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Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer.

ABSTRACT: Stereotactic body radiation therapy (SBRT) can positively influence an antitumor immune response by inducing necrotic cell death. SBRT also been shown to eliminate tumors outside the radiation therapy field through an immune-mediated process known as the abscopal effect. Recent advances in immunotherapy may provide new therapeutic approaches for patients with liver cancer. Therefore, understanding the immune status of patients with cancer will likely guide how immunotherapy might be used in combination with SBRT. We hypothesized that we would observe changes in circulating blood immune cell populations of patients who received SBRT for liver tumors. Therefore, we assessed 110 immunophenotypes in the peripheral blood of 10 patients with liver cancer or metastases to the liver pretreatment and 2 posttreatment time points. Patients with liver cancer and metastatic patients both exhibited several immunophenotypic abnormalities at baseline compared with a group of healthy volunteer controls. In longitudinal studies, SBRT caused a specific reduction in CD3+ T cell counts and immature CD56brCD16- NK cell counts. The immune profiling and potential identification of circulating biomarkers shown here could lead to the design of combinatorial approaches with SBRT and immunotherapy to optimize the timing of treatment and direct the most effective immunotherapy with SBRT.

SUBMITTER: Gustafson MP

PROVIDER: S-EPMC5707422 | biostudies-literature | 2017 Oct-Dec

REPOSITORIES: biostudies-literature

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Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer.

Gustafson Michael P MP Bornschlegl Svetlana S Park Sean S SS Gastineau Dennis A DA Roberts Lewis R LR Dietz Allan B AB Hallemeier Christopher L CL

Advances in radiation oncology 20170818 4

Stereotactic body radiation therapy (SBRT) can positively influence an antitumor immune response by inducing necrotic cell death. SBRT also been shown to eliminate tumors outside the radiation therapy field through an immune-mediated process known as the abscopal effect. Recent advances in immunotherapy may provide new therapeutic approaches for patients with liver cancer. Therefore, understanding the immune status of patients with cancer will likely guide how immunotherapy might be used in comb ...[more]

PMID: 29204520

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Project description:PurposeTo quantitatively evaluate published experiences with hepatic stereotactic body radiation therapy (SBRT), to determine local control rates after treatment of primary and metastatic liver tumors and to examine whether outcomes are affected by SBRT dosing regimen.Methods and materialsWe identified published articles that reported local control rates after SBRT for primary or metastatic liver tumors. Biologically effective doses (BEDs) were calculated for each dosing regimen using the linear-quadratic equation. We excluded series in which a wide range of BEDs was used. Individual lesion data for local control were extracted from actuarial survival curves, and data were aggregated to form a single dataset. Actuarial local control curves were generated using the Kaplan-Meier method after grouping lesions by disease type and BED (<100 Gy10 vs >100 Gy10). Comparisons were made using log-rank testing.ResultsThirteen articles met all inclusion criteria and formed the dataset for this analysis. The 1-, 2-, and 3-year actuarial local control rates after SBRT for primary liver tumors (n = 431) were 93%, 89%, and 86%, respectively. Lower 1- (90%), 2- (79%), and 3-year (76%) actuarial local control rates were observed for liver metastases (n = 290, log-rank P = .011). Among patients treated with SBRT for primary liver tumors, there was no evidence that local control is influenced by BED within the range of schedules used. For liver metastases, on the other hand, outcomes were significantly better for lesions treated with BEDs exceeding 100 Gy10 (3-year local control 93%) than for those treated with BEDs of ≤100 Gy10 (3-year local control 65%, P < .001).ConclusionsStereotactic body radiation therapy for primary liver tumors provides high rates of durable local control, with no clear evidence for a dose-response relationship among commonly utilized schedules. Excellent local control rates are also seen after SBRT for liver metastases when BEDs of >100 Gy10 are utilized.

Project description:We present our initial experience with CyberKnife stereotactic body radiation therapy (SBRT) in a heavily pretreated group of patients with liver metastases and primary liver tumors. From October 2007 to June 2009, 48 patients were treated at the Philadelphia CyberKnife Center for liver metastases or primary liver tumors. We report on 30 patients with 41 discrete lesions (1-4 tumors per patient) who received an ablative radiation dose (BED ≥ 79.2 Gy10 = 66 Gy EQD2). The treatment goal was to achieve a high SBRT dose to the liver tumor while sparing at least 700 cc of liver from radiation doses above 15 Gy. Twenty-three patients were treated with SBRT for metastatic cancer to the liver; the remainder (n = 7) were primary liver tumors. Eighty-seven percent of patients had prior systemic chemotherapy with a median 24 months from diagnosis to SBRT; 37% had prior liver directed therapy. Local control was assessed for 28 patients (39 tumors) with 4 months or more follow-up. At a median follow-up of 22 months (range, 10-40 months), 14/39 (36%) tumors had documented local failure. A decrease in local failure was found with higher doses of SBRT (p = 0.0237); 55% of tumors receiving a BED ≤ 100 Gy10 (10/18) had local failure compared with 19% receiving a BED > 100 Gy10 (4/21). The 2-year actuarial rate of local control for tumors treated with BED > 100 Gy10 was 75% compared to 38% for those patients treated with BED ≤ 100 Gy10 (p = 0.04). At last follow-up, 22/30 patients (73%) had distant progression of disease. Overall, seven patients remain alive with a median survival of 20 months from treatment and 57 months from diagnosis. To date, no patient experienced persistent or severe adverse effects. Despite the heavy pretreatment of these patients, SBRT was well tolerated with excellent local control rates when adequate doses (BED > 100 Gy10) were used. Median survival was limited secondary to development of further metastatic disease in the majority of patients.

Project description:PurposeDaily magnetic resonance (MR)-guided radiation has the potential to improve stereotactic body radiation therapy (SBRT) for tumors of the liver. Magnetic resonance imaging (MRI) introduces unique variables that are untested clinically: electron return effect, MRI geometric distortion, MRI to radiation therapy isocenter uncertainty, multileaf collimator position error, and uncertainties with voxel size and tracking. All could lead to increased toxicity and/or local recurrences with SBRT. In this multi-institutional study, we hypothesized that direct visualization provided by MR guidance could allow the use of small treatment volumes to spare normal tissues while maintaining clinical outcomes despite the aforementioned uncertainties in MR-guided treatment.Methods and materialsPatients with primary liver tumors or metastatic lesions treated with MR-guided liver SBRT were reviewed at 3 institutions. Toxicity was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4. Freedom from local progression (FFLP) and overall survival were analyzed with the Kaplan-Meier method and χ2 test.ResultsThe study population consisted of 26 patients: 6 hepatocellular carcinomas, 2 cholangiocarcinomas, and 18 metastatic liver lesions (44% colorectal metastasis). The median follow-up was 21.2 months. The median dose delivered was 50 Gy at 10 Gy/fraction. No grade 4 or greater gastrointestinal toxicities were observed after treatment. The 1-year and 2-year overall survival in this cohort is 69% and 60%, respectively. At the median follow-up, FFLP for this cohort was 80.4%. FFLP for patients with hepatocellular carcinomas, colorectal metastasis, and all other lesions were 100%, 75%, and 83%, respectively.ConclusionsThis study describes the first clinical outcomes of MR-guided liver SBRT. Treatment was well tolerated by patients with excellent local control. This study lays the foundation for future dose escalation and adaptive treatment for liver-based primary malignancies and/or metastatic disease.

Project description:PURPOSE:To assess the long-term stability of the anchored radiofrequency transponders and compare displacement rates with other commercially available lung fiducial markers. We also sought to describe late toxicity attributable to fiducial implantation or migration. MATERIALS AND METHODS:The transponder cohort was comprised of 17 patients at our institution who enrolled in a multisite prospective clinical trial and underwent bronchoscopic implantation of three anchored transponders into small (2-2.5 mm) airways. We generated a comparison cohort of 34 patients by selecting patients from our institutional lung SBRT database and matching 2:1 based on the lobe containing tumor and proximity to the bronchial tree. Assessment of migration was performed by rigidly registering the most recent follow-up CT scan to the simulation scan, and assessing whether the relative geometry of the fiducial markers had changed by more than 5 mm. Toxicity outcomes of interest were hemoptysis and pneumothorax. RESULTS:The median follow-up of patients in the transponder cohort was 25.3 months and the median follow-up in the comparison cohort was 21.7 months. When assessing the most recent CT, all fiducial markers were within 5 mm of their position at CT simulation in 11 (65%) patients in the transponder group as compared to 23 (68%) in the comparison group (P = 0.28). One case of hemoptysis was identified in the transponder cohort, and bronchoscopy confirmed bleeding from recurrent tumor; no cases of hemoptysis were noted in the comparison cohort. No case of pneumothorax was noted in either group. CONCLUSION:No significant difference in the rates of fiducial marker retention and migration were noted when comparing patients who had anchored transponders placed into small airways and a 2:1 matched cohort of patients who had other commercially available lung fiducial markers placed. In both groups, no late or chronic toxicity appeared to be related to the implanted fiducial markers.

Project description:Hilar cholangiocarcinoma (CCA) is a difficult malignancy to treat surgically because of its anatomical location and its frequent association with primary sclerosing cholangitis. Neoadjuvant chemoradiotherapy followed by liver transplantation in lymph node-negative patients has been advanced by select liver transplant centers for the treatment of patients with unresectable disease. This approach has most commonly used external-beam radiotherapy in combination with biliary brachytherapy and 5-fluorouracil-based chemotherapy. Our center recently embarked on a protocol using stereotactic body radiation therapy (SBRT) followed by capecitabine in lymph node-negative patients until liver transplantation. We, therefore, retrospectively determined the tolerability and pathological response in this pilot study. During a 3-year period, 17 patients with unresectable hilar CCA were evaluated for treatment under this protocol. In all, 12 patients qualified for neoadjuvant therapy and were treated with SBRT (50-60 Gy in 3-5 fractions over the course of 2 weeks). After 1 week of rest, capecitabine was initiated at 1330 mg/m(2) /day, and it was continued until liver transplantation. During neoadjuvant therapy, there were 35 adverse events in all, with cholangitis and palmar-plantar erythrodysesthesia being the most common. Capecitabine dose reductions were required on 5 occasions. Ultimately, 9 patients were listed for transplantation, and 6 patients received a liver transplant. The explant pathology of hilar tumors showed at least a partial treatment response in 5 patients, with extensive tumor necrosis and fibrosis noted. Additionally, high apoptotic indices and low proliferative indices were measured during histological examinations. Eleven transplant-related complications occurred, and the 1-year survival rate after transplantation was 83%. In this pilot study, neoadjuvant therapy with SBRT, capecitabine, and liver transplantation for unresectable CCA demonstrated acceptable tolerability. Further studies will determine the overall future efficacy of this therapy.

Project description:Aim:Radiation therapy has been proven “safe and effective” in the management of colorectal cancer liver metastases, especially for oligometastases. However, to date, there is no consensus on optimal prescribed doses or dose fraction schemes. The current study was conducted to investigate the effectiveness and safety of 2 different radiation therapy methods, conventional conformal radiation therapy and stereotactic body radiation therapy, in the treatment of limited colorectal cancer liver metastases.Methods:From December 2011 to December 2016, twenty-six patients with colorectal cancer having postoperative liver metastases (?3) who were being treated with radiation therapy, either conventional conformal radiation therapy (50 Gy in 25 fractions) or stereotactic body radiation therapy (50 Gy in 10 fractions), were selected for this study. Overall survival and local control survival were analyzed by log-rank and Cox regression methods.Results:Radiation therapy delivered to each of the 26 patients with a total of 50 liver lesions. Conformal radiation therapy was delivered to 32 lesions in a total of 15 patients. Stereotactic body radiation therapy was delivered to 18 lesions in a total of 11 patients. Median follow-up was 13 months. Three-year overall survival and local control survival were 0% and 38.5%, 20.5%, and 53.0%, respectively, for the conformal radiation therapy and stereotactic body radiation therapy groups. The slightly better overall survival and local control survival in the stereotactic body radiation therapy group in comparison to the conformal radiation therapy group (P = .323 and .297) is insignificant. There were no differences in grade 3 hepatic toxicity between the 2 groups. Eastern Cooperative Oncology Group performance status and the number of liver lesions were significant prognostic factors in both univariate and multivariate analyses.Conclusions:Noninvasive radiation therapy provides satisfactory survival benefit for limited colorectal cancer liver metastases without intolerable toxicity and is therefore especially suitable for those elderly patients with poor performance status. Furthermore, stereotactic body radiation therapy with a higher biological equivalent dose and an abbreviated course of treatment has been shown to provide a better outcome than conventional conformal radiation therapy.

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Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer.

Publications

Comprehensive assessment of circulating immune cell populations in response to stereotactic body radiation therapy in patients with liver cancer.

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