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.

Review of current best practice and priorities for research in radiation oncology for elderly patients with cancer: the International Society of Geriatric Oncology (SIOG) task force.

Radiotherapy (RT) is a key component of the management of older cancer patients. Level I evidence in older patients is limited. The International Society of Geriatric Oncology (SIOG) established a task force to make recommendations for curative RT in older patients and to identify future research priorities. Evidence-based guidelines are provided for breast, lung, endometrial, prostate, rectal, pancreatic, oesophageal, head and neck, central nervous system malignancies and lymphomas. Patient selection should include comorbidity and geriatric evaluation. Advances in radiation planning and delivery improve target coverage, reduce toxicity and widen eligibility for treatment. Shorter courses of hypofractionated whole breast RT are safe and effective. Conformal RT and involved-field techniques without elective nodal irradiation have improved outcomes in non-small-cell lung cancer (NSCLC) without increasing toxicity. Where comorbidities preclude surgery, stereotactic body radiotherapy (SBRT) is an option for early-stage NSCLC and pancreatic cancer. Modern involved-field RT for lymphoma based on pre-treatment positron emission tomography data has reduced toxicity. Significant comorbidity is a relative contraindication to aggressive treatment in low-risk prostate cancer (PC). For intermediate-risk disease, 4-6 months of hormones are combined with external beam radiotherapy (EBRT). For high-risk PC, combined modality therapy (CMT) is advised. For high-intermediate risk, endometrial cancer vaginal brachytherapy is recommended. Short-course EBRT is an alternative to CMT in older patients with rectal cancer without significant comorbidities. Endorectal RT may be an option for early disease. For primary brain tumours, shorter courses of postoperative RT following maximal debulking provide equivalent survival to longer schedules. MGMT methylation status may help select older patients for temozolomide alone. Stereotactic RT provides an alternative to whole-brain RT in patients with limited brain metastases. Intensity-modulated radiation therapy provides an excellent technique to reduce dose to the carotids in head and neck cancer and improves locoregional control in oesophageal cancer. Best practice and research priorities are summarised.

The 2022 Assisi Think Tank Meeting: White paper on optimising radiation therapy for breast cancer.

The present white paper, referring to the 4th Assisi Think Tank Meeting on breast cancer, reviews state-of-the-art data, on-going studies and research proposals. <70% agreement in an online questionnaire identified the following clinical challenges: 1: Nodal RT in patients who have a) 1-2 positive sentinel nodes without ALND (axillary lymph node dissection); b) cN1 disease transformed into ypN0 by primary systemic therapy and c) 1-3 positive nodes after mastectomy and ALND. 2. The optimal combination of RT and immunotherapy (IT), patient selection, IT-RT timing, and RT optimal dose, fractionation and target volume. Most experts agreed that RT- IT combination does not enhance toxicity. 3: Re-irradiation for local relapse converged on the use of partial breast irradiation after second breast conserving surgery. Hyperthermia aroused support but is not widely available. Further studies are required to finetune best practice, especially given the increasing use of re-irradiation.

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.

Specific induction of tumor neovasculature death by modified murine PPE-1 promoter armed with HSV-TK.

BACKGROUND: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. OBJECTIVES: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). RESULTS: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. CONCLUSIONS: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.

Development in modeling submicron particle formation in two phases flow of solvent-supercritical antisolvent emulsion.

The use of a supercritical Solvent (S)-Antisolvent (AS) process (SAS) for fine particle production is finding widespread industrial applications. The perfection of this technology requires insight into many basic laws of interface and colloid science. In SAS the solute is dissolved in an organic solvent and the solution is sprayed into a near critical AS stream. SAS is a complex process involving the interaction of jet hydrodynamics, droplet formation, mass transfer, phase equilibrium, intra-droplet nucleation, and microcrystal growth. A complete description would have to take into account all of these processes; however, such a model is not currently available. In the two-phase flow of an S/AS emulsion, S diffuses from droplets into AS, while AS dissolves inside the S droplets. S replacement by AS (Supercritical CO2) causes solute supersaturation in the droplets. When it occurs near the critical point of the S/AS emulsion (80 bar, 32 degrees C), intra-droplet nucleation and precipitation of the solute occurs. The possibility of solute particle production and the particle size is controlled by the droplet size and by the interrelationship between three time scales. These are the droplet mass transfer time tau N, the nucleation time tau N, i.e., the time necessary for one particle nucleus to form in one droplet, and the droplet residence in the supersaturated stream tau res. An approximate analytical theory for intra-droplet nucleation is developed and the conditions necessary for nanoparticle production are established. The smaller the droplet dimension and the lower the solute concentration, the smaller the particle dimension that is obtained. The recent success in membrane emulsifying may be used for the production of micron-sized droplets. After the AS stream is saturated with S due to partial dissolution of the droplets, a quasi-equilibrium between the droplets and AS stream occurs and a steady and uniform zone with intra-droplet supersaturation is formed downstream. But tau res>tau N is necessary for one nucleus formation per droplet, i.e., tau res has to be much longer than that reported in the literature (10(-3) s), because tau N increases with decreasing droplet dimension. Accordingly, a long residence time version of the SAS process (tau res approximately 1 s) is necessary. However, a long tau res is problematic because of micro-droplet turbulent coagulation. Since an increase in tau res is difficult, a decrease in tau N by means of an increase in S becomes significant. This is achieved by using a phenomenon which we call supersaturation of the second kind S2 In the literature attention is paid only to a decrease in the equilibrium solute concentration, when solvent and antisolvent are mixed. However, S2 occurs due to an actual increase in concentration of solute within the droplets as they shrink due to S dissolution. The smaller the ratio of solvent to antisolvent flow rate, the larger the droplet shrinkage and the higher the S2 achieved. Due to large S2, nanoparticle production becomes possible even for solutes with high surface tension sigma and large molecular volume V o, while earlier it was impossible because of the exponential increase of tau N with increasing V o and sigma. Combining a long tau res and variable and precisely controllable supersaturation, which is uniform in space and enhanced due to S2, creates an opportunity for standardization of characterizing different solutes through their tau N, which is the key solute property affecting nanoparticle production by SAS.

Assessing the quality of conformal treatment planning: a new tool for quantitative comparison.

We develop a novel radiotherapy plan comparison index, critical organ scoring index (COSI), which is a measure of both target coverage and critical organ overdose. COSI is defined as COSI=1-(V(OAR)>tol/TC), where V(OAR)>tol is the fraction of volume of organ at risk receiving more than tolerance dose, and TC is the target coverage, VT,PI/VT, where VT,PI is the target volume receiving at a least prescription dose and VT is the total target volume. COSI approaches unity when the critical structure is completely spared and the target coverage is unity. We propose a two-dimensional, graphical representation of COSI versus conformity index (CI), where CI is a measure of a normal tissue overdose. We show that this 2D representation is a reliable, visual quantitative tool for evaluating competing plans. We generate COSI-CI plots for three sites: head and neck, cavernous sinus, and pancreas, and evaluate competing non-coplanar 3D and IMRT treatment plans. For all three sites this novel 2D representation assisted the physician in choosing the optimal plan, both in terms of target coverage and in terms of critical organ sparing. We verified each choice by analysing individual DVHs and isodose lines. Comparing our results to the widely used conformation number, we found that in all cases where there were discrepancies in the choice of the best treatment plan, the COSI-CI choice was considered the correct one, in several cases indicating that a non-coplanar 3D plan was superior to the IMRT plans. The choice of plan was quick, simple and accurate using the new graphical representation.

Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging.

Convection-enhanced drug delivery (CEDD) is a novel approach to enhance the delivery of drugs directly into brain tumors. We have used diffusion-weighted MRI (DWMRI) to monitor the effects of intratumoral CEDD in three brain tumor patients treated with Taxol. Clear changes in the images and the water diffusion parameters were observed shortly after the initiation of treatment. Initially, a bright area corresponding to decreased diffusion appeared, followed by the appearance of a dark area of increased diffusion within the bright area. The time to appearance of the dark area varied among the patients, suggesting different response rates. In this work, we have demonstrated the feasibility of using DWMRI as a noninvasive tool to achieve unique early tissue characterization not attainable by other conventional imaging methods.

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.

Olfactory tests as possible probes for detecting and monitoring Alzheimer's disease.

One of the characteristics of Alzheimer's disease is the early loss of neurons in pathways involved in processing olfactory information. Olfactory function was assessed in subjects with Alzheimer's disease using a conventional Smell Identification Test and a simple three odor match-to-sample problem. The patients exhibited a diminished capacity to identify common odors but were severely impaired in their ability to use novel odors in a match-to-sample task. Subjects with Parkinson's disease had a severe deficit for identifying common odors with the majority scoring as anosmic. Multiple sclerosis was not accompanied by detectable changes in olfactory functioning. The results of the Alzheimer's group are similar to recent animal studies that have shown lesions of the piriform-entorhinal cortex produce a variety of memory deficits that are particularly acute in tasks involving novel odors.

Cadmium reduces extraocular muscle contractility in vitro and in vivo.

Cadmium, a blocker of calcium channels in various excitable cells, reduces the contractility of extraocular muscles. When applied to rat extraocular muscles in vitro, it reduces the sustained or tonic tension generated by the tonic multiply innervated fibers of the global layer of the muscles. When injected in vivo into rabbit extraocular muscles, it produces a temporary paralysis of the muscles and a deviation of the eye position. These effects are presumed to involve a blockade of the calcium channels of the muscle fibers and of the neuromuscular junctions. It is proposed that, on the basis of these effects, a non-surgical treatment of strabismus could be developed.

Staging methods for the assessment of dementia: Perspectives.

Most dementias in old age are characterized by a progressive course with interindividual variability in pattern and rate of progression. Developing a system for staging such dementia poses a challenge in capturing this variability in a system that will afford comparisons among individuals and predictions of future change. Several core questions underlie the development of such systems: (1) Is there a definable order in which abilities are lost? (2) Which skills and functions should be considered essential for the staging of dementia and what is their relative weight? (3) Can the different skills be captured within one staging system? (4) How is the whole range of function captured, and are the differences between stages clearly defined? (5) Which populations can be rated with each staging system? The determination of this last question is based on understanding which other medical conditions may interfere with the course of dementia and how prior characteristics, such as education, affect ratings on specific scales for the staging of dementia. Several systems for staging dementia in older adults are described. These include the Clinical Dementia Rating, the Global Deterioration Scale/Brief Cognitive Rating Scale/Functional Assessment Staging System, the Six Clinical Phases of Cognitive Decline, the Hierarchic Dementia Scale, and the Functional Capacity Scale. Some aspects of the utility of these systems are reviewed, and the issues for further research are discussed.

Adjuvant treatment of high-risk stage II breast cancer with doxorubicin followed by high-dose chemotherapy and autologous stem-cell transplantation: a single-institution experience with 132 consecutive patients.

Several studies have shown conflicting results with the use of intensive consolidation chemotherapy for breast cancer. The aim of the present study was to investigate the efficacy, feasibility and toxicity of high-dose chemotherapy with stem cell support in patients with high-risk stage II breast cancer. From February 1994 to November 1998, 132 consecutive patients with multinode positive breast cancer were entered to the study. In total, 86 patients had >or=10 positive axillary lymph nodes, and 46 had 4-9 positive axillary lymph nodes with at least two additional predetermined risk factors at diagnosis. All patients were offered adjuvant chemotherapy (doxorubicin, 75 mg/m(2) x 4) followed by high-dose chemotherapy (cyclophosphamide 6000 mg/m(2), carboplatin 800 mg/m(2) and thio-tepa 500 mg/m(2)) and autologous stem cell support with growth factor. In all, 131 patients also received local radiation therapy and tamoxifen based on receptor status. After a median follow-up of 51 months (range 27-87), the disease-free and overall survival rates were 72 and 81%, respectively. There was no difference in the outcome for high-risk patients with > or < than 10 positive axillary lymph nodes. On Cox regression analysis only progesterone receptor status was predictive of disease-free, but not overall survival. There were no treatment-related deaths; grades III-IV toxicity was relatively low. This combined approach of doxorubicin followed by high-dose chemotherapy and stem-cell support, followed by locoregional radiotherapy, was safe and seems to be effective in patients with multinode positive stage II breast cancer. In previous trials of adjuvant high-dose therapy in this patient population, treatment-related morbidity and mortality markedly influenced the outcome. For this high-risk patient population, further testing of intensive chemotherapy regimens with a lower toxicity profile is warranted.

Diagnosis of esophageal carcinoma because of findings on transesophageal echocardiography.

A patient in whom transesophageal echocardiography was performed to evaluate a possible source of cerebral embolization. The fact that the probe could not be passed easily beyond 35 cm from the incisors suggested esophageal obstruction or compression. A mass was seen posterior to the left atrium that was heterogenous and contained blood vessels, suggesting a malignancy. There were no complications of the procedure. Esophageal adenocarcinoma was confirmed on biopsy. Transesophageal echocardiography may be diagnostic of paracardiac mediastinal masses, both benign and malignant. Great care must be taken if passage of the probe through the esophagus is met with resistance, to avoid serious complications.

Delayed breast cellulitis following breast conserving operation.

A complication of breast conservation, which has been increasingly reported in the literature, is 'delayed cellulitis' in the treated breast. This is to be distinguished from wound infection in the breast following lumpectomy. This study reports 16 cases diagnosed with delayed cellulitis following breast conserving surgery, unresponsive to antibiotic therapy. Diagnostic criteria included: pain, erythema and edema in the operated breast. Symptoms appeared up to 10 months after surgery and time to resolution was seven and a half months. No patients had positive cytology and bacteriology tests were negative. Thirteen patients were observed, and three patients were treated with antibiotics with no apparent immediate effect. The appearance of breast cellulitis after surgery poses a problematic diagnostic and management dilemma. It is important to distinguish between this entity and infection, or inflammatory carcinoma. The picture may be attributed to impairment or occlusion of the lymphatic circulation in the breast. This seems to be a newly defined complication with an incidence of 3-5%.

Linear accelerator radiosurgery for vestibular schwannoma.

OBJECT: The use of radiosurgery in the treatment of acoustic neuromas has increased substantially during the last decade. Most published experience relates to the use of the gamma knife. In this report, the authors review the methods and results of linear accelerator (LINAC) radiosurgery in 44 patients with acoustic neuromas who were treated between 1993 and 1997. METHODS: Computerized tomography scanning was selected as the stereotactic imaging modality for target definition. A single, conformally shaped isocenter was used in the treatment of 40 patients; two or three isocenters were used in four patients who harbored very irregular tumors. The radiation dose directed to the tumor border was the only parameter that changed during the study period: in the first 24 patients who were treated the dose was 15 to 20 Gy, whereas in the last 20 patients the dose was reduced to 11 to 14 Gy. After a mean follow-up period of 32 months (range 12-60 months), 98% of the tumors were controlled. The actuarial hearing preservation rate was 71%. New transient facial neuropathy developed in 24% of the patients and persisted to a mild degree in 8%. Radiation dose correlated significantly with the incidence of cranial neuropathy, particularly in large tumors (> or = 4 cm3). CONCLUSIONS: Single-isocenter LINAC radiosurgery proved to be an effective treatment for acoustic neuromas in this series, with results that were comparable with those reported for gamma knife radiosurgery and multiple isocenters.

High affinity dopamine D2 receptor radioligands. 3. [123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain.

Studies of [123I]epidepride uptake in rhesus monkey brain were performed using single photon tomography. Striatal uptake peaked at 0.85% of administered dose/g at 107 min post-injection, then declined slowly to 0.70% of administered dose/g at 6 h. Striatal:posterior brain ratios rose from 2 at 25 min to 6.8 at 105 min, to 15 at 4 h and to 58 at 6.4 h. [123I]Epidepride was displaced by haloperidol (0.1 and 1 mg/kg) with a half-life of washout of 55 min. Little displacement of [123I]epidepride was observed following administration of 1 or 2 mg/kg d-amphetamine, respectively, indicating [123I]epidepride is not easily displaced by endogenous dopamine. In vitro equilibrium binding studies using rat striatum revealed a KD of 46 pM and Bmax of 33 pmol/g tissue at 37 degrees C, while at 25 degrees C the KD was 25 pM and the Bmax 32 pmol/g tissue. In vitro kinetic analysis of association and dissociation curves revealed a half-life for receptor dissociation at 37 degrees C of 15 min and 79-90 min at 25 degrees C. Allowing for the temperature difference, there is good correspondence between in vivo and in vitro dissociation kinetics at 25 degrees C. Increasing in vitro incubation temperature from 25 to 37 degrees C caused a 6-fold increase in the dissociation rate, suggesting that there is a change in binding kinetics at the dopamine D2 receptor at 37 degrees C compared to in vivo binding. The results of this study indicate that [123I]epidepride is an excellent radioligand for SPECT studies of the dopamine D2 receptor in man.

Reoperation for amputation neuroma of the cystic duct.

Two cases of amputation neuroma of the cystic duct are reported. In both instances, significant symptoms were totally relieved by excision of the neuroma. Review of the literature reveals at least twenty similar cases with the same results. Emphasis is placed on the importance of considering this diagnosis in postcholecystectomy patients after all the usual causes of right upper quadrant symptoms have been ruled out.

Radiosurgery for acoustic neurinomas (vestibular schwannomas).

BACKGROUND: Radiosurgery is a therapeutic technique characterized by the delivery of a single high dose of ionizing radiation from an external source to a precisely defined intracranial target. The application of radiosurgery to the treatment of acoustic neurinomas has increased substantially in the last decade. Most of the published experience pertains to the use of the gamma knife. OBJECTIVES: To report the experience at the first Israeli Linear Accelerator Radiosurgery Unit in the management of 44 patients with acoustic neurinomas. METHODS: We analyzed the clinical records and imaging studies of all patients undergoing radiosurgery for acoustic neurinomas between 1993 and 1997, and quantified the changes in tumor volume, hearing status, and facial and trigeminal nerve function. The contribution of radiation dose and original tumor volume upon those variables was also studied. RESULTS: At a mean follow-up of 32 months (range 12-60), 98% of the tumors were controlled (75% had shrunk; 23% had stable volume). The actuarial hearing preservation rate was 71%. New transient facial neuropathy developed in 24% of the patients, persisting in mild degrees in 8%. Neuropathy correlated primarily with tumor volume. Tumors with volumes > 4 ml were at high risk when marginal radiation doses were > 1,400 cGy. Dose reduction to a maximum of 1,400 cGy produced no neuropathies in the last 20 patients, still preserving tumor control rates. CONCLUSIONS: Radiosurgery is an effective and cost-efficient therapeutic modality for newly diagnosed acoustic neurinomas in the elderly or medically infirm population, and for all residual or recurrent tumors after conventional surgery.