Stereotactic body radiation therapy (SBRT) is an effective and well tolerated treatment for early stage non-small cell lung cancer (NSCLC). The high doses used in thoracic SBRT can sometimes cause adverse effects ranging from mild fatigue and transient esophagitis to fatal events such as pneumonitis or hemorrhage. Efforts continue to expand in both the utility of this technique as well as our understanding of the mechanisms of the adverse effects it can cause. In this review, we discuss the current literature regarding the potential mechanisms, dosimetric constraints and toxicities associated with SBRT alone and in conjunction with definitive chemoradiotherapy and immunotherapy. As the use of SBRT expands to these spheres, we examine the available recommendations for mitigating potential associated treatment related toxicities.

LDR-BT yields excellent survival rates, with a 17-year PCSS rate of 97%. In all, 18% of patients with biochemical relapse failed at >10 years after implantation, which justifies their continued follow-up.

Purpose Acute lymphoblastic leukemia (ALL) has a predilection for CNS involvement. Patients with high-risk ALL are often managed with transplant using a radiation-based conditioning regimen. Historically, a high-dose prophylactic cranial boost (CB) of ≥12 Gy was given to reduce risk of central nervous system (CNS) recurrence. However, the use of CB has fallen out of favor because of toxicity concerns. In high-risk adults undergoing transplant at our institution, we have used a low-dose 6 Gy CB to reduce toxicity while conditioning adults with fully developed brains. The safety, efficacy, and utility of a low-dose CB in adults are poorly studied; herein, we report their outcomes and toxicity. Methods and materials We identified all high-risk ALL patients undergoing total body irradiation as part of their conditioning regimen. Those who received 6 Gy CB or no CB were included (55 total). Their charts were reviewed and statistical analyses were completed with R, version 2.15.2. Results In patients undergoing CB, 3-year CNS disease-free survival and overall survival were 94.7% and 62.7%. In those not undergoing CBs, survivals were 81.8% and 51.5%. Notably, within the CB cohort, patients without prior CNS involvement had no CNS failures. In contrast, in the non-CB cohort, there were 2 CNS failures in patients with no history of CNS involvement. In the CB cohort, the only notable acute toxicity was parotitis (2.8%). Late toxicity in the CB cohort included 1 instance of cataracts (2.8%) without any evidence of cognitive impairment or potential radiation induced secondary malignancy. Conclusions A dose of 6 Gy CB is well-tolerated in the adult ALL population as part of a radiation-based conditioning regimen. Low-dose CB may be considered in adult patients with high-risk ALL without prior CNS involvement to reduce the likelihood of recurrence.

Purpose/Objective(s): Approximately 30% of patients with cervical cancer do not respond to concurrent chemoradiation (CRT) and have significantly decreased survival. Gene expression changes during CRT are likely to offer novel insight into mechanisms of treatment resistance. We aimed to determine the changes in human and viral gene expression in cervical tumors during CRT and hypothesized that the change in human papillomavirus (HPV) gene expression during CRT is associated with survival. Materials/Methods: Paired cervical tumor biopsies were prospectively collected with informed consent both prior to treatment (PT) and 3 weeks into treatment (mid-treatment, MT) with CRT. Frozen specimens were sectioned and stained with H&E for pathologic review. Tumor associated lymphocytes, necrosis, and neoplastic cells were quantified. Viable tumor tissue was macrodissected and RNA was isolated and sequenced (RNAseq). Viral and human gene expression was normalized and analyzed using DESeq. Results: Out of 115 MT biopsies analyzed, 20 had adequate viable tumor tissue for further analysis. Of these, 6 patients were HPV negative, 3 were HPV-18 positive, and 11 were HPV-16 positive prior to CRT. Median follow-up was 3.1 years. At last follow-up, 7 patients (1 HPV negative, 3 HPV16+, and 3 HPV18+) died of disease (DOD) while 13 had no evidence of disease (NED). HPV gene expression decreased in all patients during CRT; however, patients DOD maintained significantly higher HPV gene expression during treatment than NED patients (50% vs. 16% of PT expression, P Z 0.008). HPV gene expression at each time point (PT or MT) alone was not different and did not correlate with survival. Gene set enrichment analysis revealed enrichment of the E2F target pathway MT in patients DOD consistent with increased HPV E7 downstream effects. The number of infiltrating lymphocytes decreased in all patients during CRT but patients DOD had significantly fewer lymphocytes MT than NED patients (3% vs. 8%, P Z 0.01) while they were not different PT. Genes associated with a Th1 immune response (CD3, CD4, CD8, LCK, and cytolytic proteins granulysin and perforin) were significantly decreased (> 2 fold, all P < 0.02) MT in patients DOD compared to NED patients, while the PT levels were not different. This does not appear to be due to upregulation of immunomodulatory genes that suppress the immune system as FOXP3, CTLA-4 and BTLA were also significantly downregulated in patients DOD (all P < 0.05) MT, but not PT. However, PD-L1 expression was approximately 2-fold higher in patients DOD both PT and MT though this did not reach significance (P Z 0.1). Conclusion: Analysis of cervical tumors during CRT provides valuable insight into treatment resistance. Tumors of patients who died of cervical cancer maintained higher HPV gene expression during CRT, which may be mediated by a decreased immune response to the tumor. Further studies are ongoing to determine the molecular mechanisms of this phenomenon.

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