Bradford A. Perez

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.

Imaging Primary Lung Cancers in Mice to Study Radiation Biology

PURPOSE To image a genetically engineered mouse model of non-small-cell lung cancer with micro-computed tomography (micro-CT) to measure tumor response to radiation therapy. METHODS AND MATERIALS The Cre-loxP system was used to generate primary lung cancers in mice with mutation in K-ras alone or in combination with p53 mutation. Mice were serially imaged by micro-CT, and tumor volumes were determined. A comparison of tumor volume by micro-CT and tumor histology was performed. Tumor response to radiation therapy (15.5 Gy) was assessed with micro-CT. RESULTS The tumor volume measured with free-breathing micro-CT scans was greater than the volume calculated by histology. Nevertheless, this imaging approach demonstrated that lung cancers with mutant p53 grew more rapidly than lung tumors with wild-type p53 and also showed that radiation therapy increased the doubling time of p53 mutant lung cancers fivefold. CONCLUSIONS Micro-CT is an effective tool to noninvasively measure the growth of primary lung cancers in genetically engineered mice and assess tumor response to radiation therapy. This imaging approach will be useful to study the radiation biology of lung cancer.

Tumor cells, but not endothelial cells, mediate eradication of primary sarcomas by stereotactic body radiation therapy

Tumor cells, rather than endothelial cells, are critical targets that regulate primary sarcoma eradication by radiation therapy. Not all cells are eradicated equally Personalized cancer therapies dominate the news. But radiation therapy continues to be an essential part of the treatment regimens of nearly half of all cancer patients—sometimes achieving complete tumor regression through the safe delivery of high doses of radiation. Previous research with transplanted tumor models in mice has suggest that radiation targets, not only the tumor cells themselves, but also components of the surrounding milieu, which comprises blood vessels and various cell types that influence tumor growth. Now Moding et al. challenge the earlier findings in studies conducted with primary sarcomas in mice that carried, in either tumor or endothelial cells, genetic mutations that modulate radiation sensitivity. The authors found that it was the tumor, rather than endothelial, cells that mediate primary sarcoma shrinkage by radiation therapy and that selective small-molecule inhibition of a DNA-damage response enzyme can enhance radiosensitization of some tumors. Cancer clinics currently use high-dose stereotactic body radiation therapy as a curative treatment for several kinds of cancers. However, the contribution of vascular endothelial cells to tumor response to radiation remains controversial. Using dual recombinase technology, we generated primary sarcomas in mice with targeted genetic mutations specifically in tumor cells or endothelial cells. We selectively mutated the proapoptotic gene Bax or the DNA damage response gene Atm to genetically manipulate the radiosensitivity of endothelial cells in primary soft tissue sarcomas. Bax deletion from endothelial cells did not affect radiation-induced cell death in tumor endothelial cells or sarcoma response to radiation therapy. Although Atm deletion increased endothelial cell death after radiation therapy, deletion of Atm from endothelial cells failed to enhance sarcoma eradication. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Treatment with BEZ235, a small-molecule protein kinase inhibitor, radiosensitized primary sarcomas more than the heart. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors.

Uveal Melanoma Treated With Iodine-125 Episcleral Plaque: An Analysis of Dose on Disease Control and Visual Outcomes

PURPOSE To investigate, in the treatment of uveal melanomas, how tumor control, radiation toxicity, and visual outcomes are affected by the radiation dose at the tumor apex. METHODS AND MATERIALS A retrospective review was performed to evaluate patients treated for uveal melanoma with (125)I plaques between 1988 and 2010. Radiation dose is reported as dose to tumor apex and dose to 5 mm. Primary endpoints included time to local failure, distant failure, and death. Secondary endpoints included eye preservation, visual acuity, and radiation-related complications. Univariate and multivariate analyses were performed to determine associations between radiation dose and the endpoint variables. RESULTS One hundred ninety patients with sufficient data to evaluate the endpoints were included. The 5-year local control rate was 91%. The 5-year distant metastases rate was 10%. The 5-year overall survival rate was 84%. There were no differences in outcome (local control, distant metastases, overall survival) when dose was stratified by apex dose quartile (<69 Gy, 69-81 Gy, 81-89 Gy, >89 Gy). However, increasing apex dose and dose to 5-mm depth were correlated with greater visual acuity loss (P=.02, P=.0006), worse final visual acuity (P=.02, P<.0001), and radiation complications (P<.0001, P=.0009). In addition, enucleation rates were worse with increasing quartiles of dose to 5 mm (P=.0001). CONCLUSIONS Doses at least as low as 69 Gy prescribed to the tumor apex achieve rates of local control, distant metastasis-free survival, and overall survival that are similar to radiation doses of 85 Gy to the tumor apex, but with improved visual outcomes.

Assessing the Radiation Response of Lung Cancer with Different Gene Mutations Using Genetically Engineered Mice

Purpose: Non-small cell lung cancers (NSCLC) are a heterogeneous group of carcinomas harboring a variety of different gene mutations. We have utilized two distinct genetically engineered mouse models of human NSCLC (adenocarcinoma) to investigate how genetic factors within tumor parenchymal cells influence the in vivo tumor growth delay after one or two fractions of radiation therapy (RT). Materials and Methods: Primary lung adenocarcinomas were generated in vivo in mice by intranasal delivery of an adenovirus expressing Cre-recombinase. Lung cancers expressed oncogenic KrasG12D and were also deficient in one of two tumor suppressor genes: p53 or Ink4a/ARF. Mice received no radiation treatment or whole lung irradiation in a single fraction (11.6 Gy) or in two 7.3 Gy fractions (14.6 Gy total) separated by 24 h. In each case, the biologically effective dose (BED) equaled 25 Gy10. Response to RT was assessed by micro-CT 2 weeks after treatment. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining were performed to assess the integrity of the p53 pathway, the G1 cell-cycle checkpoint, and apoptosis. Results: Tumor growth rates prior to RT were similar for the two genetic variants of lung adenocarcinoma. Lung cancers with wild-type (WT) p53 (LSL-Kras; Ink4a/ARFFL/FL mice) responded better to two daily fractions of 7.3 Gy compared to a single fraction of 11.6 Gy (P = 0.002). There was no statistically significant difference in the response of lung cancers deficient in p53 (LSL-Kras; p53FL/FL mice) to a single fraction (11.6 Gy) compared to 7.3 Gy × 2 (P = 0.23). Expression of the p53 target genes p21 and PUMA were higher and bromodeoxyuridine uptake was lower after RT in tumors with WT p53. Conclusion: Using an in vivo model of malignant lung cancer in mice, we demonstrate that the response of primary lung cancers to one or two fractions of RT can be influenced by specific gene mutations.

Radiotherapy before and after radical prostatectomy for high-risk and locally advanced prostate cancer

OBJECTIVES Men with localized high-risk prostate cancer carry significant risk of prostate cancer-specific mortality. The best treatment approach to minimize this risk is unclear. In this review, we evaluate the role of radiation before and after radical prostatectomy. METHODS AND MATERIALS A critical review of the literature was performed regarding the application of external radiation therapy (RT) in combination with prostatectomy for high-risk localized prostate cancer. RESULTS Up to 70% of men with high-risk localized disease may require adjuvant therapy because of adverse pathologic features or biochemical recurrence in the absence of systemic disease. The utility of adjuvant RT among men with adverse pathologic features are well established at least regarding minimizing biochemical recurrence risk. The optimal timing of salvage radiation is the subject of ongoing studies. Neoadjuvant RT requires further study but is a potentially attractive method because of decreased radiation field sizes and potential radiobiologic benefits of delivering RT before surgery. Salvage prostatectomy is effective at treating local recurrence after radiation but is associated with significant surgical morbidity. CONCLUSIONS Combining local therapies including radical prostatectomy and RT can be a reasonable approach. Care should be taken at the initial presentation of high-risk localized prostate cancer to consider and plan for the likelihood of multimodality care.

Phase-selective image reconstruction of the lungs in small animals using Micro-CT

Gating in small animal imaging can compensate for artifacts due to physiological motion. This paper presents a strategy for sampling and image reconstruction in the rodent lung using micro-CT. The approach involves rapid sampling of freebreathing mice without any additional hardware to detect respiratory motion. The projection images are analyzed postacquisition to derive a respiratory signal, which is used to provide weighting factors for each projection that favor a selected phase of the respiration (e.g. end-inspiration or end-expiration) for the reconstruction. Since the sampling cycle and the respiratory cycle are uncorrelated, the sets of projections corresponding to any of the selected respiratory phases do not have a regular angular distribution. This drastically affects the image quality of reconstructions based on simple filtered backprojection. To address this problem, we use an iterative reconstruction algorithm that combines the Simultaneous Algebraic Reconstruction Technique with Total Variation minimization (SART-TV). At each SART-TV iteration, backprojection is performed with a set of weighting factors that favor the desired respiratory phase. To reduce reconstruction time, the algorithm is implemented on a graphics processing unit. The performance of the proposed approach was investigated in simulations and in vivo scans of mice with primary lung cancers imaged with our in-house developed dual tube/detector micro-CT system. We note that if the ECG signal is acquired during sampling, the same approach could be used for phase-selective cardiac imaging.

Adaptive planning using positron emission tomography for locally advanced lung cancer: A feasibility study.

PURPOSE To evaluate the feasibility of adaptive planning using positron emission tomography-computed tomography (PET-CT) in locally advanced non-small cell lung cancer. METHODS AND MATERIALS Patients with locally advanced non-small cell lung cancer receiving definitive radiation therapy (RT) were eligible. Initial planning PET-CT was performed and a conventional RT plan (2 Gy/fraction to 60 Gy) was designed. A second planning PET-CT was obtained at ~50 Gy. Dose escalation to ~70 Gy for residual fludeoxyglucose-avid disease was pursued at the discretion of the treating oncologists. The primary endpoint was feasibility of adaptive planning using interim PET-CT. Normal tissue dose-volume parameters were calculated for both adaptive and simulated nonadaptive plans. RESULTS From 2012 to 2014, 33 eligible patients were enrolled and underwent planning PET-CT, 3 of which were found to have new distant metastases. Of 30 patients who initiated RT, interim PET-CT was obtained in 29. This showed complete response in 2 patients, partial response/stable disease in 24, and new distant metastases in 3. Selective dose escalation was performed in 17 patients. For those receiving a boost, the median gross tumor volumes pre-RT and at ~50 Gy were 78 mL and 29 mL, respectively (P = .01). Reasons for no dose escalation were normal tissue constraints (n = 3), poorly defined residual disease (n = 2), acute toxicity (n = 1), and refusal of further therapy (n = 1). Adaptive planning compared with a simulated nonadaptive approach allowed for significant dose reductions to the lungs, heart, and esophagus (all P < .01). CONCLUSIONS Adaptive planning using PET-CT was feasible and allows for significant dose reductions to normal tissues compared with traditional planning techniques.

Anal Canal Cancer

Radiation therapy with concurrent chemotherapy is the standard treatment for patients with nonmetastatic squamous cell carcinoma of the anal canal. In the studies that established this approach, high rates of locoregional control have been reported, but the incidence of acute and late toxicity has been significant. Moreover, treatment-related acute toxicity may cause treatment interruptions that are potentially detrimental to locoregional control and colostomy-free survival. Intensity-modulated radiation therapy (IMRT) has recently been instituted as an alternative to conventional two-dimensional (2D) or three-dimensional (3D) conformal radiotherapy. Multiple institutional experiences, as well as a single phase II multi-institution prospective study, have demonstrated improved acute toxicity rates with IMRT, potentially minimizing treatment interruptions and improving treatment outcomes. Pilot studies evaluating IMRT show no reduction in overall or colostomy-free survival versus historical studies. Due to its high precision, the use of IMRT in anal cancer requires thorough understanding of the patterns of spread of anal cancer with thoughtful delineation of target volumes and organs at risk. In this chapter, we highlight the available data on the use of IMRT for anal cancer and summarize established approaches for IMRT planning in this disease.