Olivier, Kenneth R.

409 Background: For patients with metastatic renal cell carcinoma (RCC), metastasis-directed local therapies can delay progression and need to initiate/switch systemic therapy. We examined our experience treating lung or mediastinal metastases from RCC with radiotherapy (RT). Methods: We reviewed patients with lung or mediastinal metastases from RCC treated with RT. Overall survival (OS) and local control (LC) was measured from the start of RT using the Kaplan-Meier method. Results: Seventy-one patients were treated with RT for 89 lung or mediastinal metastases. Median follow-up was 2.0 years (range 0.02-11.4 years) after RT for surviving patients. Most patients were male (n=53, 74.6%). Median age was 58.4 years at initial diagnosis. Histology was most frequently clear cell carcinoma (n=62, 89.9%). At the time of treatment, 18 patients (25.4%) had 1-3 metastases, and the remainder (74.6%) had 4 or more metastases. Forty-one patients (57.5%) received systemic therapy prior to thoracic radiation. Initial systemic therapy was most commonly sunitinib (45%) or pazopanib (32.5%). Median time from starting systemic therapy to initiation of radiation was 2.0 years. Fifty-eight lung metastases and 31 mediastinal metastases were treated with a median 5 fractions (range 1-40), to a median total dose of 4800 cGy (range 400-7000), with a median fraction size of 500 cGy (range 150-2000). Thirty-three lesions were treated with concurrent systemic therapy, which was most commonly nivolumab (n=16). Of 89 treated lesions, 11 (12%) had local tumor recurrence, at a median of 1.6 years (range 0.4-2.9 years) after initiation of radiation. 1, 3, and 5 year MC (metastasis control) were 96.6%, 83.5% and 67.9%, respectively. Nine patients were treated with radiation in order to delay initiation of systemic therapy. Of these, 3 eventually received systemic therapy, initiated at a median 2.5 years after radiation. At last follow-up, 41 patients (57.7%) had died. Median OS was 2.6 years. Survival at 1, 3, and 5 years was 65.2%, 48.5%, and 38%, respectively. Conclusions: Radiation achieves high metastasis control rates for lung and mediastinal metastases from RCC, potentially delaying the need for systemic therapy.

The purpose of the present study was to compare the impact of pulmonary function, body habitus, and stereotactic body radiation therapy (SBRT) immobilization on setup and reproducibility for upper lung tumor. From 2008 through 2011, our institution's prospective SBRT database was searched for patients with upper lung tumors. Two SBRT immobilization strategies were used: full‐length BodyFIX and thermoplastic S‐frame. At simulation, free‐breathing, four‐dimensional computed tomography was performed. For each treatment, patients were set up to isocenter with in‐room lasers and skin tattoos. Shifts from initial and subsequent couch positions with cone‐beam computed tomography (CBCT) were analyzed. Accounting for setup uncertainties, institutional tolerance of CBCT‐based shifts for treatment was 2, 2, and 4 mm in left–right, anterior–posterior, and cranial–caudal directions, respectively; shifts exceeding these limits required reimaging. Each patient's pretreatment pulmonary function test was recorded. A multistep, multivariate linear regression model was performed to elucidate intervariable dependency for three‐dimensional calculated couch shift parameters. BodyFIX was applied to 76 tumors and S‐frame to 17 tumors. Of these tumors, 41 were non–small cell lung cancer and 15 were metastatic from other sites. Lesions measured , 1.1 to 2 (50%), 2.1 to 3 (25%), and cm. Errors from first shifts of first fractions were significantly less with S‐frame than BodyFIX (). No difference in local control (LC) was found between S‐frame and BodyFIX (); two‐year LC rate was 94%. Multivariate modeling confirmed that the ratio of forced expiratory volume in the first second of expiration to forced vital capacity, body habitus, and the immobilization device significantly impacted couch shift errors. For upper lung tumors, initial setup was more consistent with S‐frame than BodyFIX, resulting in fewer CBCT scans. Patients with obese habitus and poor lung function had more SBRT setup uncertainty; however, outcome and probability for LC remained excellent.PACS number: 89.20.‐a

The purpose of this study is to investigate changes in lung tumor internal target volume during stereotactic body radiotherapy treatment (SBRT) using magnetic resonance imaging (MRI). Ten lung cancer patients (13 tumors) undergoing SBRT (48 Gy over four consecutive days) were evaluated. Each patient underwent three lung MRI evaluations: before SBRT (MRI‐1), after fraction 3 of SBRT (MRI‐3), and three months after completion of SBRT (MRI‐3m). Each MRI consisted of T1‐weighted images in axial plane through the entire lung. A cone‐beam CT (CBCT) was taken before each fraction. On MRI and CBCT taken before fractions 1 and 3, gross tumor volume (GTV) was contoured and differences between the two volumes were compared. Median tumor size on CBCT before fractions 1 (CBCT‐1) and 3 (CBCT‐3) was 8.68 and 11.10 cm3, respectively. In 12 tumors, the GTV was larger on CBCT‐3 compared to CBCT‐1 (median enlargement, 1.56 cm3). Median tumor size on MRI‐1, MRI‐3, and MRI‐3m was 7.91, 11.60, and 3.33 cm3, respectively. In all patients, the GTV was larger on MRI‐3 compared to MRI‐1 (median enlargement, 1.54 cm3). In all patients, GTV was smaller on MRI‐3m compared to MRI‐1 (median shrinkage, 5.44 cm3). On CBCT and MRI, all patients showed enlargement of the GTV during the treatment week of SBRT, except for one patient who showed minimal shrinkage (0.86 cm3). Changes in tumor volume are unpredictable; therefore, motion and breathing must be taken into account during treatment planning, and image‐guided methods should be used, when treating with large fraction sizes.PACS number: 87.53.Ly

Abstract Background: Numerous studies have focused on the treatment of non-small cell lung cancer patients with brain metastases. However, to our knowledge, few have sought to examine outcomes in patients who required whole brain radiation and developed radiation-refractory disease. Methods: This study examined the medical records of all non-small cell lung cancer patients who developed brain metastases between 2004 and 2013, required whole brain radiation, and received their cancer treatment at the Mayo Clinic in Rochester, Minnesota. Results: A total of 141 patients, most of whom were symptomatic, met the above criteria. Of these, 33 (23%) did not tolerate a corticosteroid taper and were therefore deemed to have radiation-refractory disease. The median survival of patients with and without radiation-refractory disease was 3.12 and 4.27 months, respectively, (hazard ratio [HR]: 0.65 [95% confidence interval (CI): 0.44–0.99]; p =0.04 by log rank test). In a subgroup analysis of patients with radiation-refractory disease ( n =33) and radio-responsive disease ( n =43), median survival was 3.12 and 5.94 months, respectively (HR: 0.43 [95% CI: 0.26–0.70]). Among patients with radiation-refractory disease, 12 received chemotherapy after radiation, and two received erlotinib. Systemic therapy was associated with improved symptoms in two patients but did not appear to improve survival. Conclusion: Non-small cell lung cancer patients with radiation-refractory brain metastases represent a small subgroup who have a short survival and who appear to derive minimal benefit from systemic cancer therapy.

Abstract We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR-induced antitumor response in PD-1–expressing wild-type (WT) and PD-1–deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1–blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11ahigh CD8+ T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer. Cancer Immunol Res; 3(6); 610–9. ©2015 AACR.

Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma.Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012.Results. We identified 14 patients with a total of 27 lesions from osteosarcoma(n=19)or ES(n=8). The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16–50 Gy in 1–10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation.Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare variant of hepatocellular carcinoma (HCC) that commonly affects young individuals without a prior history of liver disease. FLHCC commonly results in a better prognosis than HCC; however, the risk of recurrence and metastatic disease is high. FLHCC is typically treated by primary resection of the tumor with 50-75% cure rates. The use of radiation therapy in FLHCC has not been assessed on its own, and may show some success in a very few reported combination therapy cases. We report on the successful use of radiation therapy in a case of metastatic FLHCC to the lung following primary and secondary resections. Our treatment of the large, metastatic, pulmonary FLHCC tumor with 40 Gy in 10 fractions resulted in an 85.9% tumor volume decrease over six months. This suggests FLHCC may be a radiosensitive tumor and radiotherapy may be valuable in unresectable or metastatic tumors.