The prognostic impact of PD-L1 and CD8 expression in anal cancer patients treated with chemoradiotherapy.

Background: Programmed death-ligand 1 (PD-L1) expression has been shown to be prognostic in many cancer types and used in consideration of checkpoint inhibitor immunotherapy. However, there are very limited and conflicting data on the prognostic impact of PD-L1 in patients with anal squamous cell carcinoma (ASCC). The objectives of this study were to measure the expression of PD-L1 and CD8 in patients with ASCC treated with radical chemoradiotherapy (CRT) and to correlate tumor expression with progression-free survival (PFS) and overall survival (OS). Methods: Ninety-nine patients with ASCC treated with primary CRT at two tertiary care cancer centers between 2000 and 2013, with available pre-treatment tumors, were included. Tissue microarrays (TMAs) from pre-treatment tumor specimens were stained for PD-L1 and CD8. PD-L1 expression in the tumor and stroma was quantified using HALO image analysis software, and results were interpreted using quantitative methods. The density of CD8 cells within the tumor was interpreted by a trained pathologist semi-quantitatively, using a 0-4 scoring system. Kaplan-Meier analysis with log-rank was used to determine the significance in the association of tumor markers with PFS and OS. Cox multivariate analysis was used to explore independent predictors of PFS and OS. Results: Of the 99 patients, 63 (64%) had sufficient tumor samples available for full analysis. CD8 high status was documented in 32 of 63 (50.8%) % of cases. PD-L1 expression was positive in 88.9% of cases. Approximately half the patients had tumor PD-L1 ≥ 5%. Patients with tumor PD-L1 ≥ 5% had better OS vs those with lower expression, HR=0.32 (95% CI 0.11-0.87), p=0.027; 10 years OS: 84% for tumor PD-L1 ≥ 5% vs 49% for PD-L1 < 5%. PD-L1 expression was not associated with PFS. On multivariate analysis, tumor PD-L1 ≥ 5% showed a trend to statistical significance for better OS, HR=0.55 (95% CI 0.12- 1.00), p=0.052. Conclusions: Tumor PD-L1≥5% is associated with OS in patients with ASCC treated with CRT. PD-L1 expression status using this unique cut-point warrants further validation for prognostication in patients with this disease. Future studies are required to determine the benefit of alternative treatment strategies based on PD-L1 status.

Heart Dose and Outcomes in Radiation Treatment for Esophageal Cancer.

Purpose Studies have shown that radiation dose to the heart may be associated with worse outcomes in patients receiving chemoradiation for lung cancer. As esophageal cancer radiation treatment can result in relatively high cardiac doses, we evaluated a single-institution database of patients treated for esophageal cancer for heart dose and outcomes. Methods We retrospectively reviewed 59 patients with stage IIA-IIIB esophageal cancer treated with neoadjuvant chemoradiation to 50.4 Gy followed by esophagectomy from 2007-2015. Patient demographics and outcome data, including pathological response, local recurrence, distant metastases, and overall survival, were obtained. Mean heart dose (MHD), heart V5, V40, and V50, were calculated. Differences in patient characteristics between the three radiation therapy modalities: three-dimensional (3D) conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), and proton beam radiation therapy (PBT) were tested using non-parametric Kruskal-Wallis (K-W) analysis of variance (ANOVA). Patient characteristics and heart dosimetric parameters were screened by univariate Cox regression for an association to overall survival, and univariate predictors (p < 0.05) were then selected as inputs into a multivariate Cox regression model using stepwise backward elimination. Kaplan-Meier risk-stratified survival curves were plotted for the best univariate or multivariate Cox model variables. An exploratory subgroup univariate Cox regression was conducted in each of the treatment modalities (proton, IMRT, 3D-CRT). Results The median follow-up was 20 months. The median overall survival was 73 months. Eleven patients (20%) experienced a complete pathologic response (pCR). Only two patients (4%) experienced a local recurrence. On univariate analysis, predictors of survival were age, prior radiation, pathologic response in involved lymph nodes, and tumor length post-treatment. On a multivariate analysis, only pathologic nodal response (yN) remained significant (p = 0.007). There was no relationship between any heart dosimetric variables analyzed and any clinical outcomes. Conclusions In this retrospective review, radiation dose to the heart was not associated with inferior treatment outcomes in patients receiving trimodality therapy for esophageal cancer.

Chest wall toxicity after hypofractionated proton beam therapy for liver malignancies.

PURPOSE: Normal liver-sparing with proton beam therapy (PBT) allows for dose escalation in the treatment of liver malignancies, but it may result in high doses to the chest wall (CW). CW toxicity (CWT) data after PBT for liver malignancies are limited, with most published reports describing toxicity after a combination of hypofractionated proton and photon radiation therapy. We examined the incidence and associated factors for CWT after hypofractionated PBT for liver malignancies. METHODS AND MATERIALS: We retrospectively reviewed the charts of 37 consecutive patients with liver malignancies (30 hepatocellular carcinoma, 6 intrahepatic cholangiocarcinoma, and 1 metastasis) treated with hypofractionated PBT. CWT was scored using Common Terminology Criteria for Adverse Events, version 4. Receiver-operating characteristic curves were used to identify patient and dosimetric factors associated with CWT and to determine optimal dose-volume histogram parameters/cutoffs. Cox regression univariate analysis was used to associate factors to time-dependent onset of CWT. RESULTS: Thirty-nine liver lesions were treated with a median dose of 60 GyE (range, 35-67.5) in 15 fractions (range, 13-20). Median follow-up was 11 months (range, 2-44). Grade ≥2 and 3 CW pain occurred in 7 (19%) and 4 (11%) patients, respectively. Median time to onset of pain was 6 months (range, 1-14). No patients had radiographic rib fracture. On univariate analysis, CW equivalent 2 Gy dose with an α/ß = 3 Gy (EQD2α/ß=3), V57 >20 cm3 (hazard ratio [HR], 2.7; P = .004), V63 >17 cm3 (HR, 2.7; P = .003), and V78 >8 cm3 (HR, 2.6; P = .003) had the strongest association with grade ≥2 CW pain, as did tumor dose of >75 Gy EQD2α/ß=10 (HR, 8.7; P = .03). No other patient factors were associated with CWT. CONCLUSIONS: CWT after hypofractionated PBT for liver malignancies is clinically relevant. For a 15-fraction regimen, V47 >20 cm3, V50 >17 cm3, and V58 >8 cm3 were associated with higher rates of CWT. Further investigation of PBT techniques to reduce CW dose are warranted.

Toward consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: Defining clinically relevant endpoints.

BACKGROUND: Our purpose was to define the most clinically relevant "nonclassic" radiation-induced liver disease (RILD) endpoints in cirrhotic patients receiving stereotactic body radiation therapy or proton beam therapy for primary liver cancer. METHODS AND MATERIALS: We retrospectively collected pretreatment, detailed toxicity (≤6 months posttreatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate and multivariate Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS). RESULTS: With median follow-up of 13 months, 23 patients (48%) had an increase in Child-Pugh (CP) score (≥2, 25%) and 3 (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. Univariate analysis showed that CP score increases of ≥1 and ≥2 and CP class change predicted OS, as did ≥G3 aspartate transaminase (AST) elevation and ≥1 Common Terminology Criteria for Adverse Events (CTCAE) AST toxicity grade change. On multivariate analysis, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent nonclassic RILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥grade 3 CTCAE alanine transaminase, and ≥grade 2 bilirubin elevations were predictive. CONCLUSIONS: Increased CP score ≥2 strongly predicts for both OS and RILD-SS and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes.

Proton beam therapy for hepatocellular carcinoma.

INTRODUCTION: Radiation therapy is an effective treatment option for hepatocellular carcinoma (HCC) patients. However, radiotherapy for HCC still has limited recognition as a standard treatment option in international consensus guidelines due to a paucity of randomized controlled trials and the risk of hepatotoxicity, which is primarily mediated by baseline liver function and dose delivered to non-tumor liver cells. Proton beam therapy (PBT) may offer advantages over photon-based radiation treatments through its dosimetric characteristic of sparing more liver volume at low to moderate doses. PBT has the potential to reduce radiation-related hepatotoxicity and allow for tumor dose escalation. Areas covered: This article reviews the clinical rationale for using PBT for HCC patients and clinical outcome and toxicity data from retrospective and prospective studies. PBT-specific technical challenges for these tumors and appropriate selection of patients to be treated with PBT are discussed. Expert commentary: Local control, overall survival, and toxicity results are promising for liver PBT. Future studies, including ongoing randomized cooperative group trials, will aim to determine the incremental benefit of PBT over photons and which patients are most suitable for PBT.

Institutional analysis of stereotactic body radiotherapy (SBRT) for oligometastatic lymph node metastases.

BACKGROUND: In limited metastatic burden of disease, stereotactic body radiotherapy (SBRT) has been shown to achieve high local control rates. It has been hypothesized that SBRT may translate to a better quality of life by delaying the need for systemic chemotherapy and possibly increasing survival. There is limited published literature on the efficacy of SBRT in limited nodal metastases. The primary aim is to review institutional outcomes of patients with solitary or oligometastatic lymph nodes treated with SBRT. METHODS: A retrospective study of patients treated with SBRT to metastatic lymph nodes (March 2010-June 2015) was conducted. Endpoints of this study were local control (LC), chemotherapy-free survival (CFS) following SBRT, toxicities, progression free survival (PFS), and overall survival (OS). RESULTS: Eighteen patients with a mean age of 65 years underwent SBRT to metastatic lymph nodes. Median follow-up was 33.6 months. There were four hepatocellular carcinoma, seven colorectal, four pancreatic, one esophageal, one gallbladder and one lung primary. Eleven (61%) patients had lymph node metastases at initial presentation of metastatic disease. Seven patients (39%) had systemic therapy prior to SBRT, with five patients receiving two lines of chemotherapy. Eight patients had solitary metastatic disease at the time of radiotherapy. All patients had <5 metastases. Median size of lymph node metastases was 1.95 cm (range: 0.8-6.2 cm). RT doses were 31 to 60 Gy in four to ten fractions, with 44% of patients receiving 35 Gy in 5 fractions. At 1 year, LC was 94% and CFS from SBRT was 60%. One-year PFS and OS were 39% and 89% respectively. There were no grade 3 or higher toxicities. CONCLUSIONS: In this single institution study, SBRT to oligometastatic lymph nodes provided excellent LC and a moderate chemotherapy-free interval with minimal toxicities. Disease progression remains prominent in these patients and larger studies are warranted to identify those who benefit most from SBRT.

Evaluation of target and cardiac position during visually monitored deep inspiration breath-hold for breast radiotherapy.

A low-resource visually monitored deep inspiration breath-hold (VM-DIBH) technique was successfully implemented in our clinic to reduce cardiac dose in left-sided breast radiotherapy. In this study, we retrospectively characterized the chest wall and heart positioning accuracy of VM-DIBH using cine portal images from 42 patients. Central chest wall position from field edge and in-field maximum heart distance (MHD) were manually measured on cine images and compared to the planned positions based on the digitally reconstructed radiographs (DRRs). An in-house program was designed to measure left anterior descending artery (LAD) and chest wall separation on the planning DIBH CT scan with respect to breath-hold level (BHL) during simulation to determine a minimum BHL for VM-DIBH eligibility. Systematic and random setup uncertainties of 3.0 mm and 2.6 mm, respectively, were found for VM-DIBH treatment from the chest wall measurements. Intrabeam breath-hold stability was found to be good, with over 96% of delivered fields within 3 mm. Average treatment MHD was significantly larger for those patients where some of the heart was planned in the field compared to patients whose heart was completely shielded in the plan (p < 0.001). No evidence for a minimum BHL was found, suggesting that all patients who can tolerate DIBH may yield a benefit from it.

Cardiac dose reduction with deep inspiration breath hold for left-sided breast cancer radiotherapy patients with and without regional nodal irradiation.

BACKGROUND: Deep inspiration breath hold (DIBH) reduces heart and left anterior descending artery (LAD) dose during left-sided breast radiation therapy (RT); however there is limited information about which patients derive the most benefit from DIBH. The primary objective of this study was to determine which patients benefit the most from DIBH by comparing percent reduction in mean cardiac dose conferred by DIBH for patients treated with whole breast RT ± boost (WBRT) versus those receiving breast/chest wall plus regional nodal irradiation, including internal mammary chain (IMC) nodes (B/CWRT + RNI) using a modified wide tangent technique. A secondary objective was to determine if DIBH was required to meet a proposed heart dose constraint of Dmean < 4 Gy in these two cohorts. METHODS: Twenty consecutive patients underwent CT simulation both free breathing (FB) and DIBH. Patients were grouped into two cohorts: WBRT (n = 11) and B/CWRT + RNI (n = 9). 3D-conformal plans were developed and FB was compared to DIBH for each cohort using Wilcoxon signed-rank tests for continuous variables and McNemar's test for discrete variables. The percent relative reduction conferred by DIBH in mean heart and LAD dose, as well as lung V20 were compared between the two cohorts using Wilcox rank-sum testing. The significance level was set at 0.05 with Bonferroni correction for multiple testing. RESULTS: All patients had comparable target coverage on DIBH and FB. DIBH statistically significantly reduced mean heart and LAD dose for both cohorts. Percent reduction in mean heart and LAD dose with DIBH was significantly larger in the B/CWRT + RNI cohort compared to WBRT group (relative reduction in mean heart and LAD dose: 55.9 % and 72.1 % versus 29.2 % and 43.5 %, p < 0.02). All patients in the WBRT group and five patients (56 %) in the B/CWBRT + RNI group met heart Dmean <4 Gy with FB. All patients met this constraint with DIBH. CONCLUSIONS: All patients receiving WBRT met Dmean Heart < 4 Gy on FB, while only slightly over half of patients receiving B/CWRT + RNI were able to meet this constraint in FB. DIBH allowed a greater reduction in mean heart and LAD dose in patients receiving B/CWRT + RNI, including IMC nodes than patients receiving WBRT. These findings suggest greatest benefit from DIBH treatment for patients receiving regional nodal irradiation.

Intensity-Modulated Radiotherapy (IMRT) vs Helical Tomotherapy (HT) in Concurrent Chemoradiotherapy (CRT) for Patients with Anal Canal Carcinoma (ACC): an analysis of dose distribution and toxicities.

PURPOSE: Intensity-modulated radiotherapy (IMRT) and helical tomotherapy (HT) have been adopted for radiotherapy treatment of anal canal carcinoma (ACC) due to better conformality, dose homogeneity and normal-tissue sparing compared to 3D-CRT. To date, only one published study compares dosimetric parameters of IMRT vs HT in ACC, but there are no published data comparing toxicities. Our objectives were to compare dosimetry and toxicities between these modalities. METHODS AND MATERIALS: This is a retrospective study of 35 ACC patients treated with radical chemoradiotherapy at two tertiary cancer institutions from 2008-2010. The use of IMRT vs HT was primarily based on center availability. The majority of patients received fluorouracil (5-FU) and 1-2 cycles of mitomycin C (MMC); 2 received 5-FU and cisplatin. Primary tumor and elective nodes were prescribed to ≥54Gy and ≥45Gy, respectively. Patients were grouped into two cohorts: IMRT vs HT. The primary endpoint was a dosimetric comparison between the cohorts; the secondary endpoint was comparison of toxicities. RESULTS: 18 patients were treated with IMRT and 17 with HT. Most IMRT patients received 5-FU and 1 MMC cycle, while most HT patients received 2 MMC cycles (p<0.01), based on center policy. HT achieved more homogenous coverage of the primary tumor (HT homogeneity and uniformity index 0.14 and 1.02 vs 0.29 and 1.06 for IMRT, p=0.01 and p<0.01). Elective nodal coverage did not differ. IMRT achieved better bladder, femoral head and peritoneal space sparing (V30 and V40, p ≤ 0.01), and lower mean skin dose (p<0.01). HT delivered lower bone marrow (V10, p<0.01) and external genitalia dose (V20 and V30, p<0.01). Grade 2+ hematological and non-hematological toxicities were similar. Febrile neutropenia and unscheduled treatment breaks did not differ (both p=0.13), nor did 3-year overall and disease-free survival (p=0.13, p=0.68). CONCLUSIONS: Chemoradiotherapy treatment of ACC using IMRT vs HT results in differences in dose homogenity and normal-tissue sparing, but no significant differences in toxicities.

Long circulating lipid nanocapsules for drug detoxification.

Uncoated and poly(ethylene glycol) (PEG)-decorated lipid nanocapsules (NC) prepared from medium chain triglycerides were investigated both in vitro and in vivo as parenteral detoxifying colloids for their ability to sequester haloperidol, docetaxel and paclitaxel. In vitro studies showed that the uptake depended on the nature of the drug and the composition of NC core and shell. In the case of haloperidol, maximal affinity was achieved upon incorporation of a complexing fatty acid. In plasma lipoprotein distribution studies, the association of both haloperidol and docetaxel into triglyceride-rich lipoprotein fraction was significantly increased in the presence of NC. The ability of the NC to lower the free drug concentrations in incubation medium was confirmed by cytotoxicity studies, where the antiproliferative activity of docetaxel was significantly decreased in the presence of NC. Using docetaxel as drug model, the NC were finally evaluated for their uptake potential in mice by one of the following administration sequences between the drug solution (Taxotere, DTX) and NC: NC-DTX, PEG(NC)-DTX and DTX-PEG(NC). Irrespective of the administration sequence, the NC increased the blood levels of docetaxel due to the in situ sequestration of drug by the circulating carrier. These findings suggest that lipid NC could be used as a non-specific mode to deal with the sequestration of molecules with high affinity for oils.