Summary Background Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. Methods This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. Findings 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Interpretation Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient’s response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. Funding National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Many solid tumors contain an overabundance of phospholipid ethers relative to normal cells. Capitalizing on this difference, we created cancer-targeted alkylphosphocholine (APC) analogs through structure-activity analyses. Depending on the iodine isotope used, radioiodinated APC analog CLR1404 was used as either a positron emission tomography (PET) imaging (124I) or molecular radiotherapeutic (131I) agent. CLR1404 analogs displayed prolonged tumor-selective retention in 55 in vivo rodent and human cancer and cancer stem cell models. 131I-CLR1404 also displayed efficacy (tumor growth suppression and survival extension) in a wide range of human tumor xenograft models. Human PET/CT (computed tomography) and SPECT (single-photon emission computed tomography)/CT imaging in advanced-cancer patients with 124I-CLR1404 or 131I-CLR1404, respectively, demonstrated selective uptake and prolonged retention in both primary and metastatic malignant tumors. Combined application of these chemically identical APC-based radioisosteres will enable personalized dual modality cancer therapy of using molecular 124I-CLR1404 tumor imaging for planning 131I-CLR1404 therapy.

Background This study examined the effectiveness of an online support system (CHESS) versus the Internet in relieving physical symptom distress in patients with nonsmall cell lung cancer (NSCLC). Methods 285 informal caregiver-patient dyads were randomly assigned to standard care plus the Internet or CHESS for up to 25 months. Caregivers agreed to use CHESS or the Internet and complete bimonthly surveys; for patients, these tasks were optional. The primary endpoint, patient symptom distress, was measured by caregiver reports using a modified Edmonton Symptom Assessment Scale (ESAS). Results Caregivers in the CHESS arm consistently reported lower patient physical symptom distress than caregivers in the Internet arm, with significant differences at 4 months (P = .031, Cohen’s d = .42) and 6 months (P = .004, d = .61). Similar but marginally significant effects were observed at 2 months (P = .051, d = .39) and 8 months (P = .061, d = .43). Exploratory analyses showed that survival curves did not differ significantly between the arms (log rank, P = .172), although a survival difference in an exploratory subgroup analysis suggests an avenue for further study. Conclusions An online support system may reduce patient symptom distress. The effect on survival bears further investigation.

A B S T R A C T PurposeLocal failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined. Patients and MethodsSeventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with Յ 20% risk of severe toxicity. ResultsNo grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P ϭ .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree. ConclusionAlthough this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.

SUMMARYBackgroundAdjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase III study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC (E1505). The primary endpoint was overall survival.MethodsAdult patients (≥ 18 years old) with ECOG performance status 0 or 1 with completely resected stage IB (≥4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6–12 weeks of surgery and stratified by chemotherapy regimen, stage, histology, and sex. Minimum mediastinal lymph node sampling at specified levels was required (level 7 and 4 for right-sided tumors or level 7 and 5 and/or 6 for left-sided tumors). Normal laboratory values within two weeks of randomisation were required for enrollment. Chemotherapy, which was selected for each patient prior to randomisation, consisted of four, 3-week (21-day) cycles of cisplatin (75 mg/m2 in all regimens) with either vinorelbine 30 mg/m2 days 1 and 8; docetaxel 75 mg/m2 day 1; OR gemcitabine 1200 mg/m2 days 1 and 8; OR, starting in 2009 with an amendment, pemetrexed 500 mg/m2 day 1 along with B12 and folic acid supplementation. Patients were randomised 1:1 to Arm A (chemotherapy) or Arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for one year. Randomisation to treatment arm was performed centrally and determined using permuted blocks within strata with dynamic balancing on institution. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0·025-level test. The primary endpoint was overall survival, which was defined as the time from randomisation to death from any cause, and patients who were thought to be alive at the time of final analysis were censored at the last date of contact with analysis done based on intention to treat. This is final analysis of the primary endpoint of overall survival of E1505 (NCT00324805).FindingsFrom July 2007 to September 2013, 1501 patients were enrolled, of whom 26% (N=383) had stage IB, 44% (N=636) stage II, and 30% (N=439) stage IIIA) with 28% (N=422) squamous cell histology. Cisplatin-based chemotherapy regimens utilized were vinorelbine 25% (N=377), docetaxel 23% (N=343), gemcitabine 19% (N=283), and pemetrexed 33% (N=497). At a median follow-up time of 50·3 months (IQR 32.9–68.0), estimated OS hazard ratio (B/A) was 0·99 (95% CI: 0·82–1·19, p=0·90). The median OS on Arm A has not been reached and is 85.8 months (95% CI 74.9-NA) on Arm B. Statistically significantly increased grade 3–5 toxicities of note (all attributions) included: overall worst grade (ie all grade 3/4/5 toxicities) (67%(N=496) versus 83%(N=610)); hypertension (8%(N=60) versus 30%(N=219)), and neutropenia (33%(N=241) versus 37%(N=275)) on Arms A and B, respectively. There was no s...