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Background In the randomized phase III SELECT study, LEN demonstrated a significant prolongation of progression-free survival compared with placebo (PBO) in pts with RR-DTC. There was no significant difference in overall survival (OS) between LEN and PBO arms which was likely due to > 80% of pts on the PBO arm crossing over to open-label LEN treatment. This exploratory post hoc analysis investigated the impact of measurable lung metastasis on OS from the SELECT study. Methods The hazard ratio (HR) for OS (data cutoff, September 1, 2016) and the 95% CIs were estimated using the Cox proportional hazards model. The influence of various baseline characteristics on OS was analyzed using a multivariate analysis based on a Cox proportional hazards model. Subgroup analysis of OS was conducted based on maximum size of measurable lung metastasis (≥ 1 cm per RECIST 1.1) at baseline. Results In the overall population (392 pts), median OS of LEN (261 pts) and PBO (131 pts, with 115 pts crossed over to LEN) arms, were 40.3 months (M) and 34.5 M, respectively (hazard ratio [HR] 0.87, 95% CI 0.66 –1.15, P = 0.3170). In 306 pts with lung metastasis of ≥ 1.0 cm, significant prolongation of OS was observed with LEN (199 pts) compared with PBO (107 pts, with 95 pts crossed over to LEN) (HR 0.63, 95% CI 0.47–0.85, P = 0.0025). This was maintained after adjustment for baseline characteristics in the multivariate model. Similar trends of OS prolongation by LEN were observed in pts with lung metastasis of ≥ 1.5 cm, ≥ 2.0 cm, and 1.0–2.0 cm (Table). Conclusions In pts with lung metastasis of ≥ 1.0 cm, LEN significantly prolonged OS compared to pts treated by PBO including those crossed over to LEN. This post-hoc analysis suggests that RR-DTC pts with lung metastasis could be candidates for targeted therapy. Table . 1862PD Overall survival by size of measurable lung metastasis at baseline Lung Lesion Number of Pts Median OS (M) HR 95% CI P Value LEN PBO LEN PBO ≥1.0 cm 199 107 44.7 33.1 0.63 0.47 – 0.85 0.0025 ≥1.5 cm 150 84 44.1 22.3 0.63 0.45 – 0.89 0.0082 ≥2.0 cm 94 58 34.7 19.3 0.65 0.44 – 0.98 0.0383 1.0–2.0 cm 105 49 49.2 38.6 0.63 0.40 – 0.99 0.0438 *≥ 1 cm per RECIST 1.1 Clinical trial identification NCT01321554; Release date: December 30, 2016. Editorial acknowledgement Oxford PharmaGenesis, Newtown, PA, USA; Funded by Eisai Inc. Legal entity responsible for the study Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure M. Tahara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Merck Serono; Honoraria (self): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Boehringer-Ingelheim; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Novartis. N. Kiyota: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Astra-Zeneca; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Chugai Pharmaceutical. A..O. Hoff: Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Astra-Zeneca; Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genzyme. T.K. Owonikoko: Advisory / Consultancy, Research grant / Funding (institution): Novartis, Celgene, Bayer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune, Abbvie; Advisory / Consultancy, Research grant / Funding (institution): G1 Therapeutics, Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Amgen, Loxo/Lilly; Research grant / Funding (institution): Astellas, Stemcentrx, Regeneron, Corvus Pharmaceuticals; Research grant / Funding (institution): United Therapeutics, Fujifilm, Pfizer; Research grant / Funding (institution): Aeglea Biotherapeutics, Incyte, Merck; Advisory / Consultancy: Sandoz, Eisai, Takeda, Seattle Genetics; Advisory / Consultancy: BerGenBio, PharmaMar, Boehringer Ingelheim; Advisory / Consultancy: EMD Serono, Xcovery; Advisory / Consultancy: Heron Pharmaceuticals, Armo BioSciences; Shareholder / Stockholder / Stock options: Cambium Oncology. C.E. Dutcus: Full / Part-time employment: Eisai Inc.. T. Suzuki: Full / Part-time employment: Eisai Co., Ltd. M. Ren: Full / Part-time employment: Eisai Inc.. S. Misir: Full / Part-time employment: Eisai Inc. L.J. Wirth: Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Loxo; Advisory / Consultancy: Merck. All other authors have declared no conflicts of interest.

6082 Background: Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by a high rate of distant recurrence. Systemic therapy has generally failed to produce durable benefit. Radiation (RT) is used for localized disease and as directed treatment for metastases. Here, we report the safety and efficacy of pembrolizumab (pembro) administered with or without hypofractionated RT in a phase II randomized study. Methods: Eligible patients (pts) had recurrent or metastatic ACC with evidence of progressive disease (PD) within the last 12 mos and >=1 measurable non-CNS lesion, along with 1-5 additional lesions deemed appropriate for RT to 30 Gy in 5 fractions. Pts were randomized to pembro alone (200 mg IV q3 weeks) or in combination with RT given within 7 days of cycle 1, day 1. The primary endpoint was objective response rate (ORR) outside the RT field by RECIST 1.1. Using a parallel two-stage design, if >=1 response out of 10 was observed in either arm, 10 more pts would be enrolled to that arm. If >=3 responded, the null hypothesis (ORR=5%) would be rejected in favor of a 25% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses of tumor growth rate (TGR) excluding RT lesions and immune biomarkers were exploratory. Results: Ten pts per arm were randomized into the trial’s first stage with median age 65 (45-79). No objective responses were seen. Stable disease (SD) was observed in 13 pts; 6 had PD as best response, 1 was unevaluable. Median PFS was 7 mos 95% CI (3 - 13 mos), with 9 pts without progression at 6 mos. 3 pts remain on study treatment (range 8-11 mos). In pts with SD, TGR decreased by >25% in 7 of 12 pts and by >75% in 4 pts. There was no difference in likelihood of SD or PFS between arms. Treatment related AEs (TRAEs) occurred in 18 pts but there were no G3-5 TRAEs. Among 8 biopsies analyzed, PD-L1+ tumor/immune cells ranged from 12-52%. Conclusions: Pembro alone or with hypofractionated RT was well tolerated. We observed no objective responses, but 65% of pts with PD prior to study entry achieved SD, the majority with decreased TGR, and 15% had prolonged SD. Additional strategies are needed to further delay progression and effect response. Clinical trial information: NCT03087019.

6087 Background: Systemic therapies targeting specific genomic alterations in advanced MTC are available or under investigation. The Afirma Genomic Sequencing Classifier (GSC) uses RNA sequencing to assess FNA specimens from cytologically indeterminate thyroid nodules, which are also tested for specific molecular aberrations associated with thyroid cancer via a suite of highly accurate malignancy classifiers. This suite can be applied independently to Bethesda V/VI nodules. The Afirma Xpression Atlas (XA) is an additional test that can be combined with Afirma GSC to report nucleotide variants and fusions across 511 cancer-associated genes. Here we report the prevalence and genomic landscape of MTC classifier positive (MTC+) FNA samples. Methods: All Afirma GSC and malignancy classifier tests run in the Veracyte Clinical Laboratory between July 2017 and January 2019 were deidentified and examined for MTC+ cases. Afirma XA was run on all such cases, and all variants and fusions were tabulated. Results: Examination of 29,895 FNAs revealed 90 MTC cases. Of 22,793 Bethesda III cases, 32 (0.14%) were MTC+. Of 5,491 Bethesda IV cases, 33 (0.60%) were MTC+. Provider-ordered testing was done on an additional 16 and 9 MTC cases from Bethesda V and VI nodules, respectively. 58% of all MTC+ samples harbored a RET variant (+/- others), 9% contained a KRAS variant (+/- others), 6% included an HRAS variant, 1% had a BRAF fusion, 1% demonstrated other fusions, and 26% held no variant/fusion. Conclusions: In our cohort, Afirma XA identified a variant or fusion in 74% of MTC+ FNAs. Currently approved or investigational therapies exist for cancers with RET, BRAF and HRAS alterations, suggesting that 64% of our series might be eligible for treatment based on genomic information from FNA. In advanced MTC, noninvasive FNA sample collection at the time of diagnosis may ultimately impact on targeted therapy selection, with the option to repeat FNA testing should the disease progress. Future studies may investigate how finding a genomic alteration by FNA can inform the management of MTC and, in the case of progressive disease, improve our understanding of the mechanisms of disease progression and drug resistance.

TPS6098 Background: Notch signaling plays a key role in tumorigenesis. Notch cleavage by γ-secretase frees the Notch intracellular domain, which promotes the expression of target genes involved in cancer. AL101, a small molecule, is a γ-secretase inhibitor that potently inhibits Notch1-4, resulting in robust antitumor activity in vivo (PMID 26005526), including ACC xenograft models with Notchact mut (Ferrarotto, AACR 2019, Abstr 4885). Three P1 trials tested AL101 as monotherapy or in combination regimens in > 200 solid/hematologic cancer pts. In the P1 trial of AL101 monotherapy, conducted in 94 pts with advanced/metastatic solid tumors refractory to standard therapies (Tx), AL101 was generally well tolerated, with manageable AEs, and the recommended P2 dose was 4 mg IV once weekly (QW; El-Khoueiry, ASCO 2018, Abstr 2515). 4 pts had objective responses, 2 of those had Notchmut (1 of which had ACC). ACC, a rare cancer that most commonly develops in the major salivary glands, but can also arise in minor salivary glands in the trachea, lacrimal gland, and other sites, is refractory to chemotherapy, with a high recurrence rate. Notchact mut are found in a subset of ACC pts (11%–22%), with particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC pts (PMID 27870570). Methods: ACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4 mg IV QW) in pts with R/M ACC (bone-exclusive disease included) with known Notch1-4act mut. Pts with disease progression within 6 months of enrollment or newly diagnosed metastatic pts are allowed; pts who received > 3 prior systemic Tx are excluded. Primary endpoint: ORR by RECIST v1.1 (or modified MDA bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per the Simon optimal design, 12 pts are enrolled in stage 1; if ≥2 pts respond, 24 additional pts are enrolled in stage 2. If ≥4 pts in stage 2 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. 4 of planned 36 pts have been enrolled as of 2/12/19. Clinical trial information: NCT03691207.

6081 Background: In SELECT, lenvatinib significantly improved progression-free survival (PFS) of pts with RR-DTC versus placebo (18.3 v 3.6 months; hazard ratio [HR]: 0.21 [99% CI: 0.14, 0.31]; P60 mm versus tumor size ≤60 mm (HR [95% CI]: 1.450 [0.708, 2.967]). Additional results are summarized in the table. Conclusions: Among pts with RR-DTC, PFS, OS, ORR, and time to ECOG ≥2 were generally better for patients with lower ECOG PS or smaller tumor size at baseline. These results may indicate that it is beneficial to start lenvatinib in pts with RR-DTC early, before ECOG PS worsens and tumor size increases. Clinical trial information: NCT01321554. [Table: see text]

2590 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 & 11. RRP proliferates in the squamous epithelium lining the respiratory tract impacting breathing, swallowing, and voice and carries a 3-5% risk of malignant transformation. Given the multi-focality of the disease and tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of systemic pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts > 12 years of age were treated with pembro 200mg every 3 weeks. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease response out of 21 (assuming > 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). HPV-specific CD8+ T cell frequency and functional states and biomarkers of response and immune resistance are being evaluated in serial tissue and liquid biopsies (up to 8 biopsies/patient over the 24 months of treatment). Results: The Simon two-stage, stage 1 criteria was met. A total of 21 patients were enrolled and all are now off treatment. Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. 48% (10/21) had Juvenile-onset (Jo)-RRP, 57% (12/21) had pulmonary RRP involvement, and 19% (4/21) had SCC derived from their RRP. 62% (13/21) completed 24 months of treatment. Reasons for discontinuation included disease progression (14%, 3/21), treatment related adverse event (TRAEs) (14%, 3/21), and study withdrawal (10%, 2/21). A partial response (≥25% reduction in endoscopic tumor burden score) was observed in 57% (12/21) (95% CI: 34%-78.2%) of pts (7 of 10 with Jo-RRP and 5 of 11 with Adult-onset (Ao)-RRP disease responded). Stable disease was observed in 33% (7/21). No complete responses were observed. Fatigue was the most frequent TRAEs; Grade 3 TRAEs included uveitis and hypophysitis, both of which were reversible upon pembro discontinuation and steroid use. At a median follow-up: 25.6 (6.2-38.1 months), the mean number of surgical interventions was reduced by 7 surgeries/year (p = 0.004) in pts treated on the trial for > 12 months, and, upon treatment completion, durable clinical benefit was observed with no additional treatment needed for the duration of the clinical trial follow-up for some pts. Conclusions: Pembro reduces the need for routine surgical interventions based on the durable response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.

Thyroid cancer is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising ~93% of all thyroid cancers. While most cases of DTC are curable with the use of surgery and radioactive iodine (RAI) ablation of the remaining thyroid remnant, prognosis is dire and treatment options limited when DTC becomes RAI-refractory (RAI-R). Standard cytotoxic chemotherapy has limited efficacy, making enrollment in clinical trials of novel targeted therapies the preferred treatment approach. Thus, we conducted a comprehensive systematic review of the clinical trial scientific literature with a focus on efficacy, safety, and economics to identify all potential treatment options that have been or are currently being evaluated for the treatment of RAI-R DTC.Embase.com (including Medline), Medline In-Process and other nonindexed citations, the Cochrane Libraries, ClinicalTrials.gov, and relevant recent conference proceedings were searched using predefined search criteria. Important inclusion criteria included English language, randomized controlled studies or interventional single-arm studies only, and studies of drug therapies only. Search results were screened utilizing the discretion of multiple researchers, and key data were abstracted.Forty-five unique trials (16 full-text, 4 conference abstracts, and 25 ClinicalTrials.gov entries) were included in the clinical review. No studies that met criteria for inclusion in the economic review were identified. Among 20 trials with results available, all were Phase II and only one was randomized. The most commonly studied drugs were tyrosine kinase inhibitors (TKIs); other drugs included celecoxib, doxorubicin with interferon alpha-2b, rosiglitazone, selumetinib (AZD6244), thalidomide, VEGF trap, and vorinostat. Overall, efficacy and safety profiles were specific to treatment regimen, with objective response rates (ORR) ranging from 0% on gefitinib, rosiglitazone, VEGF trap, and vorinostat to 50% on lenvatinib, a TKI.Limited clinical research and no economic research has been conducted in RAI-R DTC. Certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo-controlled trials are ongoing. New research on the economic and humanistic burden of RAI-R DTC must be paired with the clinical evidence currently in development to examine the existing burden and future promise in treating patients with RAI-R DTC.

A 52-year-old woman was seen in the thyroid clinic of this hospital because of a mass in the neck. Imaging revealed abnormal cervical lymph nodes and two thyroid nodules with calcifications. A diagnostic procedure was performed.

Purpose: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland cancers for which cytotoxic chemotherapy has limited efficacy. We investigated whether genotyping analysis could detect novel tumor-specific mutations that would help direct SDC patient treatment using targeted agents. Experimental Design: We genotyped 27 SDC archival specimens from patients followed at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary (Boston, MA) between 2000 and 2011. These included the tumors of 8 patients who were tested prospectively. Targeted mutational analysis of 13 clinically relevant cancer genes was conducted using SNaPshot multiplexed genotyping. FISH was conducted to detect HER2 gene amplification. Patient medical records and tumor histopathologic features were retrospectively reviewed. Results: Mutually exclusive genetic aberrations were detected in 15 of 27 (56%) tumors, including 2 (7%) mutations in BRAF, 5 (19%) mutations in PIK3CA, and 8 (30%) cases of HER2 gene amplification. To our knowledge, this is the first time that BRAF and PIK3CA mutations have been reported in this tumor type. Prospective clinical testing of 8 patients with SDC identified actionable genetic alterations in 6 tumors and influenced therapeutic decisions for all 6 patients. Conclusion: SNaPshot molecular profiling identified novel genetic changes in SDCs, expanded the therapeutic options for patients with this rare tumor, and is changing SDC management at our institution. These findings highlight the importance of using broad-based genetic profiling to expedite the identification of effective-targeted therapies for patients with rare malignancies. Clin Cancer Res; 19(2); 480–90. ©2012 AACR.

Background: Duligotuzumab, a novel dual -action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody -dependent cell -mediated cytotoxicity. High tumor -expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. Methods: This multicenter, open -label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1 high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1 w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) status]. Results: Patients (N =121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 years; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression -free survival [4.2 vs. 4.0 months; HR: 1.23 (90% confidence interval (Cl): 0.89-1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% Cl: 0.81-1.63)], and objective response rate (12 vs. 14.5%), with no difference between patients with NRG/ -high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade >3 adverse events (AEs) (duligotuzumab vs. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10 vs. 16%); any grade rash -related events were less with duligotuzumab (49 vs. 67%). Conclusion: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRGI, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab.

Early-stage and intermediate-stage nasopharyngeal cancer (NPC) generally carry a good prognosis, but for patients with recurrent, metastatic disease, options are limited. In the current study, the authors present a phase 1/2 study to evaluate the efficacy of Epstein-Barr virus (EBV)-stimulated cytotoxic T-lymphocyte (EBV-CTL) immunotherapy in this patient population.Screening for patients with active, recurrent, metastatic EBV-associated NPC began in February 2007, and the study was closed to accrual in January 2012. After informed consent was obtained, patients had their blood drawn to initiate manufacturing of the EBV-CTL product. During product manufacturing, patients were placed on interim standard-of-care chemotherapy, and only after disease progression on the interim chemotherapy did patients receive investigational immunotherapy. Patients were restaged every 2 months until disease progression and then followed for survival.A total of 28 patients were enrolled, and 21 patients were treated. There was 1 complete response achieved, and at the time of last follow-up, the patient had been in remission for8 years since treatment. The median progression-free survival was 2.2 months, and the median overall survival was 16.7 months. Two other patients, after failing EBV-CTL immunotherapy, unexpectedly demonstrated strong responses to the chemotherapy regimens they had previously failed. Patient EBV viral load and EBV-CTL specificity for tumor-associated viral antigens did not appear to correlate with clinical response.A durable response was observed with EBV-CTL immunotherapy, but the overall response rate for patients with recurrent, metastatic NPC was low. Further research is necessary to increase the efficacy of EBV-specific immunotherapy in patients with incurable NPC, and to characterize mechanisms for refacilitation to chemotherapy. Cancer 2017;123:2642-50. © 2017 American Cancer Society.

Summary Background About half of patients with papillary thyroid cancer have tumours with activating BRAF V600E mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF -positive melanoma, showed clinical benefit in three patients with BRAF V600E -positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF V600E -positive papillary thyroid cancer. Methods We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF V600E mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. Findings Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2–26·0) in cohort 1 and 12·0 months (6·7–20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2–59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased γ-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. Interpretation Vemurafenib showed antitumour activity in patients with progressive, BRAF V600E -positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. Funding F Hoffmann-La Roche.

This phase 2 estimation study evaluated docetaxel/cisplatin with/without panitumumab, an anti-epidermal growth factor receptor monoclonal antibody, as first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).Randomized patients received docetaxel/cisplatin (75mg/m(2) each) with/without panitumumab (9mg/kg) in 21-day cycles. Patients randomized to panitumumab+chemotherapy could continue panitumumab monotherapy after completing six chemotherapy cycles without progression; patients randomized to chemotherapy alone could receive second-line panitumumab after progression. Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall survival (OS), overall response rate (ORR), time to response (TTR), duration of response (DOR), and safety. A protocol amendment limited enrollment to patients70years owing to excess toxicity in older patients and added mandatory pegfilgrastim/filgrastim support. Outcomes were also analyzed by human papillomavirus status.103 of the 113 enrolled patients were evaluable and randomized to receive ⩾1 dose of first-line treatment. Median PFS for panitumumab+chemotherapy was 6.9 (95% CI=4.7-8.3) months versus 5.5 (95% CI=4.1-6.8) months for chemotherapy alone (hazard ratio [HR]=0.629; 95% CI=0.395-1.002; P=0.048). ORR for panitumumab+chemotherapy was 44% (95% CI=31-58%) versus 37% (95% CI=24-51%) for chemotherapy alone (odds ratio [OR]=1.37; 95% CI=0.57-3.33). Median OS for panitumumab+chemotherapy was 12.9 (95% CI=9.4-18.5) months versus 13.8 (95% CI=11.8-22.9) months for chemotherapy alone (HR=1.103; 95% CI=0.709-1.717). Median TTR for panitumumab+chemotherapy treatment was 6.9weeks versus 11.0weeks for chemotherapy alone. Median DOR was 8.0 (95% CI=5.7-11.1) months with panitumumab+chemotherapy versus 5.1 (95% CI=4.4-7.2) months with chemotherapy alone. Grade 3/4 adverse event incidence was 73% with panitumumab+chemotherapy versus 56% with chemotherapy alone. 41% and 55% of patients in the panitumumab+chemotherapy and chemotherapy-alone arms, respectively, received panitumumab monotherapy.The addition of panitumumab to docetaxel/cisplatin may improve PFS in recurrent/metastatic SCCHN and has the potential to improve outcomes in these fully, or mostly, active patients.

A 49-year-old man had fever, pain, and cranial-nerve deficits 4 days after completion of chemoradiation for squamous-cell cancer of the oral cavity. Imaging revealed dural thickening and abnormalities of the cavernous sinuses and skull base.

Introduction: Epidemiologic observations have suggested a protective effect of soybeans against a number of epithelial cancers including oral malignancies and by inference precursor lesions such as leukoplakia. Several compounds in soybeans have shown activity in preclinical models; we have focused our studies on BBI (Bowman-Birk inhibitor), which is active against the protease chymotrypsin. Our phase I trial demonstrated a very low toxicity profile and a 31% response rate in a 1-month nonrandomized study that was associated with favorable modulation of protease activity and neu oncogene in exfoliated buccal mucosal cells (EBMC). Methods: An intent-to-treat(ITT) randomized placebo (Quaker mass harina, a corn flour)-controlled, double-blind clinical trial of a soybean concentrate (C) of BBI (600 C.I. units) was performed in a multinstitutional investigation (7 sites). The study duration was 6 months and included pre/interim/postevaluation of lesions sizes and pre/post photographic assessments and oral mucosa biopsies(with post central pathology review) of the involved area(s). Intermediate biomarkers (IBM) included serial measurements of EBMC neu protein (ng/mg) and protease (Delrfu/min/ug protein) and serum neu protein (ng/ml). 325 patients underwent preliminary screening and 148 per protocol eligible were enrolled. Of these, 132 were randomized and 105 completed 6 months on study. All data on lesion sizes, photo judgments, and pathology indications of degree of abnormality or change in abnormality were entered into SAS datasets and subjected to 100% verification against the crf forms by the statistician. The several IBM measurements were converted from the original Microsoft Excel sheets into SAS data sets, and subject to spot checks against the original spreadsheets. Similarly, host-factor information from the questionnaires was spot checked against the original records. In all cases, the primary, per-protocol analyses was ITT. The per-protocol, intent-to-treat cohort, and all other categorizations of study participants will also be described with appropriate descriptive summary measures. Results: The ITT data set is composed of all those with valid, two-dimensional measurements on all lesions observed at both the randomization and 6-month visit. 89 evaluable patients met these criteria: 43 in the treatment and 46 in the placebo group. For the BBIC group, the mean relative percent change in total lesion area was −20.6% and for the placebo group −17.1%. Clinical responses for the 89 patients were: four showed a complete response (4.5%), 22 showed a partial response (25%), 53 showed stable disease (60%), and 10 showed disease progression (11.2%). For the drug group the CR+PR(>50% change) was 27.91% and for placebo group 30.43%. Neither the lesion size nor response comparisons demonstrated differences between the two groups that were significantly different (p>0.05). Photos of the same lesion at baseline and at the 6-month exam were available for 91 participants. Five qualified reviewers made judgments of the degree of change in abnormality on a seven-point scale, blinded to study arm and timepoint of photos. For mean comparison scores, 1 was substantial improvement over time, 4 indicated no change and 7 meaning much worse decline over time. Preliminary assessments of 77% of the patients having pre/post photos indicates that there were no significant differences between the placebo and treatment groups. Conclusion: BBIC is not effective as a chemoprevention agent for the management of oral leukoplakia. Central pathology review by two reviewers is near completion, but is unlikely to affect this conclusion. Final measurements of the three biomarkers should be available by the time of presentation and subanalysis will be presented for the two groups and for the patients who seemed to have had a clinical response. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN02-05.

102Background: Multikinase inhibitors (MKIs) have limited activity in RET fusion-positive (+) and RET-mutant cancers, questioning the therapeutic potential of these targets. LOXO-292 selectively ta...

9048Background: LOXO-292 is a novel, highly-selective, small molecule RET inhibitor in clinical development for pts with advanced cancers harboring oncogenic RET alterations (e.g. non-small cell lu...

6016Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET...

6052Background: Head and neck squamous cell carcinoma (HNSCC) patients have a 16-25% response rate to single agent immune checkpoint inhibitors (ICI). Prognostic biomarkers to ICIs are needed to id...

9564Background: ICI has shown major benefit in cutaneous malignancies including melanoma and Merkel cell carcinoma. Efficacy data in cSCC is, however, limited. Here we report our institutional expe...

Radiotherapy (RT) is a standard treatment for cancer; however, RT is associated with an increase in atherosclerotic cardiovascular events (ASCVD). Whether the primary prevention ACC/AHA and USPSTF statin guidelines, using the pooled cohort risk equation (PCE), predict ASCVD after RT is unknown.

Purpose Phase I study to determine the maximum tolerated dose (MTD) of fluorouracil (FU) in the docetaxel/cisplatin/FU (TPF) regimen when combined with cetuximab (C) for induction treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with previously untreated SCCHN were enrolled. FU cohorts were 700, 850, and 1,000 mg/m2/d for 4 days via continuous infusion. TPF given every 3 weeks for three cycles and C was given weekly for a total of 9 weeks, starting on day 1 of TPF. All patients received chemoradiotherapy after C-TPF. Results A total of 30 patients were enrolled and 28 were assessable. The median age was 57 years, 92% had stage 4 disease, 71% were oropharynx, and 100% had a performance status of 0. No dose-limiting toxicity (DLT) was encountered on dose levels 1 and 2. At dose level 3 of 1000 mg/m2, one DLT was encountered and three more patients were enrolled with no DLTs. In the expansion cohort at the MTD, three DLT's were encountered. The decision was made to decrease the FU from 1,000 mg/m2 to dose level 2 of 850 mg/m2. A total of 13 patients were enrolled at the MTD of 850 mg/m2. The number of average weeks that C was delivered was seven of nine planned. Conclusion C-TPF appears to be safe and feasible as given in this study. GI toxicity (mucositis, enteritis, and diarrhea) appears to be the major combined DLT. Reducing the FU in TPF to 850 mg/m2 reduces GI toxicity and is the recommended phase II dose.

Background Locally advanced laryngeal and hypopharyngeal cancers (LHC) represent a group of cancers for which surgery, laryngectomy-free survival (LFS), overall survival (OS), and progression-free survival (PFS) are clinically meaningful end points. Patients and methods These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324, a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil (TPF) against cisplatin and fluorouracil (PF), followed by chemoradiotherapy. Results Among 501 patients enrolled in TAX 324, 166 had LHC (TPF, n = 90; PF, n = 76). Patient characteristics were similar between subgroups. Median OS for TPF was 59 months [95% confidence interval (CI): 31–not reached] versus 24 months (95% CI: 13–42) for PF [hazard ratio (HR) for death: 0.62; 95% CI: 0.41–0.94; P = 0.024]. Median PFS for TPF was 21 months (95% CI: 12–59) versus 11 months (95% CI: 8–14) for PF (HR: 0.66; 95% CI: 0.45–0.97; P = 0.032). Among operable patients (TPF, n = 67; PF, n = 56), LFS was significantly greater with TPF (HR: 0.59; 95% CI: 0.37–0.95; P = 0.030). Three-year LFS with TPF was 52% versus 32% for PF. Fewer TPF patients had surgery (22% versus 42%; P = 0.030). Conclusions In locally advanced LHC, sequential therapy with induction TPF significantly improved survival and PFS versus PF. Among operable patients, TPF also significantly improved LFS and PFS. These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC.

The Epstein–Barr virus (EBV) nuclear antigen-1 (EBNA-1) is potentially a universal target for immune recognition of EBV-infected normal or malignant cells. EBNA-1-specific CD8+ T-cell responses have been assessed against a few epitopes presented on a limited number of HLA class I alleles. We now assess CD8+ T-cell responses to a complete panel of EBNA-1 peptides in an HLA-characterized population. We detected EBNA-1-specific CD8+ T cells in 10 of 14 healthy donors by analysis of peripheral blood mononuclear cells and EBV-specific T-cell lines. The frequent detection of CD8+ T-cell responses was confirmed by mapping EBNA-1 epitopes and demonstrating HLA class I presentation to CD8+ T cells in 6 of 6 donors, including 2 new EBNA-1 epitopes presented by HLA A0206 and A6802. Importantly, EBNA-1-specific CD8+ T cells were significantly less frequent in EBV-specific T-cell lines from patients with EBV-associated nasopharyngeal carcinoma (3 out of 22, P = 0.0003), whereas the frequency of LMP2-specific responses (14 out of 22) was not significantly different from healthy donors (11 out of 14). EBNA-1-specific CD8+ T-cell responses were rescued in approximately half of nasopharyngeal carcinoma patients by peptide and cytokine stimulation of peripheral blood mononuclear cells, suggesting these EBNA-1-specific CD8+ T cells were functionally defective in their response to EBV-infected cells. These results indicate that humans normally mount a significant EBNA-1-specific CD8+ T-cell response to EBV infection, but the immune response to this tumor antigen has been significantly altered in nasopharyngeal carcinoma patients. Overcoming this defect in EBV-specific immunity may prevent or enhance treatment of EBV-associated nasopharyngeal carcinoma.

Locally advanced squamous cell cancer of the head and neck is a major contributor to morbidity and mortality worldwide. Despite progress through the use of multimodality treatment involving surgery, radiotherapy, and chemotherapy in recent years, the survival remains poor, and treatment-related morbidity-mainly caused by radiation-induced effects such as soft tissue scarring, esophageal stenosis, xerostomia, dental decay, and osteoradionecrosis-is a major problem in long-term survivors. Data from early trials and encouraging results from meta-analyses have revived interest in the use of neoadjuvant or induction chemotherapy before definitive local treatment. Recent randomized trials have demonstrated marked improvements in survival with the addition of the taxane docetaxel (Taxotere) to the traditional induction regimen consisting of cisplatin and 5FU (TPF) compared with cisplatin and 5FU (PF) alone and have established a new standard of care. The newer TPF induction chemotherapy regimens also appear to be tolerated better than PF when accompanied by adequate supportive measures. Studies to enhance the efficacy of TPF induction chemotherapy by adding new targeted agents, such as the EGF-R inhibitors cetuximab and panitumumab, are underway.

This study evaluated changes in prostaglandin E2 (PGE2) levels and related biomarkers in oral premalignant lesions (OPL) in response to celecoxib treatment. Twenty-two subjects were enrolled and treated with celecoxib. Pretreatment and 12-week biopsies were done. Subjects whose biopsy showed ≥30% decrease in PGE2 remained on celecoxib for a total of 12 months when repeat biopsy was done. Biopsies were examined to assess degree of dysplasia, DNA ploidy, and immunohistochemical expression of BCL2, pAKT-Ser473, Ki-67, and CD31 (microvessel density). In 18 paired biopsies available at baseline and 12 weeks, mean normalized PGE2 levels decreased by 38% (P = 0.002). After 12 months, PGE2 decreased by 31% (P = 0.340). Twelve biopsies (67%; P = 0.0129) showed improvement in degree of dysplasia after 12 weeks, and 8 of 11 biopsies (73%; P = 0.0703) continued to show an improvement in the degree of dysplasia after 12 months. Trends suggested down-modulation of cyclooxygenase-2 and Ki-67 in some tissues, increased pAKT-Ser473 expression, and an inverse relationship between PGE2 and BCL2 expression. This study documents the feasibility of measuring potential surrogate endpoint biomarkers of chemopreventive agent response in OPLs. Treatment with celecoxib in subjects with OPLs favorably modulates the primary mediator of cyclooxygenase-2 activity, PGE2, after 12 weeks.

To determine the efficacy of gefitinib in patients with advanced thyroid cancer.In this open-label phase II trial, 27 patients with radioiodine-refractory, locally advanced, or metastatic thyroid cancer were treated with 250 mg of daily gefitinib. Histologic subtypes included papillary (41%), follicular (22%), anaplastic (19%), medullary (15%), and Hürthle cell carcinomas (4%). The primary endpoint was overall response rate. Secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS).There were no objective responses among the 25 patients evaluated. After 3, 6, and 12 months of treatment, 48%, 24%, and 12% of patients had stable disease (SD), respectively. Median PFS and OS were 3.7 and 17.5 months, respectively. Five patients with SD had a decrease in thyroglobulin (Tg) to90% of baseline that was maintained for at least 3 months.Although gefitinib therapy did not result in any tumor responses, 32% of patients had reductions in tumor volume that did not meet criteria for partial response rate. Along with falling Tg levels and prolonged SD in a subset of patients, this may indicate biologic activity.

Predictive biomarkers are urgently needed for individualization of radiation therapy and treatment with radiosensitizing anti-cancer agents. Genomic profiling of human cancers will provide us with unprecedented insight into the mutational landscape of genes directly or indirectly involved in the response to radiation-induced DNA damage. However, to what extent this wealth of structural information about the cancer genome will produce biomarkers of sensitivity to radiation remains to be seen. Investigators are increasingly studying the subnuclear accumulation (i.e., foci) of proteins in the DNA damage response (DDR), such as γ-H2AX, 53BP1, or RAD51, as a surrogate of treatment sensitivity. Recent findings from preclinical studies have demonstrated the predictive potential of DDR foci by correlating foci with clinically relevant endpoints such as tumor control probability. Therefore, pre-clinical investigations of DDR foci responses are increasingly moving into cells and tissues from patients, which is the major focus of this review. The advantage of using DDR foci as functional biomarkers is that they can detect alterations in DNA repair due to various mechanisms. Moreover, they provide a global measurement of DDR network function without needing to know the identities of all the components, many of which remain unknown. Foci assays are thus expected to yield functional insight that may complement or supersede genomic information, thereby giving radiation oncologists unique opportunities to individualize cancer treatments in the near future.

The objective of this study was to investigate the effects of recorded lullabies and taped maternal voice in premature infants. Sixty-two preterm infants in a stable condition with 30

BRAF(V600E) is a common mutation in papillary thyroid carcinoma (PTC) correlated with aggressive features. Our objective was to assess the feasibility and accuracy of a novel RNA-based blood assay to identify individuals with a high-risk tumor mutation in patients with PTC. Patients with benign or malignant thyroid disorders were included between September 2013 and July 2014 before either thyroidectomy (n = 62) or treatment of recurrent or metastatic PTC (n = 8). RNA was isolated from peripheral blood lymphocytes and reverse transcribed and followed by two rounds of nested PCR amplification with a restriction digest specific for wild-type BRAF. BRAF(V600E) levels were quantified with standardization curves. Circulating BRAF(V600E) levels were compared with BRAF mutation status from surgical pathologic DNA-based tissue assays. Testing characteristics and receiving-operator curve using tissue results as the gold standard were assessed. Matched blood and tissue assays for BRAF(V600E) were performed on 70 patients with PTC (stages I to IV, n = 48) or other (n = 22) thyroid tumors. Sixty-three percent of PTC patients tested positive for BRAF(V600E) with conventional tissue assays on surgical specimens. The correlation between the RNA-based blood assay and tissue BRAF status was 0.71. PTC patients harbor detectable BRAF(V600E) circulating tumor cells. This blood assay is feasible and has potential as a biomarker for prognosis, surveillance, clinical decision making, and assessment of treatment response to BRAF-targeted therapies.

Purpose: In a Phase I/II trial, we investigated concurrent weekly docetaxel and concomitant boost radiation in patients with locally advanced squamous cell cancer of the head and neck (SCCHN) after induction chemotherapy. Patients and Methods: Patients presented with American Joint Committee on Cancer Stage III/IV and were treated initially with induction chemotherapy using cisplatinum/5-fluorouracil (PF), carboplatinum-5-FU, or docetaxel-PF. Patients then received docetaxel four times weekly with concomitant boost (CB) radiation (1.8 Gy once-daily X20, 1.8/1.5 Gy twice a day). Fifteen patients each received 20 mg/M 2 and 25 mg/M 2 . Results: Thirty-one patients were enrolled and 30 were evaluable for response and toxicity. Median follow-up was 42 months (range, 27‐63 months). Primary sites were: oropharynx 19, oral cavity 2, larynx/hypopharynx 5, and unknown primary 4. Eighty-seven percent of patients had N2/N3 disease; 60% had T3/T4 disease. Twenty percent of patients had a complete response (CR) to induction chemotherapy. After chemoradiotherapy, 21 of 30 patients had a CR, 2 had progressive disease, and 7 had partial response (PR). Nineteen of 26 patients presenting with neck disease had neck dissections, and 7 of 19 were positive. Ninety-three percent of all patients were rendered disease-free after all planned therapy. Treatment failed in 8 patients, and 7 have died of disease. An additional patient died with no evidence of disease. Twenty-one patients (70%) are currently alive with no evidence of disease. No acute dose-limiting toxicity was observed at either dose level. Conclusions: This intensive treatment regimen of concurrent docetaxel/concomitant boost radiation and surgery after induction chemotherapy in poor prognosis patients yields good local regional control and survival. Docetaxel/CB chemoradiotherapy represents an aggressive alternative regimen to platinum-based chemoradiotherapy or surgery in patients who have a poor response to induction chemotherapy. © 2006 Elsevier Inc. Head-and-neck cancer, Chemoradiation, Concomitant boost radiation, Docetaxel.

Assess impact of sequential chemoradiation therapy (SCRT) for advanced head and neck cancer (HNCA) on swallowing, nutrition, and quality of life.Prospective cohort study of 59 patients undergoing SCRT for advanced head and neck cancer. Follow-up median was 47.5 months.Regional Cancer Center.Median time to gastrostomy tube removal was 21 weeks. Eighteen of 23 patients who underwent modified barium swallow demonstrated aspiration; none developed pneumonia. Six of 7 with pharyngoesophageal stricture underwent successful dilatation. Functional Assessment of Cancer Therapy-Head and Neck Scale questionnaires at median 6 months after treatment revealed "somewhat" satisfaction with swallowing. At the time of analysis, 97% have the gastronomy tube removed and take soft/regular diet.Early after treatment dysphagia adversely affected weight, modified barium swallow results, and quality of life. Diligent swallow therapy, and dilation as needed, allowed nearly all patients to have their gastronomy tubes removed and return to a soft/regular diet.Dysphagia is significant after SCRT but generally slowly recovers 6 to 12 months after SCRT.C-4.

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents.

The authors reviewed records of patients with advanced laryngeal cancer treated with induction chemotherapy (IC) and hyperfractionated radiation therapy (RT) or chemoradiation (CRT) to determine the rates of organ preservation and function.A total of 29 patients with stage III (45%) and stage IV (55%) squamous cell carcinoma of the larynx (SCCL), were treated with IC and RT or CRT in 1 of 7 consecutive trials. Fifty-five percent had clinically node-positive disease. Fifty-five percent and 45% had T3 or T4 tumors, respectively. All received 3 cycles of platinum-based IC. Daily RT was given to 48%, twice-daily RT to 45%, and concomitant boost RT to 7%. CRT was carboplatin (28%) or docetaxel (28%). Those treated with twice-daily RT did not receive CRT.The median follow-up is 52 months. Overall survival is 66%. Relapse occurred in 12 patients (41%), and 6 underwent salvage laryngectomy (5 stage III, 1 stage IV). Fifty-nine percent of patients (17 of 29) are alive at last follow-up with an anatomically intact larynx, and 48% (14 of 29) are alive with a functional larynx. Of the 23 patients for whom detailed information on gastrostomy tube (g-tube) placement/removal was available, median time with g-tube was 12 months, and 15 of 23 patients (65%) had a g-tube for 6 months or more. Twenty-three of all 29 patients (79%) retained an anatomically intact larynx, but 7 of 23 (30%) never resumed their pretreatment organ function. The overall rate of functional organ preservation, regardless of survival, was 55% (16/29). The 7 of 29 patients (26%) who retained a nonfunctional larynx required permanent g-tube or were unable to return to pretreatment oral intake capability. Nine of 13 with T4 SCCL (69%) compared with 7 of 16 (44%) T3 SCCL retained a functional larynx.The rate of larynx preservation is high, but toxicity remains significant with IC followed by hyperfractionated RT or CRT in advanced laryngeal cancer. Half of all patients were alive, able to retain their larynx, and return to pretreatment function. Advanced stage was not an indicator of poor outcome.

Objectives: The objective of this study was to describe and evaluate the efficacy of an endoscopic technique for the management of postchemoradiation hypopharyngeal stenosis in head and neck cancer patients. Study Design: Retrospective review. Methods: Patients with postchemoradiation hypopharyngeal stenoses were identified from the Dana Farber Cancer Institute head and neck database. Patients who had undergone extirpative surgery and reconstruction were excluded. All patients underwent either anterograde dilatation (AD) by the lead author (C.A.S.) or transgastric retrograde esophagoscopy with anterograde dilatation (TREAD) (C.A.S., M.T.J.). Chemoradiation records, clinic notes, operative reports, and swallowing test data were reviewed. Removal of the gastric feeding tube was considered the endpoint of rehabilitation. Results: Seventeen patients had postcricoid stenoses identified by modified barium swallow. Endoscopy confirmed 15 postcricoid stenoses and 2 proximal esophageal stenoses. Nine (53%) patients had partial stenoses, and eight (47%) had complete stenoses. Eight partial stenosis patients underwent 10 AD procedures and 3 TREAD procedures. Eight complete stenosis patients underwent 9 TREAD procedures and 26 subsequent AD procedures. Fifteen of 16 (93%) patients resumed swallowing after dilatation. Thirteen (81%) patients maintained their weight on an oral diet and had their gastric feeding tubes removed. Complications included hypopharyngeal perforation (13%), abdominal wall infection (6%), stomach wall dehiscence (6%), and chondroradionecrosis of the cricoid cartilage (6%). Conclusions: Postcricoid hypopharyngeal stenosis may be partial or complete after organ sparing chemoradiation for head and neck cancer. Using the TREAD technique, successful rehabilitation of swallowing can be achieved with a low incidence of complications.

Study objectives: To determine the outcome of patients with pulmonary typical and atypical carcinoid tumors treated with chemotherapy with or without radiotherapy. Methods: Patients with pulmonary neuroendocrine tumors treated at our institution from 1990 to 2001 were identified. The medical records of patients with diagnoses of typical or atypical pulmonary carcinoids were reviewed for the presence of evaluable disease, treatment with chemotherapy with or without radiotherapy, response to these treatments, survival and cause of death. Results: Eighteen patients with typical ( n =8) or atypical ( n =10) pulmonary carcinoid tumors who were treated with chemotherapy with or without radiotherapy were identified. Of these, four received chemotherapy plus chest radiotherapy. Three of these had stable disease and one had a partial response. One of the patients with stable disease to chemoradiotherapy subsequently received chemotherapy alone, to which he had a complete response. Fourteen additional patients were treated with 18 chemotherapy regimens. There were two partial responses, eight stable disease, seven progressive disease and one allergic reaction precluding further treatment. The overall response rate to any chemotherapy was 3/15 (20%, 95% CI 0.07–0.45), and the best overall response rate to chemotherapy with or without chest radiotherapy was 4/18 (22%, 95% CI 0.09–0.45). Median overall survival was 20 months (95% CI 0–51 months). Conclusions: Patients with typical and atypical pulmonary carcinoid tumors can respond to chemotherapy with or without chest radiotherapy, though with response rates that appear less than those of small cell lung cancers. Further characterization of pulmonary carcinoid tumors and study of treatment alternatives for unresectable disease is warranted.

The treatment of head and neck cancer continues to evolve. The recent use of aggressive chemoradiotherapy protocols has resulted in significant morbidity involving mucositis, dysphagia, and a higher rate of feeding tube dependency. We have initiated a randomized phase II study with concomitant chemoradiotherapy with or without subcutaneous amifostine (Ethyol, WR-2721; MedImmune, Inc, Gaithersburg, MD). This article presents a detailed background, rationale, and endpoints for this study and discusses future directions in the treatment of head and neck cancer.

The role of chemotherapy for locoregionally advanced head and neck cancer continues to evolve. Chemotherapy can be given as induction therapy, concomitant with radiation or occasionally in an adjuvant form following definitive local therapy. Timing and sequence of chemotherapy varies between institutions. The recent advances in the treatment of head and neck cancer will be reviewed, with focus on the recent application of sequential chemoradiotherapy regimens, which combines high-dose induction chemotherapy with concomitant chemoradiation. Surgery is reserved for advanced nodal-stage disease and for salvage at the primary site. This novel approach has resulted in a higher rate of organ preservation and is ultimately expected to improve survival in this patient population.

IntroductionWe sought to test the safety and efficacy of cabozantinib in patients with advanced solid (non-breast, non-prostate) malignancies and bony metastasis (ClinicalTrials.gov Identifier: NCT01588821). Patients with bone metastasis were enrolled in this study. Primary endpoint of the study was change in bone biomarkers in serum and urine. Tumor responses were an additional endpoint and measured by RECIST v1.1. Methods:Participants with progressive metastatic solid tumors other than breast and prostate cancer, age >/= 18 yrs, and with bone metastasis were consented and enrolled onto open label phase II study at Massachusetts General Hospital. The starting dose was 60 mg/d cabozantinib. CT of the tumor, chest, abdomen, and pelvis were performed every 2 cycles (each cycle = 28 days). Serial PET and Tc99m bone scans were performed in a subset of participants. Radiologic tumor responses were evaluated by RECIST. Bone biomarkers were measured at baseline and week 8, with a bony response to treatment defined as ≥ 40% decrease in urinary Ntx, serum Ntx, or serum Ctx at week 8. Results:37 patients enrolled onto this study. 14 had sarcoma, 7 renal cell carcinoma, 5 non-small cell lung cancer, 4 head and neck carcinoma, 2 thyroid cancer, 2 melanoma, 1 adenoid cystic carcinoma, 1 metastatic chondroblastoma, and 1 chordoma. Patient age at enrollment ranged from 18 to 83 years, with an average age of 54.4 years old. 37 % of patients were female. 19 patients were evaluable for determination of response by bone biomarkers. 13 had ≥ 40% decrease in serum Ctx, 9 had ≥ 40% decrease in serum Ntx, and 8 had ≥ 40% decrease in urinary Ntx. These measurements, however, had low correlation with RECIST measurements (r^2 of .05, .00, and .15, respectively).The average time to disease progression was 6.6 months. 3 patients had a partial response by RECIST (with chondroblastoma, head and neck cancer, and thyroid cancer), 16 of 20 radiologically measureable patients had some decrease in tumor size as best response, and 9 of those 16 had decrease in tumor size by 10% or greater by RECIST, and 6 of those 9 had sarcoma or chondroblastoma. The other 17 of 37 enrolled patients had bone only disease or were otherwise not measureable by RECIST. 55% of patients required dose reduction. Most common all grade adverse events were fatigue (59%), nausea (46%), anorexia (32%), and plantar-palmar erythrodysesthesia (27%). Conclusion:Cabozantinib is an active drug for patients with bone metastasis as measured by changes in serum/urine Ntx and Ctx. Plantar-palmar erythrodysesthesias, fatigue, nausea, and anorexia were common adverse events. Adverse events were manageable by dose reduction to 40 mg QD. This is the first study showing that cabozantinib has significant anti-tumor activity in patients with metastatic sarcoma with bone metastasis. Citation Format: Edwin Choy, Gregory M. Cote, M. Dror Michaelson, Lori Wirth, Justin F. Gainor, Lecia V. Sequist, Ryan J. Sullivan, Panagiotis M. Fidias, Alice Shaw, Rebecca S. Heist. Phase 2 study of cabozantinib in patients with non-breast, non-prostate cancer with bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT129. doi:10.1158/1538-7445.AM2017-CT129