scientific literature about the role of PET-CT using FDG in the assessment of response to treatment with TKIs in patients affected by advanced RCC was systematically reviewed.

Results

Seven studies about the role of PET-CT using FDG in the response assessment after treatment with TKIs (essentially sunitinib and sorafenib) in advanced RCC were retrieved in full-text and analysed, to determine the predictive role of this morpho-functional imaging method on patient outcome.

Conclusions

To date, the role of PET-CT using FDG in evaluating the response to TKIs in metastatic RCC patients is still not well defined, partly due to heterogeneity of available studies; however, PET-CT reveals potential role for the selection of patients undergoing therapy with TKIs. The use of contrast-enhanced PET-CT appears to be promising for a “multi-dimensional” evaluation of treatment response in these patients.     

Incidence of thyroid cancer in England by ethnic group, 2001–2007

Background:

Thyroid cancer incidence is increasing worldwide, but with large variations in incidence that may reflect either diagnostic bias or true ethnic differences. We sought to determine the effect of ethnicity on the incidence of thyroid cancer in England, a multiethnic population with a single health-care system.

Methods:

We analysed 11 263 thyroid cancer registrations with ethnicity obtained by linkage to the Hospital Episodes Statistics database. Incidence rate ratios (RRs) adjusted for age, sex and income were calculated for the six main non-White ethnic groups in England compared with Whites and to each other.

Results:

Thyroid cancer incidence was higher in all ethnic groups, except Indians, compared with Whites: in Pakistanis (RR 1.79, 99% floating confidence interval (FCI) 1.47–2.19); Bangladeshis (RR 1.99, 99% FCI 1.46–2.71); Black Africans (RR 1.69, 99% FCI 1.34–2.13); Black Caribbeans (RR 1.56, 99% FCI 1.25–1.93); and Chinese (RR 2.14, 99% FCI 1.63–2.80).

Conclusion:

The risk of thyroid cancer in England varies significantly by ethnicity. The elevated incidence in most ethnic minorities is unlikely to be due to diagnostic bias and warrants further investigation.     

Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway

Background:

A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival.

Methods:

Survival of breast cancer patients that received chemotherapy and xenograft tumour model was used to assess the effect of chemotherapy on fascin-positive and -negative breast cancer cells. Molecular and cellular assays were used to gain in-depth understanding of the relationship between fascin and chemoresistance.

Results:

We showed a significant correlation between fascin expression and shorter survival in breast cancer patients who received chemotherapy. In xenograft experiments, fascin-positive cancer cells displayed significantly more resistance to chemotherapy-mediated apoptotic cell death than fascin-negative counterparts. This increased chemoresistance was at least partially mediated through PI3K/Akt signalling, and was paralleled by increased FAK phosphorylation, enhanced expression of the inhibitor of apoptosis proteins (XIAP and Livin) and suppression of the proapoptotic markers (caspase 9, caspase 3 and PARP).

Conclusions:

This is the first report to demonstrate fascin involvement in breast cancer chemotherapeutic resistance, supporting the development of fascin-targeting drugs for better treatment of chemoresistance breast cancer.     

Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

Objectives

Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy.

Materials and Methods

Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded.

Results and Conclusion

PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control.     

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

Background:

Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest a progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such progression and identify novel therapeutic targets, we assessed the genome-wide expression in normal and tumour thyroid tissues.

Methods:

Microarray analyses of 24 thyroid carcinomas – 7 classic papillary, 8 follicular variants of papillary (fvPTC), 4 follicular (FTC) and 5 PDTC – were performed and correlated with RAS, BRAF, RET/PTC and PAX8-PPARG alterations. Selected genes were validated by quantitative RT–PCR in an independent set of 28 thyroid tumours.

Results:

Unsupervised analyses showed that gene expression similarity was higher between PDTC and fvPTC, particularly for tumours harbouring RAS mutations. Poorly differentiated thyroid carcinomas presented molecular signatures related to cell proliferation, poor prognosis, spindle assembly checkpoint and cell adhesion. Compared with normal tissues, PTC had 307 out of 494 (60%) genes over-expressed, FTC had 137 out of 171 (80%) genes under-expressed, whereas PDTC had 92 out of 107 (86%) genes under-expressed, suggesting that gene downregulation is involved in tumour dedifferentiation. Significant UHRF1 and ITIH5 deregulated gene expression in PDTC, relatively to normal tissues, was confirmed by quantitative RT–PCR.

Conclusion:

Our findings suggest that fvPTC are possible precursors of PDTC. Furthermore, UHRF1 and ITIH5 have a potential therapeutic/prognostic value for aggressive thyroid tumours.     

Does thyroid-stimulating hormone influence the prognosis of patients with endometrial cancer? A multicentre trial

Background:

Thyroid function has been suggested to interfere with tumour biology and prognosis in different cancers. The present study was performed to investigate the impact of pre-therapeutic serum thyroid-stimulating hormone (TSH) levels on the prognosis of patients with endometrial cancer.

Methods:

Pre-therapeutic serum TSH was investigated in 199 patients with endometrial cancer. After stratification in TSH risk groups, univariate and multivariable survival analyses were performed.

Results:

Elevated TSH was independently associated with poor disease-specific survival in univariate/multivariable survival analyses (P=0.01 and P=0.03, respectively).

Conclusion:

Thyroid-stimulating hormone may serve as a novel and independent prognostic parameter for disease-specific survival in patients with endometrial cancer.     

Overview and Management of Cardiac Adverse Events Associated With Tyrosine Kinase Inhibitors

Background.

Small-molecule tyrosine kinase inhibitors (TKIs) may provide an effective therapeutic option in patients with hematologic malignancies and solid tumors. However, cardiovascular (CV) events, including hypertension, heart failure, left ventricular systolic dysfunction, and QT prolongation, have emerged as potential adverse events (AEs) with TKI therapy.

Purpose.

We review what is known about the mechanism of action of CV AEs associated with TKI use and discuss therapeutic interventions that may prevent and manage these events in clinical practice.

Methods.

References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Search terms included “cardiac,” “cardiovascular,” “cancer,” and “kinase inhibitor.” Related links in the databases were reviewed, along with relevant published guidelines.

Results.

Although the link between rising blood pressure (BP) and CV AEs is observed but not proven, good clinical practice supports an aggressive policy on proper long-term BP management. There are insufficient data from randomized controlled clinical trials to show indisputably that aggressive or effective heart failure therapy in patients receiving TKIs will fundamentally change outcomes; however, clinical practice suggests that this is an effective long-term approach. Recognizing that QT prolongation is associated with TKI use facilitates identification of patients at high risk for this CV AE and increases awareness of the need for routine electrocardiograms and electrolyte monitoring for those receiving TKI treatment.

Conclusion.

Regular monitoring, early recognition, and appropriate interventions for CV AEs can help more patients derive the benefit of long-term TKI therapy.     

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors

Background:

Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers.

Methods:

In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib.

Results:

A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTc_females=404 ms vs QTc_males=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias.

Conclusions:

These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.     

Symptoms and Symptom Attribution Among Women on Endocrine Therapy for Breast Cancer

Background.

Adherence to adjuvant endocrine therapy (ET) influences breast cancer survival. Because ET side effects are frequently cited as reasons for nonadherence, understanding how perceptions and motivations in relation to ET are associated with symptom attribution can help promote timely symptom management.

Materials and Methods.

Participants were 2,086 breast cancer survivors recruited through the Army of Women registry who were current tamoxifen or aromatase inhibitor (AI) users. Participants reported whether they were bothered by each of 47 symptoms during the past month and whether they thought each symptom was related to taking ET. Frequencies of overall symptoms and symptoms attributed and misattributed to ET were calculated, and linear regression was used to assess sociodemographics, emotions, and illness perceptions as predictors of symptoms attributed to ET.

Results.

Women attributed a mean of 8.9 symptoms and misattributed a mean of 1.5 symptoms to ET. In the multivariable analysis, younger age, a more recent diagnosis, AI use (vs. tamoxifen), anxiety, depressive symptoms, more ET-related negative emotions, more concern about long-term ET use, and greater perceived ET necessity were independently associated with attribution of more symptoms to ET. More perceived ET necessity was associated with correctly attributing symptoms to ET, whereas higher depressive symptoms and more concern about ET use were associated with misattribution of symptoms to ET.

Conclusion.

Given that many women perceive a range of symptoms as a consequence of ET, attention to these symptoms may reduce symptom burden and improve quality of life, potentially improving ET adherence and optimizing survival.

Implications for Practice:

Many breast cancer survivors on endocrine therapy (ET) experience a range of side effects while taking ET. Targeting potentially modifiable factors associated with attributing a greater number of symptoms to ET, including perceived need for ET, concerns about long-term ET use, negative emotions toward ET, and symptoms of anxiety and depression, may reduce symptom burden and improve quality of life.