Alvin R. Cabrera

The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American society for radiation oncology evidence-based guideline

PURPOSE To present evidence-based guidelines for adjuvant radiation in the treatment of endometrial cancer. METHODS AND MATERIALS Key clinical questions to be addressed in this evidence-based guideline on endometrial cancer were identified. A comprehensive literature review was performed to identify studies that included no adjuvant therapy, or pelvic radiation or vaginal brachytherapy with or without systemic chemotherapy. Outcomes included local control, survival rates, and overall assessment of quality of life. RESULTS Patients with grade 1 or 2 cancers with either no invasion or <50% myometrial invasion (MI), especially when no other high risk features are present, can be safely observed after hysterectomy. Vaginal cuff brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence for patients with grade 1 or 2 cancers with ≥50% MI or grade 3 tumors with <50% MI. Patients with grade 3 cancer with ≥50% MI or cervical stroma invasion may benefit from pelvic radiation to reduce the risk of pelvic recurrence. There is limited evidence for a benefit to vaginal cuff brachytherapy following pelvic radiation. Multimodality treatment is recommended for patients with positive nodes or involved uterine serosa, ovaries or fallopian tubes, vagina, bladder, or rectum. CONCLUSIONS External beam and vaginal brachytherapy remain integral aspects of adjuvant therapy for endometrial cancer.

Measuring Tumor Cell Proliferation with 18F-FLT PET During Radiotherapy of Esophageal Squamous Cell Carcinoma: A Pilot Clinical Study

The primary aim of this study was to use serial 18F-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 18F-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 18F-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, 18F-FLT uptake in the tumor was greater after the interruption than before the interruption. Marked early reduction of 18F-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 18F-FLT PET/CT but high uptake on 18F-FDG PET/CT. Pathologic examination of these regions revealed inflammatory infiltrates but no residual tumor. Conclusion: 18F-FLT uptake can be used to monitor the biologic response of esophageal SCC and normal tissue to radiotherapy. Increased uptake of 18F-FLT after treatment interruptions may reflect accelerated repopulation. 18F-FLT PET/CT may have an advantage over 18F-FDG PET/CT in differentiating inflammation from tumor.

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.

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. Cancer 2014;120:942–954.

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.

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.

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.

Histopathologic validation of 3′-deoxy-3′-18F-fluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude mice18F-FLT PET repopulation -->

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.

An Active Optical Flow Model for Dose Prediction in Spinal SBRT Plans

Accurate dose predication is critical to spinal stereotactic body radiation therapy (SBRT). It enables radiation oncologists and planners to design treatment plans that maximally protect spinal cord while effectively controlling surrounding tumors. Spinal cord dose distribution is primarily affected by the shapes of tumor boundaries near the organ. In this work, we estimate such boundary effects and predict dose distribution by exploring an active optical flow model (AOFM). To establish AOFM, we collect a sequence of dose sub-images and tumor contours near spinal cords from a database of clinically accepted spine SBRT plans. The data are classified into five groups according to the tumor location in relation to the spinal cords. In each group, we randomly choose a dose sub-image as the reference and register all other dose images to the reference using an optical flow method. AOFM is then constructed by importing optical flow vectors and dose values into the principal component analysis. To develop the predictive model for a group, we also build active shape model (ASM) of tumor contours near the spinal cords. The correlation between ASM and AOFM is estimated via the multiple regression model. When predicting dose distribution of a new case, the group was first determined based on the case’s tumor contour. Then the corresponding model for the group is used to map from the ASM space to the AOFM space. Finally, the parameters in the AOFM space are used to estimate dose distribution. This method was validated on 30 SBRT plans. Analysis of dose-volume histograms revealed that at the important 2 % volume mark, the dose difference between prediction and clinical plan is less than \(4\,\%\). These results suggest that the AOFM-based approach is a promising tool for predicting accurate spinal cord dose in clinical practice.

SU‐FF‐J‐103: Concepts for Normal Tissue Sparing with Patient‐Specific Margins in IMRT Boost Treatments for Cervix

Purpose: This concept study quantifies the potential for normal tissue sparing in IMRT boost plans for cervical cancer by employing patient‐specific margins. Various PTV expansion margins are evaluated, including best‐case and standard‐case scenarios, which encompass internal organ motion over the intrafractional treatment period. Method and Materials: For 5 subjects, margins are delineated by contouring the cervix on 500 fast‐spin‐echo cine‐MR images taken at regular intervals over a 20 minute span using in‐house software (TOMAS). Organ drift is determined by magnitude of translation of contours in S‐I and P‐A directions with mm accuracy; research‐margin CTV to PTV expansion is defined by the magnitude of organ drift. Comparison is made to IMRT plans with PTV expansions for standard‐margin prostate treatment, chosen for analogous anatomical location and geometry. Dose constraints for optimization are defined by ICRU38. Plans are created in Eclipse TPS with 5 non‐opposing beams, and PTV constrained to 95% isodose line over 98% volume for all plans (limiting organs constrained to best‐possible distribution). Dosimetric savings for limiting organs is determined with EUD, calculated using CERR software (a = 8.33, 2.0 for rectum, bladder). Results: Customized margins varied between 0.1 and 0.7 cm (direction dependent), well below the 1.5 cm uniform expansion in the standard case. With patient‐specific margins, comparisons of EUD for limiting organs suggest up to 40% reduction in bladder dose and 10% reduction in rectal dose. Conclusion: This study shows that application of an advanced IGRT procedure to generate patient‐specific margins can lead to measurable dose reduction to normal tissues for cervical carcinoma boost treatments with IMRT. For some patients the dose reduction can be quite compelling, given specifics of anatomy, and the method proves useful for increasing normal tissue sparing in abdominal RT treatments.