Toxicity in combination immune checkpoint inhibitor and radiation therapy: a systematic review and meta-analysis

BACKGROUND AND PURPOSE: Immune checkpoint inhibitor with radiation therapy (ICI + RT) is under investigation for improved patient outcome, so we performed a systematic review/meta-analysis of toxicities for ICI + RT compared to immune checkpoint inhibitor (ICI) therapy alone. MATERIALS AND METHODS: A PRISMA-compliant systematic review of studies in MEDLINE (PubMed) and in the National Comprehensive Cancer Network guidelines was conducted, with primary outcome grade 3+ toxicity. Criteria for ICI alone were: phase III/IV trials that compared immunotherapy to placebo, chemotherapy, or alternative immunotherapy; and for ICI + RT: prospective/retrospective studies with an arm treated with ICI + RT. Meta-analysis was performed by random effects models using the DerSimonian and Laird method. The I(2) statistic and Cochran\u27s Q test were used to assess heterogeneity, while funnel plots and Egger\u27s test assessed publication bias. RESULTS: This meta-analysis included 51 studies (n=15,398), with 35 ICI alone (n=13,956) and 16 ICI + RT studies (n=1,442). Our models showed comparable grade 3-4 toxicities in ICI + RT (17.8%; 95% CI, 12.0-24.5%) and ICI alone (22.3%; 95% CI, 18.1-26.9%). Stratification by timing of radiation and irradiated site showed no significant differences, but anti-CTLA4 therapy and melanoma showed increased toxicity. The grade 5 toxicities were 1.1% and 1.9% for ICI alone and ICI + RT respectively. There was significant heterogeneity, but not publication bias. CONCLUSIONS: The random effects model showed comparable grade 3-4 toxicity in using ICI + RT compared to ICI alone in CNS melanoma metastases, NSCLC, and prostate cancer. ICI + RT is safe for future clinical trials in these cancers

Postoperative Cavity Stereotactic Radiosurgery for Brain Metastases

During the past decade, tumor bed stereotactic radiosurgery (SRS) after surgical resection has been increasingly utilized in the management of brain metastases. SRS has risen as an alternative to adjuvant whole brain radiation therapy (WBRT), which has been shown in several studies to be associated with increased neurotoxicity. Multiple recent articles have shown favorable local control rates compared to those of WBRT. Specifically, improvements in local control can be achieved by adding a 2 mm margin around the resection cavity. Risk factors that have been established as increasing the risk of local recurrence after resection include: subtotal resection, larger treatment volume, lower margin dose, and a long delay between surgery and SRS (>3 weeks). Moreover, consensus among experts in the field have established the importance of (a) fusion of the pre-operative magnetic resonance imaging scan to aid in volume delineation (b) contouring the entire surgical tract and (c) expanding the target to include possible microscopic disease that may extend to meningeal or venous sinus territory. These strategies can minimize the risks of symptomatic radiation-induced injury and leptomeningeal dissemination after postoperative SRS. Emerging data has arisen suggesting that multifraction postoperative SRS, or alternatively, preoperative SRS could provide decreased rates of radiation necrosis and leptomeningeal disease. Future prospective randomized clinical trials comparing outcomes between these techniques are necessary in order to improve outcomes in these patients

Preoperative Stereotactic Radiosurgery for Brain Metastases

Stereotactic radiosurgery (SRS) is increasingly utilized to treat the resection cavity following resection of brain metastases and recent randomized trials have confirmed postoperative SRS as a standard of care. Postoperative SRS for resected brain metastases improves local control compared to observation, while also preserving neurocognitive function in comparison to whole brain radiation therapy (WBRT). However, even with surgery and SRS, rates of local recurrence at 1 year may be as high as 40%, especially for larger cavities, and there is also a known risk of leptomeningeal disease after surgery. Additional treatment strategies are needed to improve control while maintaining or decreasing the toxicity profile associated with treatment. Preoperative SRS is discussed here as one such approach. Preoperative SRS allows for contouring of an intact metastasis, as opposed to an irregularly shaped surgical cavity in the post-op setting. Delivering SRS prior to surgery may also allow for a “sterilizing” effect, with the potential to increase tumor control by decreasing intra-operative seeding of viable tumor cells beyond the treated cavity, and decreasing risk of leptomeningeal disease. Because there is no need to treat brain surrounding tumor in the preoperative setting, and since the majority of the high dose volume can then be resected at surgery, the rate of symptomatic radiation necrosis may also be reduced with preoperative SRS. In this mini review, we explore the potential benefits and risks of preoperative vs. postoperative SRS for brain metastases as well as the existing literature to date, including published outcomes with preoperative SRS

Systematic Review of Focal Prostate Brachytherapy and the Future Implementation of Image-Guided Prostate HDR Brachytherapy Using MR-Ultrasound Fusion

Prostate cancer is the most common malignancy found in North American and European men and the second most common cause of cancer related death. Since the practice of PSA screening has become common the disease is most often found early and can have a long indolent course. Current definitive therapy treats the whole gland but has considerable long-term side effects. Focal therapies may be able to target the cancer while decreasing dose to organs at risk. Our objective was to determine if focal prostate brachytherapy could meet target objectives while permitting a decrease in dose to organs at risk in a way that would allow future salvage treatments. Further, we wanted to determine if focal treatment results in less toxicity. Utilizing the Medline repository, dosimetric papers comparing whole gland to partial gland brachytherapy and clinical papers that reported toxicity of focal brachytherapy were selected. A total of 9 dosimetric and 6 clinical papers met these inclusion criteria. Together, these manuscripts suggest that focal brachytherapy may be employed to decrease dose to organs at risk with decreased toxicity. Of current technology, image-guided HDR brachytherapy using MRI registered to transrectal ultrasound offers the flexibility and efficiency to achieve such focal treatments

Providing guidance for genomics-based cancer treatment decisions: insights from stakeholder engagement for post-prostatectomy radiation therapy

Abstract Background Despite the emergence of genomics-based risk prediction tools in oncology, there is not yet an established framework for communication of test results to cancer patients to support shared decision-making. We report findings from a stakeholder engagement program that aimed to develop a framework for using Markov models with individualized model inputs, including genomics-based estimates of cancer recurrence probability, to generate personalized decision aids for prostate cancer patients faced with radiation therapy treatment decisions after prostatectomy. Methods We engaged a total of 22 stakeholders, including: prostate cancer patients, urological surgeons, radiation oncologists, genomic testing industry representatives, and biomedical informatics faculty. Slides were at each meeting to provide background information regarding the analytical framework. Participants were invited to provide feedback during the meeting, including revising the overall project aims. Stakeholder meeting content was reviewed and summarized by stakeholder group and by theme. Results The majority of stakeholder suggestions focused on aspects of decision aid design and formatting. Stakeholders were enthusiastic about the potential value of using decision analysis modeling with personalized model inputs for cancer recurrence risk, as well as competing risks from age and comorbidities, to generate a patient-centered tool to assist decision-making. Stakeholders did not view privacy considerations as a major barrier to the proposed decision aid program. A common theme was that decision aids should be portable across multiple platforms (electronic and paper), should allow for interaction by the user to adjust model inputs iteratively, and available to patients both before and during consult appointments. Emphasis was placed on the challenge of explaining the model’s composite result of quality-adjusted life years. Conclusions A range of stakeholders provided valuable insights regarding the design of a personalized decision aid program, based upon Markov modeling with individualized model inputs, to provide a patient-centered framework to support for genomic-based treatment decisions for cancer patients. The guidance provided by our stakeholders may be broadly applicable to the communication of genomic test results to patients in a patient-centered fashion that supports effective shared decision-making that represents a spectrum of personal factors such as age, medical comorbidities, and individual priorities and values

Towards decision-making using individualized risk estimates for personalized medicine: A systematic review of genomic classifiers of solid tumors

<div><p>Recent advances in the understanding of the genetic underpinnings of cancer offer the promise to customize cancer treatments to the individual through the use of genomic classifiers (GCs). At present, routine clinical utilization of GCs is uncommon and their current scope and status, in a broad sense, are unknown. As part of a registered review (PROSPERO 2014:CRD42014013371), we systematically reviewed the literature evaluating the utility of commercially available GCs by searching Ovid Medline (PubMed), EMBASE, the Cochrane Database of Systematic Reviews, and CINAHL on September 2, 2014. We excluded articles involving pediatric malignancies, non-solid or non-invasive cancers, hereditary risk of cancer, non-validated GCs, and GCs involving fewer than 3 biomarkers. A total of 3,625 studies were screened, but only 37 met the pre-specified inclusion criteria. Of these, 15 studies evaluated outcomes and clinical utility of GCs through clinical trials, and the remainder through the use of mathematical models. Most studies (29 of 37) were specific to hormone-receptor positive breast cancer, whereas only 4 studies evaluated GCs in non-breast cancer (prostate, colon, and lung cancers). GCs have spurred excitement across disciplines in recent decades. While there are several GCs that have been validated, the general quality of the data are weak. Further research, including prospective validation is needed, particularly in the non-breast cancer GCs.</p></div