The Combined Use of SBRT and Immunotherapy-a Literature Review.

PURPOSE OF REVIEW: The purpose of this paper is to review all recent and relevant data regarding the combined use of immunotherapy (particularly immune checkpoint inhibitors) and radiotherapy. RECENT FINDINGS: The use of radiotherapy, specifically stereotactic body radiation therapy (SBRT), and immunotherapy may be synergistic in the treatment of non-small cell lung cancer (NSCLC). There have been many preclinical and clinical studies that have shown that the combination of SBRT and immunotherapy is both safe and effective. In many cases, the benefits are greater than either SBRT or immunotherapy alone. Several ongoing trials are testing the combination of SBRT and immunotherapy for the treatment of all stages of NSCLC. CONCLUSION: The combined use of SBRT and immunotherapy is a promising new development. The techniques may synergistically work better than either alone.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early-stage non-small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single-institution reports. The current multi-institutional study reported outcomes evaluating the largest such population reported to date. METHODS: Clinical/treatment characteristics, outcomes, toxicities, and patterns of failure were assessed in patients with primary NSCLC measuring ≥5 cm without evidence of distant/lymph node metastasis who underwent SBRT using ≤5 fractions. Statistics included Kaplan-Meier survival analyses and univariate/multivariate Cox proportional hazards models. RESULTS: A total of 92 patients treated from 2004 through 2016 were analyzed from 12 institutions. The median follow-up was 12 months (15 months in survivors). The median age and tumor size among the patients were 73 years (range, 50-95 years) and 5.4 cm (range, 5.0-7.5 cm), respectively. The median dose/fractionation was 50 Gray/5 fractions. The actuarial local control rates at 1 year and 2 years were 95.7% and 73.2%, respectively. The disease-free survival rate was 72.1% and 53.5%, respectively, at 1 year and 2 years. The 1-year and 2-year disease-specific survival rates were 95.5% and 78.6%, respectively. The median, 1-year, and 2-year overall survival rates were 21.4 months, 76.2%, and 46.4%, respectively. On multivariate analysis, lung cancer history and pre-SBRT positron emission tomography maximum standardized uptake value were found to be associated with overall survival. Posttreatment failures were most commonly distant (33% of all disease recurrences), followed by local (26%) and those occurring elsewhere in the lung (23%). Three patients had isolated local failures. Grade 3 to 4 toxicities included 1 case (1%) and 4 cases (4%) of grade 3 dermatitis and radiation pneumonitis, respectively (toxicities were graded according to the Common Terminology Criteria for Adverse Events [version 4.0]). Grades 2 to 5 radiation pneumonitis occurred in 11% of patients. One patient with a tumor measuring 7.5 cm and a smoking history of 150 pack-years died of radiation pneumonitis. CONCLUSIONS: The results of the current study, which is the largest study of patients with NSCLC measuring ≥5 cm reported to date, indicate that SBRT is a safe and efficacious option. Cancer 2017;123:688-696. © 2016 American Cancer Society.

Assessing plasma circulating tumor human papillomavirus (HPV) DNA in determining treatment response in HPV-associated oropharyngeal cancer.

BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma is a subset of head and neck cancer with a unique mechanism of carcinogenesis. Local disease is treated definitively with a multimodal approach. Navigating recurrences can be challenging, as they are sometimes indiscernible from de novo primary malignancies. Identification of dynamic biomarkers that are specific to HPV-mediated disease may assist in disease monitoring. We present a 78-year-old man who developed a squamous cell carcinoma in the lung 7 years after completing definitive chemoradiation for his p16+ head and neck squamous cell carcinoma. METHODS: A novel assay for plasma circulating tumor HPV DNA was employed and provided a tool for longitudinal disease monitoring during therapy. CONCLUSION: We bring attention to a novel assay and highlight its potential for use in the treatment paradigm of HPV-mediated oropharyngeal carcinoma.

Management of local recurrences and regional failure in early stage non-small cell lung cancer after stereotactic body radiation therapy.

Stereotactic body radiation therapy (SBRT) is a very effective way to treat early stage non-small cell lung cancer (NSCLC) and small oligometastatic lung lesions with consistently high rates of local control, but both local and regional/distant recurrences still occur. The management of recurrences remains unsettled and may entail repeat SBRT, conventionally fractionated external beam RT (EF-EBRT), chemotherapy or surgery. Most patients with local recurrences [within the initial planning target volume (PTV)] can be salvaged successfully with good cancer specific survival. Nonetheless, proximity of the initial SBRT delivery to organs at risk (ribs, blood vessels, airways) may make retreatment more difficult. With attention to detail and careful patient selection, both surgery and reirradiation can be performed safely and effectively. Strategies for management of regional (nodal) recurrences may require conventional therapies tailored to the patterns of failure. The role of immunotherapy in salvage has not been elucidated as yet. We review here data on the available literature concerning salvage of SBRT lung patients.

Comparison of outcomes of stereotactic body radiation therapy delivered with three different technologies to the lung.

PURPOSE/OBJECTIVES: Since the inception of stereotactic body radiation therapy (SBRT), treatment delivery has been performed with volumetric modulated arc therapy (VMAT), helical tomotherapy (HT) and noncoplanar static fields (SF). The purpose of this study is to compare SBRT delivery among these treatment modalities to the lung. MATERIALS/METHODS: A retrospective review of SBRT treatments of 30 to 60 Gy in 1 to 5 fractions from 2007 to 2015 was performed. Dosimetric parameters included V5, V20, D2cm, gross tumor volume (GTV) and planning target volume (PTV) size and coverage, rib/esophageal minimum/maximum doses, R30Gy, R50%, and the conformality index (CI). Clinical outcomes evaluated included local control, pneumonitis and other toxicities. ANOVA, Student's t-test and Kruskal-Wallis test were used to compare the parameters among modalities. Kaplan-Meier estimates of time-to-local failure were produced. RESULTS: 176 Treatments included 106 SF, 36 VMAT and 34 HT. HT had better PTV coverage (p=0.0166) but higher lung V5 and esophageal doses (p<0.001 and p=0.0032). R30Gy, R50%, and CI were significantly better with VMAT SBRT (p<0.001). Clinically, Grade 2+ pneumonitis was associated with larger median GTV's of 21.39 cc versus 7.65 cc (p=0.0016), larger median PTV's of 65.62 cc versus 31.75 cc (p=0.0030), and higher V20 6.62% versus 4.08% (p=0.0408). For patients surviving >1 year, overall local failure rate was 9.4%. Actuarial control rates trended toward statistical significance with time to local failure with VMAT being the most favorable group on the Kaplan-Meier curve (p=0.0733). CONCLUSION: VMAT showed superior conformality compared to the other modalities. Among the modalities examined, HT had higher values for parameters associated with toxicity such as V5 and maximum esophageal dose, but all were within acceptable limits. There was a trend to better local control with VMAT.

Dose-dense temozolomide for recurrent high-grade gliomas: a single-center retrospective study.

There are limited treatment modalities after high-grade gliomas recurrence. MGMT depletion modulated by dose-dense temozolomide (ddTMZ) remains a debated therapy for initial TMZ responders. Patients were selected retrospectively from our practice with diagnosis of high-grade gliomas (WHO grade III or IV), and were followed since the start of ddTMZ until death or change of therapy. Twenty-one patients were reviewed, with a median age of 47 (25-61) years and a median of 5.8 (1.5-38.8) cycles of ddTMZ. The majority were males (71.4%). Sixty-six percent received 21 on/28 off ddTMZ schedule, 28.6% daily, and 1 patient received a 7 days on/7 days off schedule. IDH mutation status was available for 18 (85.7%) patients, with 7 (33.3%) IDH mutant and 11 (52.5%) IDH wild type. MGMT methylation was assessed in 6 (28.6%) of the patients, being MGMT methylated in 3 (14.3%) patients, and non-methylated in 3 (14.3%) patients. The majority of patients (57.1%) were receiving ddTMZ in addition to other forms of therapy, including either bevacizumab (38.1%) or tumor-treating fields (TTFields) (19.1%). Overall ddTMZ was well tolerated, with few adverse events reported. The estimated median overall survival after ddTMZ start was 11 months. Median progression-free survival (PFS) was 6 months. Outcomes did not vary between patients receiving ddTMZ alone or those using TTFields or bevacizumab as concomitant therapy, but there was a trend to longer survival with the use of concomitant TTFields. Our results demonstrate benefit of ddTMZ after previous treatment with standard TMZ dosing with no apparent increase in treatment-related toxicities. In summary, ddTMZ should be considered in TMZ responsive patients and warrants further investigation.

Emerging Therapies for Stage III Non-Small Cell Lung Cancer: Stereotactic Body Radiation Therapy and Immunotherapy.

The current standard of care for locally advanced non-small cell lung cancer (NSCLC) includes radiation, chemotherapy, and surgery in certain individualized cases. In unresectable NSCLC, chemoradiation has been the standard of care for the past three decades. Local and distant failure remains high in this group of patients, so dose escalation has been studied in both single institution and national clinical trials. Though initial studies showed a benefit to dose escalation, phase III studies examining dose escalation using standard fractionation or hyperfractionation have failed to show a benefit. Over the last 17 years, stereotactic body radiation therapy (SBRT) has shown a high degree of safety and local control for stage I lung cancers and other localized malignancies. More recently, phase I/II studies using SBRT for dose escalation after conventional chemoradiation in locally advanced NSCLC have been promising with good apparent safety. Immunotherapy also offers opportunities to address distant disease and preclinical data suggest immunotherapy in tandem with SBRT may be a rational way to induce an "abscopal effect" although there are little clinical data as yet. By building on the proven concept of conventional chemoradiation for patients with locally advanced NSCLC with a subsequent radiation dose intensification to residual disease with SBRT concurrent with immunotherapy, we hope address the issues of metastatic and local failures. This "quadmodality" approach is still in its infancy but appears to be a safe and rational approach to the improving the outcome of NSCLC therapy.