A.R. Godley

Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling

Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.

Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Spinal Sarcomas

Purpose: Despite advancements in local and systemic therapy, metastasis remains common in the natural history of sarcomas. Unfortunately, such metastases are the most significant source of morbidity and mortality in this heterogeneous disease. As a classically radioresistant histology, stereotactic radiosurgery has emerged to control spinal sarcomas and provide palliation. However, there is a lack of data regarding pain relief and relapse following stereotactic radiosurgery. Methods: We queried a retrospective institutional database of patients who underwent spine stereotactic radiosurgery for primary and metastatic sarcomas. The primary outcome was pain relief following stereotactic radiosurgery. Secondary outcomes included progression of pain, radiographic failure, and development of toxicities following treatment. Results: Forty treatment sites were eligible for inclusion; the median prescription dose was 16 Gy in a single fraction. Median time to radiographic failure was 14 months. At 6 and 12 months, radiographic control was 63% and 51%, respectively. Among patients presenting with pain, median time to pain relief was 1 month. Actuarial pain relief at 6 months was 82%. Median time to pain progression was 10 months; at 12 months, actuarial pain progression was 51%. Following multivariate analysis, presence of neurologic deficit at consult (hazard ratio: 2.48, P < .01) and presence of extraspinal bone metastases (hazard ratio: 2.83, P < .01) were associated with pain relief. Greater pain at consult (hazard ratio: 1.92, P < .01), prior radiotherapy (hazard ratio: 4.65, P = .02), and greater number of irradiated vertebral levels were associated with pain progression. Conclusions: Local treatment of spinal sarcomas has remained a challenge for decades, with poor rates of local control and limited pain relief following conventional radiotherapy. In this series, pain relief was achieved in 82% of treatments at 6 months, with half of patients experiencing pain progression by 12 months. Given minimal toxicity and suboptimal pain control at 12 months, dose escalation beyond 16 Gy is warranted.

Workflow enhancement (WE) improves safety in radiation oncology: Putting the we and team together

PURPOSE To review the impact of a workflow enhancement (WE) team in reducing treatment errors that reach patients within radiation oncology. METHODS AND MATERIALS It was determined that flaws in our workflow and processes resulted in errors reaching the patient. The process improvement team (PIT) was developed in 2010 to reduce errors and was later modified in 2012 into the current WE team. Workflow issues and solutions were discussed in PIT and WE team meetings. Due to tensions within PIT that resulted in employee dissatisfaction, there was a 6-month hiatus between the end of PIT and initiation of the renamed/redesigned WE team. In addition to the PIT/WE team forms, the department had separate incident forms to document treatment errors reaching the patient. These incident forms are rapidly reviewed and monitored by our departmental and institutional quality and safety groups, reflecting how seriously these forms are treated. The number of these incident forms was compared before and after instituting the WE team. RESULTS When PIT was disbanded, a number of errors seemed to occur in succession, requiring reinstitution and redesign of this team, rebranded the WE team. Interestingly, the number of incident forms per patient visits did not change when comparing 6 months during the PIT, 6 months during the hiatus, and the first 6 months after instituting the WE team (P=.85). However, 6 to 12 months after instituting the WE team, the number of incident forms per patient visits decreased (P=.028). After the WE team, employee satisfaction and commitment to quality increased as demonstrated by Gallup surveys, suggesting a correlation to the WE team. CONCLUSIONS A team focused on addressing workflow and improving processes can reduce the number of errors reaching the patient. Time is necessary before a reduction in errors reaching patients will be seen.

Combining prior day contours to improve automated prostate segmentation.

PURPOSE To improve the accuracy of automatically segmented prostate, rectum, and bladder contours required for online adaptive therapy. The contouring accuracy on the current image guidance [image guided radiation therapy (IGRT)] scan is improved by combining contours from earlier IGRT scans via the simultaneous truth and performance level estimation (STAPLE) algorithm. METHODS Six IGRT prostate patients treated with daily kilo-voltage (kV) cone-beam CT (CBCT) had their original plan CT and nine CBCTs contoured by the same physician. Three types of automated contours were produced for analysis. (1) Plan: By deformably registering the plan CT to each CBCT and then using the resulting deformation field to morph the plan contours to match the CBCT anatomy. (2) Previous: The contour set drawn by the physician on the previous day CBCT is similarly deformed to match the current CBCT anatomy. (3) STAPLE: The contours drawn by the physician, on each prior CBCT and the plan CT, are deformed to match the CBCT anatomy to produce multiple contour sets. These sets are combined using the STAPLE algorithm into one optimal set. RESULTS Compared to plan and previous, STAPLE improved the average Dices coefficient (DC) with the original physician drawn CBCT contours to a DC as follows: Bladder: 0.81 ± 0.13, 0.91 ± 0.06, and 0.92 ± 0.06; Prostate: 0.75 ± 0.08, 0.82 ± 0.05, and 0.84 ± 0.05; and Rectum: 0.79 ± 0.06, 0.81 ± 0.06, and 0.85 ± 0.04, respectively. The STAPLE results are within intraobserver consistency, determined by the physician blindly recontouring a subset of CBCTs. Comparing plans recalculated using the physician and STAPLE contours showed an average disagreement less than 1% for prostate D98 and mean dose, and 5% and 3% for bladder and rectum mean dose, respectively. One scan takes an average of 19 s to contour. Using five scans plus STAPLE takes less than 110 s on a 288 core graphics processor unit. CONCLUSIONS Combining the plan and all prior days via the STAPLE algorithm to produce treatment day contours is superior to the current standard of deforming only the plan contours to the daily CBCT. STAPLE also improves the precision, with a substantial decrease in standard deviation, a key for adaptive therapy. Geometrically and dosimetrically accurate contours can be automatically generated with STAPLE on prostate region kV CBCT in a time scale suitable for online adaptive therapy.

Departmental Workload and Physician Errors in Radiation Oncology

Supplemental digital content is available in the text. Purpose The purpose of this work was to evaluate measures of increased departmental workload in relation to the occurrence of physician-related errors and incidents reaching the patient in radiation oncology. Materials and Methods All data were collected for the year 2013. Errors were defined as forms received by our departmental process improvement team; of these forms, only those relating to physicians were included in the study. Incidents were defined as serious errors reaching the patient requiring appropriate action; these were reported through a separate system. Workload measures included patient volumes and physician schedules and were obtained through departmental records for daily and monthly data. Errors and incidents were analyzed for relation with measures of workload using logistic regression modeling. Results Ten incidents occurred in the year. The number of patients treated per day was a significant factor relating to incidents (P < 0.003). However, the fraction of department physicians off-duty and the ratio of patients to physicians were not found to be significant factors relating to incidents. Ninety-one physician-related errors were identified, and the ratio of patients to physicians (rolling average) was a significant factor relating to errors (P < 0.03). The number of patients and the fraction of physicians off-duty were not significant factors relating to errors. A rapid increase in patient treatment visits may be another factor leading to errors and incidents. All incidents and 58% of errors occurred in months where there was an increase in the average number of fields treated per day from the previous month; 6 of the 10 incidents occurred in August, which had the highest average increase at 26%. Conclusions Increases in departmental workload, especially rapid changes, may lead to higher occurrence of errors and incidents in radiation oncology. When the department is busy, physician errors may be perpetuated owing to an overwhelmed departmental checks system, leading to incidents reaching the patient. Insights into workload and workflow will allow for the development of targeted approaches to preventing errors and incidents.

Using Daily Diagnostic Quality Images To validate Planning Margins for Inter-fractional Variations of Prostate Cancer

The purpose of this study is to use the same diagnostic-quality verification and planning CTs to validate planning margin account for residual interfractional variations with image-guided soft tissue alignment of the prostate. For nine prostate cancer patients treated with IMRT to 78 Gy in 39 fractions, daily verification CT-on-rails images of the first seven and last seven fractions (n=126) were retrospectively selected for this study. On these images, prostate, bladder, and rectum were delineated by the same attending physician. Clinical plans were created with a margin of 8 mm except for 5 mm posteriorly, referred to as 8/5 mm. Three additional plans were created for each patient with the margins of 6/4 mm, 4/2 mm, and 2 mm uniform. These plans were subsequently applied to daily images and radiation doses were recalculated. The isocenters of these plans were placed according to clinical online shifts, which were based on soft tissue alignment to the prostate. Retrospective offline shifts by aligning prostate contours were compared to online shifts. The resultant daily target dose was analyzed using D99, the percentage of the prescription dose received by 99% of CTV. The percent of bladder volume receiving 65 Gy (V65Gy) and rectum V70Gy were also analyzed. After interfractional correction, using CTV D99>97%% criteria, 8/5 mm, 6/4 mm, 4/2 mm, and 2 mm planning margins met the CTV dose coverage in 95%, 91%, 65%, and 53% of the 126 fractions with online shifts, and 99%, 98%, 85%, and 68% with offline shifts. The rectum V70Gy and bladder V65Gy were significantly decreased at each level of margin reduction (p<0.05). With daily diagnostic quality imaging-guidance, the interfractional planning margin may be reduced from 8/5 mm to 6/4 mm. The residual interfractional uncertainties most likely stem from prostate rotation and deformation. PACS number(s): 87.53.-j.The purpose of this study is to use the same diagnostic‐quality verification and planning CTs to validate planning margin account for residual interfractional variations with image‐guided soft tissue alignment of the prostate. For nine prostate cancer patients treated with IMRT to 78 Gy in 39 fractions, daily verification CT‐on‐rails images of the first seven and last seven fractions (n=126) were retrospectively selected for this study. On these images, prostate, bladder, and rectum were delineated by the same attending physician. Clinical plans were created with a margin of 8 mm except for 5 mm posteriorly, referred to as 8/5 mm. Three additional plans were created for each patient with the margins of 6/4 mm, 4/2 mm, and 2 mm uniform. These plans were subsequently applied to daily images and radiation doses were recalculated. The isocenters of these plans were placed according to clinical online shifts, which were based on soft tissue alignment to the prostate. Retrospective offline shifts by aligning prostate contours were compared to online shifts. The resultant daily target dose was analyzed using D99, the percentage of the prescription dose received by 99% of CTV. The percent of bladder volume receiving 65 Gy (V65Gy) and rectum V70Gy were also analyzed. After interfractional correction, using CTV D99>97%% criteria, 8/5 mm, 6/4 mm, 4/2 mm, and 2 mm planning margins met the CTV dose coverage in 95%, 91%, 65%, and 53% of the 126 fractions with online shifts, and 99%, 98%, 85%, and 68% with offline shifts. The rectum V70Gy and bladder V65Gy were significantly decreased at each level of margin reduction (p<0.05). With daily diagnostic quality imaging‐guidance, the interfractional planning margin may be reduced from 8/5 mm to 6/4 mm. The residual interfractional uncertainties most likely stem from prostate rotation and deformation. PACS number(s): 87.53.‐j

The effects of extra high dose rate irradiation on glioma stem-like cells

Radiation therapy is an integral part of treatment for patients with glioblastoma. New technological advances in linear accelerators have made extra-high dose rate irradiation possible. This shortens patient treatment time significantly compared to standard dose rate irradiation, but the biologic effects of extra high dose rate irradiation are poorly understood. Glioma stem-like cells (GSCs) are resistant to standard radiation and contribute to tumor progression. Here, we assess the therapeutic effect of extra high dose rate vs. standard dose rate irradiation on GSCs. GSCs were exposed to 2, 4 and 6 Gy X-irradiation at dose rates of 4.2 Gy/min or 21.2 Gy/min (400 monitoring units (MU)/min or 2100 MU/min). We analyzed cell survival with cell growth assays, tumorsphere formation assays and colony formation assays. Cell kill and self-renewal were dependent on the total dose of radiation delivered. However, there was no difference in survival of GSCs or DNA damage repair in GSCs irradiated at different dose rates. GSCs exhibited significant G1 and G2/M phase arrest and increased apoptosis with higher doses of radiation but there was no difference between the two dose rates at each given dose. In a GSC-derived preclinical model of glioblastoma, radiation extended animal survival, but there was no difference in survival in mice receiving different dose rates of radiation. We conclude that GSCs respond to larger fractions of radiation, but extra high dose rate irradiation has no significant biologic advantage in comparison with standard dose rate irradiation.

Temporally feathered intensity‐modulated radiation therapy: A planning technique to reduce normal tissue toxicity

Purpose Intensity‐modulated radiation therapy (IMRT) has allowed optimization of three‐dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation‐induced normal tissue toxicity is a major contributor to patients’ quality of life and often a dose‐limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation‐induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy “temporally feathered radiation therapy” (TFRT). Methods Temporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation‐induced tissue damage and repair over time. Results Model‐based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation‐induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ‐specific recovery rate of sublethal radiation‐induced damage. Conclusions TFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model‐based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation‐induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP).

Review of Pulsed Reduced Dose Rate Re-irradiation for Recurrent Tumors

Pulsed Reduced Dose Rate (PRDR) is an external beam re-irradiation technique that may be appropriate for recurrent tumors in patients who have previously undergone radiation treatment. PRDR is thought to effectively target dividing neoplastic cells that display Low-Dose Hyper-Radiosensitivity (LDHRS) while permitting sub-lethal damage repair in non-proliferating normal tissues. To date, only a few case reports and several retrospective studies have reported on efficacy after PRDR retreatment across several disease sites, including CNS, breast, and nasopharyngeal tumors. In this article, we review available publications of PRDR re-irradiation in patients. Taken together, this research demonstrates that PRDR offers a treatment option for large volume recurrent disease at previously irradiated sites. More research is needed to establish therapeutic benefit and late adverse effects for each disease site.

Intensity modulated radiation therapy with pulsed reduced dose rate as a reirradiation strategy for recurrent central nervous system tumors: An institutional series and literature review

BACKGROUND Pulsed reduced dose rate (PRDR) is a reirradiation technique that potentially overcomes volume and dose limitations in the setting of previous radiation therapy for recurrent central nervous system (CNS) tumors. Intensity modulated radiation therapy (IMRT) has not yet been reported as a PRDR delivery technique. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for CNS reirradiation. METHODS AND MATERIALS A total of 24 patients with recurrent brain tumors received PRDR reirradiation between August 2012 and December 2014. Twenty-two patients were planned with IMRT. Linear accelerators delivered an effective dose rate of 0.0667 Gy/minute. Data collected included number of prior interventions, diagnosis, tumor grade, radiation therapy dose and fractionation, normal tissue dose, radiation therapy planning parameters, time to progression, overall survival, and adverse events. RESULTS The median time to PRDR from completion of initial radiation therapy was 47.8 months (range, 11-389.1 months). The median PRDR dose was 54 Gy (range, 38-60 Gy). The mean planning target volume was 369.1 ± 177.9 cm3. The median progression-free survival and 6-month progression-free survival after PRDR treatment was 3.1 months and 31%, respectively. The median overall survival and 6-month overall survival after PRDR treatment was 8.7 months and 71%, respectively. Fifty percent of patients had ≥4 chemotherapy regimens before PRDR. Toxicity was similar to initial treatment, including no cases of radiation necrosis. CONCLUSION IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent CNS tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated. Prospective studies are necessary to determine the optimal timing of PRDR reirradiation, the role of concurrent systemic agents, and the ideal patient population who would receive the maximal benefit from this treatment approach. SUMMARY Intensity modulated radiation therapy (IMRT) has not yet been reported as a pulsed reduced dose rate (PRDR) delivery technique for recurrent brain tumors and may allow for safe and comprehensive reirradiation for large volume tumors. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for recurrent central nervous system tumors. We conclude that IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent brain tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated.