Radiation Therapy for Brain Metastases: An ASTRO Clinical Practice Guideline.

PURPOSE: This guideline provides updated evidence-based recommendations addressing recent developments in the management of patients with brain metastases, including advanced radiation therapy techniques such as stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy and the emergence of systemic therapies with central nervous system activity. METHODS: The American Society for Radiation Oncology convened a task force to address 4 key questions focused on the radiotherapeutic management of intact and resected brain metastases from nonhematologic solid tumors. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: Strong recommendations are made for SRS for patients with limited brain metastases and Eastern Cooperative Oncology Group performance status 0 to 2. Multidisciplinary discussion with neurosurgery is conditionally recommended to consider surgical resection for all tumors causing mass effect and/or that are greater than 4 cm. For patients with symptomatic brain metastases, upfront local therapy is strongly recommended. For patients with asymptomatic brain metastases eligible for central nervous system-active systemic therapy, multidisciplinary and patient-centered decision-making to determine whether local therapy may be safely deferred is conditionally recommended. For patients with resected brain metastases, SRS is strongly recommended to improve local control. For patients with favorable prognosis and brain metastases receiving whole brain radiation therapy, hippocampal avoidance and memantine are strongly recommended. For patients with poor prognosis, early introduction of palliative care for symptom management and caregiver support are strongly recommended. CONCLUSIONS: The task force has proposed recommendations to inform best clinical practices on the use of radiation therapy for brain metastases with strong emphasis on multidisciplinary care.

Radiation Therapy for Small Cell Lung Cancer: An ASTRO Clinical Practice Guideline.

PURPOSE: Several sentinel phase III randomized trials have recently been published challenging traditional radiation therapy (RT) practices for small cell lung cancer (SCLC). This American Society for Radiation Oncology guideline reviews the evidence for thoracic RT and prophylactic cranial irradiation (PCI) for both limited-stage (LS) and extensive-stage (ES) SCLC. METHODS: The American Society for Radiation Oncology convened a task force to address 4 key questions focused on indications, dose fractionation, techniques and timing of thoracic RT for LS-SCLC, the role of stereotactic body radiation therapy (SBRT) compared with conventional RT in stage I or II node negative SCLC, PCI for LS-SCLC and ES-SCLC, and thoracic consolidation for ES-SCLC. Recommendations were based on a systematic literature review and created using a consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: The task force strongly recommends definitive thoracic RT administered once or twice daily early in the course of treatment for LS-SCLC. Adjuvant RT is conditionally recommended in surgically resected patients with positive margins or nodal metastases. Involved field RT delivered using conformal advanced treatment modalities to postchemotherapy volumes is also strongly recommended. For patients with stage I or II node negative disease, SBRT or conventional fractionation is strongly recommended, and chemotherapy should be delivered before or after SBRT. In LS-SCLC, PCI is strongly recommended for stage II or III patients who responded to chemoradiation, conditionally not recommended for stage I patients, and should be a shared decision for patients at higher risk of neurocognitive toxicities. In ES-SCLC, radiation oncologist consultation for consideration of PCI versus magnetic resonance surveillance is strongly recommended. Lastly, the use of thoracic RT is strongly recommended in select patients with ES-SCLC after chemotherapy treatment, including a conditional recommendation in those responding to chemotherapy and immunotherapy. CONCLUSIONS: RT plays a vital role in both LS-SCLC and ES-SCLC. These guidelines inform best clinical practices for local therapy in SCLC.

Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline.

PURPOSE: To present evidence-based guidelines for radiation therapy in treating glioblastoma not arising from the brainstem. METHODS AND MATERIALS: The American Society for Radiation Oncology (ASTRO) convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects? (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status? (3) What are ideal target volumes for curative-intent external beam radiation therapy of glioblastoma? (4) What is the role of reirradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. RESULTS: Following biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiation therapy (eg, 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (≥70 years of age) with reasonable performance status should receive hypofractionated radiation therapy (eg, 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving 2 phases (primary and boost volumes) or 1 phase (single volume). For recurrent glioblastoma, focal reirradiation can be considered in younger patients with good performance status. CONCLUSIONS: Radiation therapy occupies an integral role in treating glioblastoma. Whether and how radiation therapy should be applied depends on characteristics specific to tumor and patient, including age and performance status.

Histopathologic validation of 3'-deoxy-3'-18F-fluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude mice.

BACKGROUND AND PURPOSE: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrates accelerated tumor repopulation during fractionated irradiation with pathological validation (Ki-67 and BrdUrd makers) in a xenograft model system. However, these and other functional assays must be performed ex vivo and post hoc. We propose a novel, in vivo, real-time assay utilizing (18)F-FLT PET. MATERIAL AND METHODS: Nude mice with FaDu-hSCC were irradiated with 12 or 18 fractions of 1.8 Gy ([Dm]=3.0 Gy), either daily or every second day. (18)F-FLT micro-PET scans were performed at different time points, FLT parameters (SUVmax, SUVmean, and T/NT) were measured. Tumor sections were stained for Ki-67 and BrdUrd, a labeling index (LI) was calculated. Imaging-pathology correlation was determined by comparing FLT parameters and immunohistochemical results. RESULTS: Measured SUVmax, SUVmean and T/NT decreased significantly after daily irradiation with 12 fractions in 12 days (P<0.05) and 18 fractions in 18 days (P<0.05). In contrast, these parameters increased in mice treated with 12 fractions in 24 days (P>0.05) and 18 fractions in 36 days (P>0.05), suggesting accelerated repopulation. Similarly, Ki-67 and BrdUrd LIs demonstrated significant decreases with daily irradiation (P<0.05), and increases with every-second-day irradiation (P>0.05). (18)F-FLT parameters correlated strongly with proliferation markers (r(2): 0.679-0.879, P<0.001). CONCLUSIONS: (18)F-FLT parameters were in good agreement with Ki-67 and BrdUrd Li. These results may support a potential role for (18)F-FLT PET in real-time detection of tumor repopulation during fractionated radiotherapy.

Stereotactic body radiotherapy: a critical review for nonradiation oncologists.

Stereotactic body radiotherapy (SBRT) involves the treatment of extracranial primary tumors or metastases with a few, high doses of ionizing radiation. In SBRT, tumor kill is maximized and dose to surrounding tissue is minimized, by precise and accurate delivery of multiple radiation beams to the target. This is particularly challenging, because extracranial lesions often move with respiration and are irregular in shape, requiring careful treatment planning and continual management of this motion and patient position during irradiation. This review presents the rationale, process workflow, and technology for the safe and effective administration of SBRT, as well as the indications, outcome, and limitations for this technique in the treatment of lung cancer, liver cancer, and metastatic disease.

Hypofractionation for clinically localized prostate cancer.

This manuscript reviews the clinical evidence for hypofractionation in prostate cancer, focusing on data from prospective trials. For the purposes of this manuscript, we categorize hypofractionation as moderate (2.4-4 Gy per fraction) or extreme (6.5-10 Gy per fraction). Five randomized controlled trials have evaluated moderate hypofractionation in >1500 men, with most followed for >4-5 years. The results of these randomized trials are inconsistent. No randomized trials or other rigorous comparisons of extreme hypofractionation with conventional fractionation have been reported. Prospective single-arm studies of extreme hypofractionation appear favorable, but small sample sizes preclude precise estimates of efficacy and short follow-up prevents complication estimates beyond 3-5 years. Over the next several years, the results of 3 large noninferiority trials of moderate hypofractionation and 2 randomized trials of extreme hypofractionation should help clarify the role of hypofractionation in prostate cancer therapy.

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial.

PURPOSE: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Contemporary radiotherapy in head and neck cancer: balancing chance for cure with risk for complication.

Radiotherapy plays an integral role in the management of most patients with cancers of the head and neck. Better understanding of radiobiology and radiation physics has allowed radiation oncologists to enhance the tumoricidal effects of radiation and reduce the severity of normal tissue toxicities. This article reviews the biologic foundation of head and neck radiotherapy, the physical principles and technological innovations that enable delivery of highly conformal radiation, the acute and late complications of radiation-based treatments, and the clinical evidence supporting contemporary practice.

Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma multiforme.

Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.

Incorporating gross anatomy education into radiation oncology residency: a 2-year curriculum with evaluation of resident satisfaction.

PURPOSE: Radiation oncologists require a thorough understanding of anatomy, but gross anatomy is not part of the standard residency curriculum. "Oncoanatomy" is an educational program for radiation oncology residents at Duke University that integrates cadaver dissection into the instruction of oncologic anatomy, imaging, and treatment planning. In this report, the authors document their experience with a 2-year curriculum. METHODS: Nineteen radiation oncology residents from Duke University and the University of North Carolina participated during academic years 2008-2009 and 2009-2010. Monthly modules, based on anatomic site, consisted of one or two clinically oriented hour-long lectures, followed by a 1-hour gross anatomy session. Clinical lectures were case based and focused on radiographic anatomy, image segmentation, and field design. Gross anatomy sessions centered on cadaver prosections, with small groups rotating through stations at which anatomists led cadaver exploration. Adjacent monitors featured radiologic imaging to facilitate synthesis of gross anatomy with imaging anatomy. Satisfaction was assessed on a 10-point scale via anonymous survey. RESULTS: Twenty modules were held over the 2-year period. Participants gave the course a median rating of 8 (interquartile range, 7-9), with 1 signifying "as effective as the worst educational activities" and 10 "as effective as the best educational activities." High resident satisfaction was seen with all module components. CONCLUSIONS: Incorporating a structured, 2-year gross anatomy-based curriculum into radiation oncology residency is feasible and associated with high resident satisfaction.

Measuring tumor cell proliferation with 18F-FLT PET during radiotherapy of esophageal squamous cell carcinoma: a pilot clinical study.

UNLABELLED: The primary aim of this study was to use serial (18)F-3'-deoxy-3'-fluorothymidine (FLT) PET/CT to measure tumor cell proliferation during radiotherapy of squamous cell carcinoma (SCC) of the esophagus. METHODS: Twenty-one patients with inoperable locally advanced SCC of the esophagus underwent serial (18)F-FLT PET/CT during radiotherapy. Each patient received a pretreatment scan, followed by 1-3 scans after delivery of 2, 6, 10, 20, 30, 40, 50, or 60 Gy to the tumor. RESULTS: Among the 19 patients who completed radiotherapy without interruption, parameters reflecting (18)F-FLT uptake in the tumor (i.e., maximum tumor standardized uptake value [SUVmax] and proliferation target volume) decreased steadily. All patients demonstrated an almost complete absence of proliferating esophageal tumor after 30 Gy and a complete absence after 40 Gy. In the 2 patients whose radiotherapy course was interrupted, (18)F-FLT uptake in the tumor was greater after the interruption than before the interruption. Marked early reduction of (18)F-FLT uptake in irradiated bone marrow was observed in all patients, even after only 2 Gy. All showed a complete absence of proliferating marrow in irradiated regions after 10 Gy. Both patients who underwent scans after completing the entire radiotherapy course showed no tumor uptake on (18)F-FLT PET/CT but high uptake on (18)F-FDG PET/CT. Pathologic examination of these regions revealed inflammatory infiltrates but no residual tumor. CONCLUSION: (18)F-FLT uptake can be used to monitor the biologic response of esophageal SCC and normal tissue to radiotherapy. Increased uptake of (18)F-FLT after treatment interruptions may reflect accelerated repopulation. (18)F-FLT PET/CT may have an advantage over (18)F-FDG PET/CT in differentiating inflammation from tumor.

Prostate cancer: is inapparent tumor at endorectal MR and MR spectroscopic imaging a favorable prognostic finding in patients who select active surveillance?

PURPOSE: To retrospectively determine whether inapparent tumor at endorectal magnetic resonance (MR) imaging and MR spectroscopic imaging is a favorable prognostic finding in prostate cancer patients who select active surveillance for management. MATERIALS AND METHODS: Committee on Human Research approval was obtained and compliance with HIPAA regulations was observed, with waiver of requirement for written consent. Ninety-two men (mean age, 64 years; range, 43-85 years) were retrospectively identified who had biopsy-proved prostate cancer, who had undergone baseline endorectal MR imaging and MR spectroscopic imaging, and who had selected active surveillance for management. Their mean baseline serum prostate-specific antigen (PSA) level was 5.5 ng/mL, and the median Gleason score was 6. Two readers with 10 and 3 years of experience independently reviewed all MR images and determined whether tumor was apparent on the basis of evaluation of established morphologic and metabolic findings. Another investigator compiled data about baseline clinical stage, biopsy findings, and serum PSA measurements. Multiple logistic regression analysis was used to investigate the relationship between the clinical parameters and tumor apparency at MR imaging and the biochemical outcome. RESULTS: At baseline MR imaging, readers 1 and 2 considered 54 and 26 patients, respectively, to have inapparent tumor (fair interobserver agreement; kappa = 0.30). During a mean follow-up of 4.8 years, 52 patients had a stable PSA level and 40 had an increasing PSA level. In multivariate analysis, no significant association was found between the baseline clinical stage, Gleason score, serum PSA level, or the presence of apparent tumor at endorectal MR imaging and MR spectroscopic imaging for either reader and the biochemical outcome (P > .05 for all). CONCLUSION: Endorectal MR imaging and MR spectroscopic imaging findings of tumor apparency or inapparency in prostate cancer patients who select active surveillance for management do not appear to be of prognostic value.

Combined modality treatment with high-dose-rate brachytherapy boost for locally advanced prostate cancer.

PURPOSE: This is a retrospective review of our experience using high-dose-rate (HDR) brachytherapy boost for prostate cancer. METHODS AND MATERIALS: During the study period, we recommended external beam radiotherapy (45 Gy) and HDR boost (18 Gy in three fractions) combined with hormonal therapy (HT) for 2 months before and during radiotherapy to patients with at least one of the following risk features: pretreatment prostate-specific antigen>10, Gleason score (GS)>or=7, and clinical T3 disease. Additional HT for 2 years after radiotherapy was recommended for patients with GS>7. To patients whose risk of positive nodes exceeded 15%, we recommended whole pelvic radiotherapy. We administered HDR via single implant, and all fractions were given within 24h. RESULTS: This report is based on our initial 64 patients treated with HDR boost. The median follow-up was 50 months (range 25-68 months). The 4-year estimates of overall and disease-free survival were 98% and 92%, respectively. One patient experienced late grade 4 gastrointestinal toxicity. CONCLUSIONS: HDR brachytherapy is an effective means of delivering conformal prostate radiotherapy, and may be used with whole pelvic radiotherapy and HT.