Kevin T. Murphy

Neurocognitive assessment following whole brain radiation therapy and radiosurgery for patients with cerebral metastases

The treatment of metastatic brain lesions remains a central challenge in oncology. Because most chemotherapeutic agents do not effectively cross the blood–brain barrier, it is widely accepted that radiation remains the primary modality of treatment. The mode by which radiation should be delivered has, however, become a source of intense controversy in recent years. The controversy involves whether patients with a limited number of brain metastases should undergo whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) delivered only to the radiographically visible tumours. Survival is comparable for patients treated with either modality. Instead, the controversy involves the neurocognitive function (NCF) of radiating cerebrum that appeared radiographically normal relative to effects of the growth from micro-metastatic foci. A fundamental question in this debate involves quantifying the effect of WBRT in patients with cerebral metastasis. To disentangle the effects of WBRT on neurocognition from the effects inherent to the underlying disease, we analysed the results from randomised controlled studies of prophylactic cranial irradiation in oncology patients as well as studies where patients with limited cerebral metastasis were randomised to SRS versus SRS+WBRT. In aggregate, these results suggest deleterious effects of WBRT in select neurocognitive domains. However, there are insufficient data to resolve the controversy of upfront WBRT versus SRS in the management of patients with limited cerebral metastases.

Surgery and postoperative radiation therapy in FIGO stage IIIC endometrial carcinoma

OBJECTIVE To determine the outcome, pattern(s) of failure, and optimal treatment volume in Stage IIIC endometrial carcinoma patients treated with surgery and postoperative radiation therapy (RT). METHODS Between 1983 and 1998, 30 Stage IIIC endometrial carcinoma patients were treated with primary surgery and postoperative RT at the University of Chicago. All underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, sampling of pelvic lymph nodes (PLN), and peritoneal cytology. All were noted to have PLN involvement. Para-aortic lymph nodes (PALN) were sampled in 26 cases, and were positive in 14 cases (54%). Twenty women received whole-pelvic RT (WPRT) and 10 (WPRT), plus paraortic RT (extended-field RT, EFRT). One EFRT patient also underwent concomitant whole-abdominal RT (WART). Adjuvant vaginal brachytherapy (VB) was delivered in 10, chemotherapy in 5, and hormonal therapy in 7 patients. RESULTS At a median follow-up of 32 months, the actuarial 5-year disease-free and cause-specific survivals of the entire group were 33.9% and 55.8%, respectively. Overall, 16 women (53%) relapsed. Sites of failure included the pelvis (23%), abdomen (13%), PALN (13%), and distant (40%). Of the 7 pelvic failures, 4 were vaginal (3 vaginal only). Patients treated with VB had a trend to a lower vaginal recurrence rate (0/10 vs. 4/20, p = 0.12) than those not receiving VB. All 4 PALN failures were in women treated with WPRT (2 negative, 1 unsampled, and 1 positive PALN). None of the 10 EFRT patients (2 negative, 8 positive PALN) recurred in the PALN. No patient developed an isolated abdominal recurrence. Two patients developed significant RT sequelae: chronic diarrhea in 1 patient treated with WPRT and VB, and small bowel obstruction in 1 patient treated with EFRT. CONCLUSION FIGO Stage IIIC disease comprises a small percentage of endometrial carcinoma patients but carries a poor prognosis. Our failure pattern suggests that the optimal adjuvant RT volume is EFRT, even in women with negative PALN sampling. VB should also be administered to improve local control. The low rate of abdominal recurrence does not support the routine use of WART in these women. Given the predominance of failure in distant sites, attention should be focused on the development of systemic chemotherapy protocols.

Single-Isocenter Frameless Intensity-Modulated Stereotactic Radiosurgery for Simultaneous Treatment of Multiple Brain Metastases: Clinical Experience

PURPOSE To describe our clinical experience using a unique single-isocenter technique for frameless intensity-modulated stereotactic radiosurgery (IM-SRS) to treat multiple brain metastases. METHODS AND MATERIALS Twenty-six patients with a median of 5 metastases (range, 2-13) underwent optically guided frameless IM-SRS using a single, centrally located isocenter. Median prescription dose was 18 Gy (range, 14-25). Follow-up magnetic resonance imaging (MRI) and clinical examination occurred every 2-4 months. RESULTS Median follow-up for all patients was 3.3 months (range, 0.2-21.3), with 20 of 26 patients (77%) followed up until their death. For the remaining 6 patients alive at the time of analysis, median follow-up was 14.6 months (range, 9.3-18.0). Total treatment time ranged from 9.0 to 38.9 minutes (median, 21.0). Actuarial 6- and 12-month overall survivals were 50% (95% confidence interval [C.I.], 31-70%) and 38% (95% C.I., 19-56%), respectively. Actuarial 6- and 12-month local control (LC) rates were 97% (95% C.I., 93-100%) and 83% (95% C.I., 71-96%), respectively. Tumors <or=1.5 cm had a better 6-month LC than those >1.5 cm (98% vs. 90%, p = 0.008). New intracranial metastatic disease occurring outside of the treatment volume was observed in 7 patients. Grade >or=3 toxicity occurred in 2 patients (8%). CONCLUSION Frameless IM-SRS using a single-isocenter approach for treating multiple intracranial metastases can produce clinical outcomes that compare favorably with those of conventional SRS in a much shorter treatment time (<40 minutes). Given its faster treatment time, this technique is appealing to both patients and personnel in busy clinics.

A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults

Objective We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. Data sources A systematic search of Medline, Embase, CINAHL and SportDiscus. Eligibility criteria Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. Design Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). Results Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength—one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size—muscle fibre cross-sectional area (CSA; 310 µm2 (51, 570)) and mid-femur CSA (7.2 mm2 (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (−0.01 kg (−0.02,–0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM. Summary/conclusion Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.

Initial Clinical Experience with a Frameless and Maskless Stereotactic Radiosurgery Treatment

PURPOSE To evaluate the initial clinical experience with a frameless and maskless technique for stereotactic radiosurgery using minimal patient immobilization and real-time patient motion monitoring during treatment. We focus on the evaluation of the patient treatment process. METHODS AND MATERIALS The study considered the first 23 patients treated with this technique. Head positioning was achieved with a patient-specific head mold made out of expandable foam that conforms to the patients head. The face of the patient is left open for maximal comfort and so that motion of a region of interest consisting of the forehead, nose, eyes, and temporal bones can be monitored during treatment using a video surface imaging system (VisionRT Inc, London, UK). Initial setup of the patient was performed with the surface imaging system using the surface of the patient obtained from the treatment planning computed tomographic (CT) scan. The initial setup was confirmed and finalized with cone-beam CT (CBCT) prior to treatment. The shifts for final setup based on the CBCT and the duration of all the steps in the treatment process were recorded. Patients were monitored during treatment with surface imaging, and a beam hold-off was initiated when the patients motion exceeded a prespecified tolerance. RESULTS The average total setup time including surface imaging and CBCT was 26 minutes, while the portion corresponding to surface imaging was 14 minutes. The average treatment time from when the patient was placed on the treatment table until the last treatment beam was 40 minutes. Eight (35%) patients needed repositioning during the treatment. The average shifts identified from CBCT after initial setup with surface imaging were 1.85 mm in the anterior-posterior direction, and less than 1.0 mm in the lateral and superior-inferior directions. The longest treatment times (including beam hold-offs) happened for patients who fell asleep on the treatment table and were moving involuntarily. CONCLUSIONS The frameless and maskless treatment using minimal immobilization and surface imaging has proven to be reasonably fast for routine clinical use. We observed that patient compliance is important. An additional degree of semi-rigid immobilization would be helpful for patients who fall asleep and involuntarily move during the procedure.

Frameless, real-time, surface imaging-guided radiosurgery: clinical outcomes for brain metastases.

Frameless stereotactic radiosurgery (SRS) for intracranial brain metastases can provide more comfortable treatment setup than rigid frame-based immobilization with equivalent accuracy. The aim of this study is to report the UCSD SRS experience and update the clinical outcomes using a novel real-time, frameless, surface imaging-guided (SIG-RS) technique in the treatment of brain metastases. Data were retrospectively examined for 163 patients totaling 490 lesions and 45 post-operative cavities treated with SIG- RS in a median delivery of 1 fraction (range, 1-5 fraction) and to a median dose of 22 Gy (range, 12-30 Gy). Local control and overall survival were estimated by the Kaplan-Meier method. Median follow-up for all patients was 6.7 months (range, 0.5-45.1 months), with 119 of 163 (73%) deceased at the time of analysis. The 134 patients (82%) with follow-up imaging studies totaling 378 lesions and 39 post-operative cavities were evaluated for local control. The actuarial 6- and 12-month local control was 90% (95% confidence interval (CI), 84-94%) and 79% (95% CI, 71-86%), respectively. The actuarial 6- and 12-month overall survival was 80% (95% CI, 74-85%) and 56% (95% CI, 49-63%), respectively. There is no significant difference in local control between treatment to post-operative cavities or intact lesions. Consistent with our earlier report of 44 patients, SIG-RS for treatment of intracranial metastases can produce outcomes comparable to those with conventional frame-based and frameless SRS techniques while providing greater patient comfort with an open-faced mask and fast treatment time.

Evaluation of patient setup uncertainty of optical guided frameless system for intracranial stereotactic radiosurgery

The optically‐guided frameless system (OFLS) has been used in our clinic for intracranial stereotactic radiosurgery (SRS) since 2006, as it is especially effective in IMRT‐based radiosurgery (IMRS), which allows treating multiple brain lesions simultaneously using single isocenter approach. This study reports our retrospective analysis of patient setup accuracy using this system. The OFLS consists of a bite block with fiducial markers and an infra‐red camera system. To test reproducibility, patients are taken for reseat verification after bite block construction. Upon the completion of radiosurgery planning, the isocenter position(s) and images are sent to the optical guidance computer where fiducials are manually registered from the CT scan. During treatment, patient setup is monitored and guided by the camera readings on the fiducials. In addition, two orthogonal kV images are acquired and used as an isocenter verification tool. In addition, we have analyzed the reseat and fiducial digitization data of 56 patients. Retrospective comparison of kV images with reference images has been carried out for all the patients to evaluate actual patient setup accuracy at the time of treatment. The histogram of the findings shows that 82.2% of patients had 3D isodisplacement (E≤1mm; 5.2% had 1<E≤2mm). Hence, for 87.5 % of the patients in the study, treatments were finished under the optical guidance with a maximum setup error of 2 mm and the median setup error of 0 mm. For the remaining 12.5% of patients in the study, the isodisplacements were greater than 2 mm and the treatment records showed that those patients were repositioned, guided by the orthogonal kV‐images. It is found that the OFLS in the SRS treatment has acceptable accuracy when used in conjunction with orthogonal kV images, and the use of orthogonal kV images as a verification tool ensures the efficacy of frameless localization in the radiosurgery treatment. PACS numbers: 87.53.Ly, 87.61.Tg, 87.55.Qr, 87.56.‐v, 29.20.Ej

Intensity-modulated radiosurgery with rapidarc for multiple brain metastases and comparison with static approach

Rotational RapidArc (RA) and static intensity-modulated radiosurgery (IMRS) have been used for brain radiosurgery. This study compares the 2 techniques from beam delivery parameters and dosimetry aspects for multiple brain metastases. Twelve patients with 2-12 brain lesions treated with IMRS were replanned using RA. For each patient, an optimal 2-arc RA plan from several trials was chosen for comparison with IMRS. Homogeneity, conformity, and gradient indexes have been calculated. The mean dose to normal brain and maximal dose to other critical organs were evaluated. It was found that monitor unit (MU) reduction by RA is more pronounced for cases with larger number of brain lesions. The MU-ratio of RA and IMRS is reduced from 104% to 39% when lesions increase from 2 to 12. The dose homogeneities are comparable in both techniques and the conformity and gradient indexes and critical organ doses are higher in RA. Treatment time is greatly reduced by RA in intracranial radiosurgery, because RA uses fewer MUs, fewer beams, and fewer couch angles.

Clinical outcomes of palliative radiation therapy for children

PURPOSE In contrast to studies of adults, there are limited published data regarding palliative radiation therapy (RT) for children, and further study is greatly needed. METHODS AND MATERIALS We performed a retrospective review of all pediatric patients referred to our radiation oncology department over a 5-year span from January 1, 2007, to December 31, 2011. RESULTS Of 244 total pediatric patients referred, a subset of 45 (18.4%) were treated specifically with palliative intent for a total of 83 courses of RT. Follow-up data until study closure or death were available for 98% of patients. The median survival after initiation of palliative RT was 6.5 months. Overall, 23% of the children were alive at last follow-up visit, and 77% were deceased. The prescribed RT was completed in 93% of courses; 7% of courses were discontinued because of clinical deterioration due to systemic disease progression. The overall symptom response rate (partial or complete) was 72%. Overall response rate by symptom was 80% for bone pain, 55% for dyspnea or chest pain, 58% for neurologic symptoms, 50% for bleeding, and 100% for liver pain or ascites. Response rates by histology were 100% for leukemias, 91% for neuroblastoma, 76% for Ewing sarcoma, 64% for rhabdomyosarcoma, 54% for osteosarcoma, and 50% for primary central nervous system neoplasms. For responders, the median time from RT initiation to response was 1 week. For 7% of patients, a repeat course of RT for the same site and symptom was performed. No patients experienced RTOG (Radiation Therapy Oncology Group) grade 3 or greater acute or late toxicities. CONCLUSIONS RT is a useful palliative tool for pediatric patients that merits continued use and further study.

Single-Isocenter Frameless Volumetric Modulated Arc Radiosurgery for Multiple Intracranial Metastases.

BACKGROUND Stereotactic radiosurgery (SRS) is a well-accepted treatment for patients with intracranial metastases, but outcomes with volumetric modulated arc radiosurgery (VMAR) are poorly described. OBJECTIVE To report our initial clinical experience applying a novel single-isocenter technique to frameless VMAR for simultaneous treatment of multiple intracranial metastases. METHODS We performed a retrospective analysis of 15 patients undergoing frameless VMAR for multiple intracranial metastases using a single, centrally located isocenter in the period 2009 and 2011. Of these, 3 patients were treated for progressive or recurrent intracranial disease. A total of 62 metastases (median, 3 per patient; range, 2-13) were treated to a median dose of 20 Gy (range, 15-30 Gy). Three patients were treated with fractionated SRS. Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. RESULTS The median follow-up for all patients was 7.1 months (range, 1.1-24.3), with 11 patients (73.3%) followed until death. For the remaining 4 patients alive at the time of analysis, the median follow-up was 19.6 months (range, 9.2-24.3). Local control at 6 and 12 months was 91.7% (95% confidence interval [CI], 84.6%-100.0%) and 81.5% (95% CI, 67.9%-100.0%), respectively. Regional failure was observed in 9 patients (60.0%), and 7 patients (46.7%) received salvage therapy. Overall survival at 6 months was 60.0% (95% CI, 40.3%-88.2%). Grade 3 or higher treatment-related toxicity was not observed. The median total treatment time was 7.2 minutes (range, 2.8-13.2 minutes). CONCLUSION Single-isocenter, frameless VMAR for multiple intracranial metastases is a promising technique that may provide similar clinical outcomes compared with conventional radiosurgery.