The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

BACKGROUND: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT-drug development programmes before patent expiration. METHODS: We identified novel drug-radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. RESULTS: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). CONCLUSIONS: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug-RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes.

Magnetic resonance guided focused ultrasound surgery. Ablation of soft tissue at bone-muscle interface in a porcine model.

BACKGROUND: Pain management treatments of patients with bone metastases have either efficacy problems or significant side effects. Percutaneous radiofrequency ablation has recently proved to be of palliative value. Magnetic resonance guided focused ultrasound surgery (MRgFUS) uses focused ultrasonic energy to non-invasively create a heat-coagulated lesion deep within the body in a controlled, accurate manner. The surgeon can monitor and control energy deposition in real time. This technology represents a potential treatment modality in oncological surgery. We investigated the ability of two MRgFUS methods to accurately and safely target and ablate soft tissue at its interface with bone. MATERIALS AND METHODS: Heat-ablated lesions were created by MRgFUS at the bone-muscle interface of 15 pigs. Two different methods of energy delivery were used. Temperature rise at the target adjacent to bone was monitored by real time MR thermal images. Results were evaluated by MRI (magnetic resonance imaging), nuclear scanning and by histopathological evaluation. RESULTS: Soft tissue lesion sizes by both methods were in the range of 1-2 cm in diameter. Targeting the focus 'behind' the bone, achieved the same result with a single sonication only. Follow up MRI and histopathological examination of all lesions showed focal damage at its interface with bone and localized damage to the outer cortex on the side closer to the targeted tissue. There was no damage to non-targeted tissue. CONCLUSION: MRgFUS by both energy deposition methods can be used to produce controlled well-localized damage to soft tissue in close proximity to bone, with minimal collateral damage.

MR-guided focused ultrasound surgery (MRgFUS) for the palliation of pain in patients with bone metastases--preliminary clinical experience.

BACKGROUND: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive thermal ablation technique, shown to be clinically effective in the treatment of uterine fibroids and is being evaluated as a method of thermal ablation of benign and malignant breast tumors. To evaluate the safety and initial efficacy of MRgFUS for the palliation of pain caused by bone metastases, in patients for whom other treatments are either not effective or not feasible. MATERIALS AND METHODS: Thirteen patients suffering from symptomatic bone metastases underwent MRgFUS procedure. Treatment safety was evaluated by assessing the incidence and severity of device-related complications up to 6 months after treatment. Effectiveness of pain palliation was evaluated by visual analog scale, pain questionnaires and changes in the patients' medication. RESULTS: Fifteen procedures were carried out. Mean follow-up was 59 days. Twelve patients received adequate treatment and were available for follow-up. Two patients died due to disease progression during the first month after treatment. No severe adverse events were recorded. The remaining 10 patients reported prolonged improvement in pain score and/or reduced analgesic dosage. CONCLUSION: MRgFUS may provide a safe and effective noninvasive alternative for the palliation of pain, caused by bone metastases.

Determinants of the use of complementary therapies by patients with cancer.

PURPOSE: We performed a survey of Israeli oncology patients to examine the extent of their use of complementary therapies (CT) and to compare sociodemographic, psychologic, and medical characteristics, attitudes, and quality of life of users and nonusers of CT. PATIENTS AND METHODS: Questionnaires were administered to 1,027 patients attending ambulatory and inpatient hematology or oncology facilities at three hospitals. Medical information was extracted from charts. Univariate and multivariate comparisons of users and nonusers of CT were performed. RESULTS: A total of 526 participants (51.2%) had used CT since their diagnosis, and 357 patients (34.9%) had used CT recently (in the past 3 months). Factors that multivariate analysis found to be significantly associated (P <.05) with recent CT use were as follows: female sex; age 35 to 59 years; more education; coming to the hospital by private car; advanced disease status; having a close friend or a relative with cancer; and attending support groups or individual counseling. After controlling for these factors, individually examined psychosocial variables associated with recent CT use included the following (odds ratios [OR] with 95% confidence intervals [CI]): needs unmet by conventional medicine (OR, 2.76; 95% CI, 1.95 to 3.89); helplessness (OR, 1.39; 95% CI, 1.0 to 1.91); incomplete trust in the doctor (OR, 1.49; 95% CI, 1.08 to 2.06); and changed outlook or beliefs since the diagnosis of cancer (OR, 1.47; 95% CI, 1.07 to 2.02). Functional quality of life (including physical, emotional, social, and role function) and symptom (fatigue and diarrhea) scores were significantly worse for recent CT users compared with nonusers, controlling for age, sex, and current disease status. CONCLUSION: Characteristics associated with CT use include age, sex, education, and advanced disease. Significant associations between CT use and attending supportive psychotherapy, unmet needs, helplessness, and worse emotional and social function indicate considerable distress, suggesting that increased attention to psychosocial needs within oncologic settings is warranted.