Tobacco smoking and risk of thyroid cancer according to BRAFV600E mutational subtypes.

OBJECTIVE: Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer. DESIGN AND PATIENTS: We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex. METHODS: Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias. RESULTS: We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99). CONCLUSION: We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers.

Risk of thyroid cancer following hysterectomy.

BACKGROUND: Hysterectomy has been associated with increased thyroid cancer risk but whether this reflects a biological link or increased diagnosis of indolent cancers due to greater medical contact remains unclear. METHODS: We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. Multivariable logistic regression was used to assess the association overall, and by tumour BRAF mutational status as a marker of potentially higher-risk cancers. We used causal mediation analysis to investigate potential mediation of the association by healthcare service use. RESULTS: Having had a hysterectomy was associated with an increased risk of thyroid cancer (odds ratio [OR] = 1.45, 95 % confidence interval [CI] 1.07-1.96). When stratified by indication for hysterectomy, the risk appeared stronger for those who had a hysterectomy for menstrual disorders (OR = 1.67, 95 % CI 1.17-2.37) but did not differ by tumour BRAF status. Approximately 20 % of the association between hysterectomy and thyroid cancer may be mediated by more frequent use of healthcare services. CONCLUSIONS: The observed increased risk of thyroid cancer among those with hysterectomy may be driven, at least partly, by an altered sex steroid hormone milieu. More frequent healthcare service use by women with hysterectomy accounts for only a small proportion of the association.

Obesity Is Associated with BRAFV600E-Mutated Thyroid Cancer.

Background: Thyroid cancer incidence has increased in many parts of the world since the 1980s, as has the prevalence of obesity. Evidence suggests that people with greater body size have higher thyroid cancer risk. However, it is unclear whether this association is causal or is driven by over-diagnosis of indolent cancers, because overweight/obese people use health services more frequently than those of normal weight, thus conferring greater opportunity for incidental diagnosis. Assessing whether obesity is associated with higher-risk thyroid cancers might help clarify this issue. Methods: We recruited 1013 people diagnosed with thyroid cancer between 2013 and 2016 and 1057 population controls, frequency matched by sex and age group. We used logistic regression to assess the association between body mass index (BMI) and overall thyroid cancer risk as well as by tumor BRAF mutational status as a marker of potentially higher-risk cancer. Results: Overall, obesity was associated with greater risk of thyroid cancer (odds ratio [OR] = 1.72; 95% confidence interval [CI 1.37-2.16] for obese vs. normal BMI). The association with obesity was significantly stronger for BRAF-mutation positive than BRAF-negative papillary thyroid cancers (PTCs; OR = 1.71 [CI 1.17-2.50] for BRAF-positive vs. BRAF-negative cancers). The increased risks associated with overweight/obesity did not vary by histological subtypes or presence/absence of adverse tumor histologic features. Conclusions: Greater risk of BRAF-mutated PTCs among those with high BMI suggests that the association may not merely reflect greater health care service use and indicates an independent relationship between obesity and clinically important thyroid cancer.

A Phase II Trial of the Multitargeted Tyrosine Kinase Inhibitor Lenvatinib (E7080) in Advanced Medullary Thyroid Cancer.

PURPOSE: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). EXPERIMENTAL DESIGN: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. RESULTS: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%-89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. CONCLUSIONS: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.

BACKGROUND: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC). METHODS: Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed. RESULTS: After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%). CONCLUSIONS: In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.

Validating the interval to biochemical failure for the identification of potentially lethal prostate cancer.

PURPOSE: To validate the interval to biochemical failure (IBF) as a prognostic factor at the time of biochemical failure for prostate cancer mortality (PCM) following radiotherapy (RT). PATIENTS AND METHODS: From a collaborative data set of men with clinically localized prostate cancer treated with RT from four institutions in three countries, we identified 1,722 men with biochemical failure (BF; prostate-specific antigen nadir + 2 ng/mL). The IBF was defined as the time interval from completion of treatment to the date of BF. The primary outcome measure was discriminatory power in the form of the concordance index (c-index). RESULTS: Seventeen percent of men had an IBF ≤ 18 months. Median potential follow-up beyond the time of BF was 67 months. There were 290 deaths from prostate cancer. The IBF was the most discriminating individual prognostic factor overall, with a sensitivity of IBF ≤ 18 months to predict PCM within 10 years of 48.4% (95% CI, 43.3% to 54.1%); the specificity was 86.1% (95% CI, 84.5% to 87.7%), equating to a c-index of 0.611 (95% CI, 0.578 to 0.647). The 5-year cumulative incidence of PCM for IBF more than 18 months versus IBF ≤ 18 months was 9.4% (95% CI, 7.7% to 11.5%) versus 26.3% (95% CI, 21.2% to 31.8%); corresponding 10-year estimates were 26.2% (95% CI, 21.5% to 30.8%) versus 55.9% (95% CI, 48.9% to 63.0%), respectively (P < .001 for both). IBF exhibited minimal change in performance across various follow-up durations. CONCLUSION: IBF is the single most robust prognostic factor for PCM following RT without androgen deprivation therapy. This external validation demonstrates that patients and clinicians can use this information to make decisions about subsequent treatments.

Clinicopathological report: bilateral choroidal metastases from papillary thyroid cancer.

Bilateral uveal metastases from papillary thyroid carcinoma are extremely rare. A 36-year-old woman with a 12-month history of papillary thyroid carcinoma presented with sudden loss of visual acuity and fields in the left eye. An examination and B-scan revealed a large, solid choroidal lesion in the left eye causing exudative retinal detachment. A small solid mass was also observed in the right eye fundus. Following left eye enucleation, immunohistopathology confirmed metastatic papillary thyroid carcinoma. The authors report the third known case of bilateral choroidal metastases.

Confirmation of a low α/ß ratio for prostate cancer treated by external beam radiation therapy alone using a post-treatment repeated-measures model for PSA dynamics.

PURPOSE: To estimate the α/ß ratio of prostate cancer treated with external beam radiation only by use of a model of long-term prostate-specific antigen (PSA) dynamics. METHODS AND MATERIALS: Repeated measures of PSA from 5,093 patients from 6 institutions treated for localized prostate cancer by external beam radiation therapy (EBRT) without planned androgen deprivation were analyzed. A biphasic linear mixed model described the post-treatment evolution of PSA, rather than a conventional model of time to biochemical recurrence. The model was adjusted for standard prognostic factors (T stage, initial PSA level, and Gleason score) and cohort-specific effects. The radiation dose fractionation effect was estimated from the long-term rate of rise of PSA level. RESULTS: Adjusted for other factors, total dose of EBRT and sum of squared doses per fraction were associated with long-term rate of change of PSA level (p = 0.0017 and p = 0.0003, respectively), an increase of each being associated with a lower rate of rise. The α/ß ratio was estimated at 1.55 Gy (95% confidence band, 0.46-4.52 Gy). This estimate was robust to adjustment of the linear mixed model. CONCLUSIONS: By analysis of a large EBRT-only cohort along with a method that uses all the repeated measures of PSA after the end of treatment, a low and precise α/ß was estimated. These data support the use of hypofractionation at fractional doses up to 2.8 Gy but cannot presently be assumed to accurately represent higher doses per fraction.

Radiotherapy for perineural invasion in cutaneous head and neck carcinomas: toward a risk-adapted treatment approach.

BACKGROUND: We retrospectively reviewed outcomes in patients treated with radiotherapy (RT) for cutaneous head and neck carcinoma with perineural invasion (PNI), with the aim of developing risk-adapted treatment guidelines. METHODS: A total of 118 patients were treated with RT between April 1992 and July 2000. Ninety-seven patients had PNI discovered through histology (pPNI) and 21 patients had symptoms/signs of PNI (cPNI). All received RT (median dose, 55 Gy; range, 17-74): 114 postoperatively and 4 definitively. Median follow-up was 84 months (range, 4-201). RESULTS: The 5-year local control (LC) rates were 90% with pPNI and 57% with cPNI (p < .0001). The pPNI and cPNI groups also differed in relapse-free survival (76% vs 46%, p = .003), disease-specific survival (90% vs 76%, p = .002), and overall survival (69% vs 57%, p = .03). pPNI patients with BCC histology (n = 42) had better LC (97% vs 84%, p = .02) than pPNI SCC (n = 55). CONCLUSION: Surgery plus RT provides a high rate of LC in patients with pPNI, particularly those with BCC. Therapeutic improvements are needed for patients with cPNI.

Psychosocial impact of newly diagnosed advanced breast cancer.

The purpose of this study was to delineate the key emotional concerns of women newly diagnosed with recurrent or metastatic breast cancer. Sixty-six women diagnosed with metastatic breast cancer within the previous 6 months, receiving treatment at the Medical Oncology Departments of two metropolitan teaching hospitals, completed measures of HADS, IES, CARES-SF and Memorial Symptom Assessment Scale, and participated in a semi-structured interview. There were high levels of psychological morbidity, 56.7% of women younger than 55 years qualifying as "cases" on the HADS, compared with 34.5% of women aged over 55 years. The total HADS score was significantly correlated with the Global and Physical Subscales of the MSAS and CARES. Women younger than 55 years had significantly higher levels of intrusive and avoidant symptoms than women over 55 years. Women also reported high numbers of physical symptoms. Key themes which emerged during the interviews were: difficulties in communicating with doctors, perceived delay in diagnosis, the emotional impact, concerns about the family, feelings about why the cancer developed, other life stress and trauma, and use of non-prescribed treatments.

Evaluating patient education materials about radiation therapy.

Targeted treatment education for cancer patients has the potential to promote adjustment through assisting patients to participate in treatment decision making, comply with treatment regimens and cope more effectively with treatment side effects. A quasi-experimental longitudinal pre-test post-test and follow-up design was used to assess the effect of a patient education video about radiation therapy on patients' psychological distress, knowledge about radiation therapy, self-efficacy about coping with treatment and physical symptoms. Patients with head and neck (n=26) and breast cancer (n=66) were recruited into the study and allocated into control and intervention groups. No significant differences were found between the control and intervention groups on any of the outcome variables. However, patients in the intervention group reported high levels of satisfaction with the video and all reported that they would recommend the video to other patients preparing for radiation therapy. As well, 90% of patients in the intervention group reported that some or all of the information in the video was new to them. Education materials that have excellent face validity and that are well received by patients may fail to produce significant change using standard controlled study designs. Future research in this area may need to consider alternative paradigms for evaluating the helpfulness of such materials.

The management of perineural spread of squamous cell carcinoma to the ocular adnexae.

PURPOSE: To analyze a series of patients with periorbital perineural spread of squamous cell carcinoma and propose treatment guidelines. METHODS: Retrospective, noncomparative, interventional case series of 17 patients with clinical, radiologic, or histologic evidence of distant perineural spread. Treatment, recurrence, progression, and mortality rates were recorded. RESULTS: Numbness and pain were the most common symptoms, whereas ophthalmoplegia, ptosis, and facial palsy were the most frequent signs. All cases received wide-field radiotherapy to at least 50 Gy. Chemotherapy and surgery (biopsy, debulking, exenteration) were used in selected cases. Disease progression occurred in 6 patients, 4 of whom died. Median disease-free survival in the remainder was 37.5 months. CONCLUSIONS: The diagnosis of perineural spread is largely clinical and may be confirmed with imaging findings in the majority of cases. The role of biopsy is usually complementary but may be essential in some cases. In patients with evidence of distant perineural spread, radiotherapy volumes inclusive of potential antegrade and retrograde spread are recommended. Three-dimensional conformal planning or intensity-modulated radiation therapy assists in minimizing damage to adjacent structures. Synchronous chemotherapy should be considered to potentiate the effectiveness of radiation. The place of surgery in the treatment of perineural spread is palliative.

Dosimetry and toxicity of Quadramet for bone marrow ablation in multiple myeloma and other haematological malignancies.

Standard treatment regimens for haematological malignancies include myeloablative chemoradiotherapy and subsequent rescue by stem cell transplantation. However, these treatment regimens have significant associated mortality and morbidity, and disease recurrence remains a problem. One alternative approach is the targeted delivery of radiotherapy to the marrow using a bone-seeking agent labelled with an appropriate radioisotope, with the aim of delivering a potentially ablative radiation dose to marrow while minimising non-haematological toxicity. Pharmacokinetics and radiation dosimetry for a commercial preparation of samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet) were evaluated in 43 tracer (average dose 740 MBq) studies of 42 patients with haematological malignancies. Measurements of 24-h retention were also available following infusion of 18-48 GBq in 15 patients. Quadramet cleared rapidly from the tissue, with a median biological half-life of 1.4 h. Activity taken up by the skeleton was firmly bound, with activity decreasing according to physical half-life at 24 h in 29 of the 43 cases. The percentage activity retained in the skeleton at 24 h with tracer doses was high (62%+/-13%), although this decreased to approximately 30% with therapy infusions. Because of this decrease in retention, the maximum feasible therapy activity for this formulation of Quadramet is 35 GBq. Median absorbed marrow radiation dose was 0.78 Gy/GBq in tracer studies: the decreased retention at high activities means that this corresponds to a median dose of 12 Gy for 35 GBq administered activity. It is possible to use 24-h retention as a rough guide to marrow dose in individual patients. In tracer studies, median bladder radiation dose was 0.22 Gy/GBq and radiation dose to the liver was very conservatively estimated at 0.2 Gy/GBq. After therapy infusions of up to 50 GBq in 37 patients, non-haematopoietic toxicity was not seen in any patient. In addition, myelosuppression was achieved without evidence of myelofibrosis. The residual dose rate to marrow fell to a level acceptable for stem cell re-infusion by 2 weeks after administration.