Defining Minimum Treatment Parameters of Ablative Radiation Therapy in Patients With Hepatocellular Carcinoma: An Expert Consensus.

PURPOSE: External beam radiation therapy (EBRT) is a highly effective treatment in select patients with hepatocellular carcinoma (HCC). However, the Barcelona Clinic Liver Cancer system does not recommend the use of EBRT in HCC due to a lack of sufficient evidence and intends to perform an individual patient level meta-analysis of ablative EBRT in this population. However, there are many types of EBRT described in the literature with no formal definition of what constitutes "ablative." Thus, we convened a group of international experts to provide consensus on the parameters that define ablative EBRT in HCC. METHODS AND MATERIALS: Fundamental parameters related to dose, fractionation, radiobiology, target identification, and delivery technique were identified by a steering committee to generate 7 Key Criteria (KC) that would define ablative EBRT for HCC. Using a modified Delphi (mDelphi) method, experts in the use of EBRT in the treatment of HCC were surveyed. Respondents were given 30 days to respond in round 1 of the mDelphi and 14 days to respond in round 2. A threshold of ≥70% was used to define consensus for answers to each KC. RESULTS: Of 40 invitations extended, 35 (88%) returned responses. In the first round, 3 of 7 KC reached consensus. In the second round, 100% returned responses and consensus was reached in 3 of the remaining 4 KC. The distribution of answers for one KC, which queried the a/b ratio of HCC, was such that consensus was not achieved. Based on this analysis, ablative EBRT for HCC was defined as a BED10 ≥80 Gy with daily imaging and multiphasic contrast used for target delineation. Treatment breaks (eg, for adaptive EBRT) are allowed, but the total treatment time should be ≤6 weeks. Equivalent dose when treating with protons should use a conversion factor of 1.1, but there is no single conversion factor for carbon ions. CONCLUSIONS: Using a mDelphi method assessing expert opinion, we provide the first consensus definition of ablative EBRT for HCC. Empirical data are required to define the a/b of HCC.

Selective de-implementation of routine in vivo dosimetry.

As cone-beam computed tomography (CBCT) has become the localization method for a majority of cases, the indications for diode-based confirmation of accurate patient set-up and treatment are now limited and must be balanced between proper resource allocation and optimizing efficiency without compromising safety. We undertook a de-implementation quality improvement project to discontinue routine diode use in non-intensity modulated radiotherapy (IMRT) cases in favor of tailored selection of scenarios where diodes may be useful. After analysis of safety reports from the last 5 years, literature review, and stakeholder discussions, our safety and quality (SAQ) committee introduced a recommendation to limit diode use to specific scenarios in which in vivo verification may add value to standard quality assurance (QA) processes. To assess changes in patterns of use, we reviewed diode use by clinical indication 4 months prior and after the implementation of the revised policy, which includes use of diodes for: 3D conformal photon fields set up without CBCT; total body irradiation (TBI); electron beams; cardiac devices within 10 cm of the treatment field; and unique scenarios on a case-by-case basis. We identified 4459 prescriptions and 1038 unique instances of diode use across five clinical sites from 5/2021 to 1/2022. After implementation of the revised policy, we observed an overall decrease in diode use from 32% to 13.2%, with a precipitous drop in 3D cases utilizing CBCT (from 23.2% to 4%), while maintaining diode utilization in the 5 selected scenarios including 100% of TBI and electron cases. By identifying specific indications for diode use and creating a user-friendly platform for case selection, we have successfully de-implemented routine diode use in favor of a selective process that identifies cases where the diode is important for patient safety. In doing so, we have streamlined patient care and decreased cost without compromising patient safety.

Patterns and kinetics of hepatocellular carcinoma relapse post-liver transplantation: oligorecurrence and role of local therapies.

Background: Amongst patients with recurrent hepatocellular carcinoma (HCC) post-liver transplantation, systemic therapy options may be limited by immunosuppression or poor performance status. Thus, we aimed to assess the impact of metastasis-directed therapy to all sites of disease (MDT-All) in HCC patients with limited disease recurrence [i.e., oligorecurrence (oligoM1)] post-transplantation and characterize pre-transplant characteristics associated with oligoM1. Methods: In this retrospective cohort study, patients at a single institution with recurrent HCC post-liver transplantation were identified. OligoM1 disease was defined as ≤3 lesions at recurrence, while polyrecurrent (polyM1) disease was defined as >3 lesions. Outcomes were compared in patients with oligoM1 disease by receipt of MDT-All. Regression analyses were used to identify predictors of polyM1 disease and characteristics associated with post-recurrence outcomes. Results: Forty-three patients with recurrent HCC post-liver transplantation from 2005-2022 were identified. Twenty-seven (63%) patients had oligoM1. Microvascular invasion was independently associated with polyM1 [odds ratio (OR): 14.64; 95% confidence interval (CI): 1.48-144.77; P=0.022]. Elevated alpha-fetoprotein (AFP) ≥400 ng/mL [hazard ratio (HR): 2.44; 95% CI: 1.08, 5.52; P=0.033] at recurrence was independently associated with inferior overall survival (OS), while oligoM1 (HR: 0.42; 95% CI: 0.21, 0.87; P=0.018) was independently associated with favorable OS. Amongst patients with oligoM1 who received MDT-All (n=15) median OS was 38.4 vs. 16.1 months for those who did not receive MDT-All (log-rank P=0.021). There was a non-significant improvement in polyprogression-free survival (polyPFS) (median 14.0 vs. 10.7 months, P=0.1) amongst oligoM1 patients who received MDT-All compared to those who did not. Conclusions: Receipt of MDT-All was associated with improved OS amongst patients with limited HCC disease recurrence following liver transplantation.

Location, Location, Location: What Should be Targeted Beyond Gross Disease for Localized Pancreatic Ductal Adenocarcinoma? Proposal of a Standardized Clinical Tumor Volume for Pancreatic Ductal Adenocarcinoma of the Head: The "Triangle Volume".

PURPOSE: In patients with borderline resectable or locally advanced pancreatic adenocarcinoma (BRPC/LAPC), local failure rates after resection remain significant, even in the setting of neoadjuvant chemotherapy and radiation. Suboptimal local control may relate to variable radiation target delineation, as no consensus exists around clinical tumor volume (CTV) design in this context. In the surgical literature, recent attention has been given to the "triangle" volume (TV) as a source of subclinical, residual disease. To understand whether the TV can inform optimal CTV design, we mapped locoregional failures after resection in a large cohort of patients with BRPC/LAPC and compared locations of failure to the TV. METHODS AND MATERIALS: Patients with BRPC/LAPC of the head or neck diagnosed between 2016 AND 2019 who developed locoregional failure after surgery, neoadjuvant chemotherapy, and radiation were identified. Descriptive statistics were generated to report the frequency of locoregional failures located within the TV and the frequency of new vascular involvement at time of failure, compared with vascular involvement at diagnosis. Additionally, dosimetric coverage of the TV with the preoperative radiation plan that had been used was assessed. RESULTS: In 31 patients who experienced locoregional failure, the centroid of failure was located within the TV in 28 cases (90%). Extent of vascular involvement at time of locoregional failure included vasculature that had not been involved at diagnosis in 13 cases (42%). The preoperative radiation plan that had been used provided a median V33 Gy and V25 Gy of the TV of only 53% (interquartile range, 34%-72%) and 70% (IQR, 48%-85%), respectively. CONCLUSIONS: The TV encompassed the vast majority of locoregional failures, but dosimetric coverage of the TV was poor when only targeting gross disease and the full circumference of involved vasculature. As such, the TV may better serve as a basis for CTV design in patients with BRPC/LAPC undergoing neoadjuvant radiation.

Bone density and fracture risk following SBRT for non-spine bone metastases.

PURPOSE/METHODS: This retrospective study evaluated local recurrence (LR) and fracture risk in non-spine bone metastases treated with SBRT. RESULTS: 181 lesions in 116 patients are reported. The median dose was 27 Gy (range 15-40) in 3 fractions (range 1-6). The cumulative incidence of LR was 2.8%, 7.2% and 12.5% at 6 mo, 1 yr and 2 yrs. Fractures occurred in 11 lesions (6%). Radioresistant histology and increasing PTV predicted for LR on univariate analysis, while rib location was associated with control. Increasing PTV remained a significant predictor for LR on multivariate analysis. Univariate predictors of fracture risk included female gender, lytic lesions and poorer KPS. Average CT-approximated L1 trabecular attenuation in patients with fracture was significantly lower than in patients without fracture (112.2 vs. 142.6 Hounsfield units). CONCLUSION: In the largest series to date, we report excellent local control for SBRT to non-spine bone metastases and a novel relationship between CT-based bone quality assessment and fracture risk.

Fiducial-based image-guided SBRT for pancreatic adenocarcinoma: Does inter-and intra-fraction treatment variation warrant adaptive therapy?

PURPOSE: Variation in target positioning represents a challenge to set-up reproducibility and reliability of dose delivery with stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma (PDAC). While on-board imaging for fiducial matching allows for daily shifts to optimize target positioning, the magnitude of the shift as a result of inter- and intra-fraction variation may directly impact target coverage and dose to organs-at-risk. Herein, we characterize the variation patterns for PDAC patients treated at a high-volume institution with SBRT. METHODS: We reviewed 30 consecutive patients who received SBRT using active breathing coordination (ABC). Patients were aligned to bone and then subsequently shifted to fiducials. Inter-fraction and intra-fraction scans were reviewed to quantify the mean and maximum shift along each axis, and the shift magnitude. A linear regression model was conducted to investigate the relationship between the inter- and intra-fraction shifts. RESULTS: The mean inter-fraction shift in the LR, AP, and SI axes was 3.1 ± 1.8 mm, 2.9 ± 1.7 mm, and 3.5 ± 2.2 mm, respectively, and the mean vector shift was 6.4 ± 2.3 mm. The mean intra-fraction shift in the LR, AP, and SI directions were 2.0 ± 0.9 mm, 2.0 ± 1.3 mm, and 2.3 ± 1.4 mm, respectively, and the mean vector shift was 4.3 ± 1.8 mm. A linear regression model showed a significant relationship between the inter- and intra-fraction shift in the AP and SI axis and the shift magnitude. CONCLUSIONS: Clinically significant inter- and intra-fraction variation occurs during treatment of PDAC with SBRT even with a comprehensive motion management strategy that utilizes ABC. Future studies to investigate how these variations could lead to variation in the dose to the target and OAR should be investigated. Strategies to mitigate the dosimetric impact, including real time imaging and adaptive therapy, in select cases should be considered.

Long-Term Results of a Phase 1 Dose-Escalation Trial and Subsequent Institutional Experience of Single-Fraction Stereotactic Ablative Radiation Therapy for Liver Metastases.

PURPOSE: We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study. METHODS AND MATERIALS: Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive <9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control. RESULTS: Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%. CONCLUSIONS: For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.

Feasibility and Outcome of Routine Use of Concurrent Chemoradiation in HIV-positive Patients With Squamous Cell Anal Cancer.

OBJECTIVES: Clinical concerns about hematologic toxicities in human immunodeficiency virus (HIV)+ patients with squamous cell anal cancer (SCAC) may lead to de-escalation of treatment intensity. The objective of this study is to evaluate clinical outcomes including toxicity following standard concurrent curative-intent chemoradiation for HIV+ and HIV- patients with SCAC. MATERIALS AND METHODS: Among 97 evaluable patients treated between 2009 and 2016 (median age 52.2 y), 43 (44.3%) were HIV+ and 54 (55.7%) HIV-. The majority of the radiation was delivered using intensity-modulated radiation therapy and chemotherapy consisting primarily (93%) of 5-fluorouracil and mitomycin C. Clinical outcomes assessed included toxicity, locoregional control (LRC), distant metastasis (DM), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), and cause-specific survival (CSS). RESULTS: With a median follow-up of 45 months, HIV+ patients exhibited a trend toward reduced OS compared with HIV- patients (4 y OS 61.2% vs. 78.3%; HR 2.09; 95% CI, 0.97-4.52; P=0.055) on univariable analysis, but HIV status was not significant after adjusting for additional parameters on multivariable analysis. Toxicity rates, LRC, CFS, PFS, freedom from DM, and CSS were similar between the 2 cohorts. On multivariable analysis, tumor size >5 cm impacted all clinical outcomes (trend for LRC) except CFS. Radiation treatment extension beyond 7 days was found to negatively impact LRC and CSS. Male sex was associated with worse CFS. CONCLUSIONS: Radiation therapy with concurrent 5-fluorouracil and mitomycin C chemotherapy is reasonably well-tolerated as curative treatment for HIV+ patients with SCAC, and no significant difference in outcomes was noted relative to HIV- patients.

Radiation treatment planning with embedded dose escalation.

BACKGROUND: Heterogeneous target doses are a common by-product from attempts to improve normal tissue sparing in radiosurgery treatment planning. These regions of escalated dose within the target may increase tumor control probability (TCP). Purposely embedding hot spots within tumors during optimization may also increase the TCP. This study discusses and compares five optimization approaches that not only eliminate homogeneity constraints, but also maximize heterogeneity and internal dose escalation. METHODS: Co-planar volumetric modulated arc therapy (VMAT) plans were produced for virtual spherical targets with 2-8 cm diameters, minimum target dose objectives of 25 Gy, and objectives to minimize normal tissue dose. Five other sets of plans were produced with additional target dose objectives: 1) minimum dose-volume histogram (DVH) objective on 10% of the target 2) minimum dose objective on a sub-structure within the target, and 3-5) minimum generalized equivalent uniform dose (gEUD) objectives assuming three different volume-effect parameters. Plans were normalized to provide equivalent maximum OAR dose and were compared in terms of target D0.1 cc, ratio of V12.5 Gy to PTV volume (R50%), monitor units per 5 Gy fraction (MU), and mean multi-leaf collimator (MLC) segment size. All planning approaches were also applied to a clinical patient dataset and compared. RESULTS: Mean ± standard deviation metrics achievable using the baseline and experimental approaches 1-5) included D0.1 cc: 27.7 ± 0.8, 64.6 ± 10.5, 56.5 ± 10.3, 48.9 ± 5.7, 44.8 ± 5.0, and 37.4 ± 4.5 Gy. R50%: 4.64 ± 3.27, 5.15 ± 2.32, 4.83 ± 2.64, 4.42 ± 1.83, 4.45 ± 1.88, and 4.21 ± 1.75. MU: 795 ± 27, 1988 ± 222, 1766 ± 259, 1612 ± 112, 1524 ± 90, and 1362 ± 146. MLC segment size: 4.7 ± 1.6, 2.3 ± 0.7, 2.6 ± 0.8, 2.7 ± 0.7, 2.7 ± 0.8, and 2.8 ± 0.8 cm. CONCLUSIONS: The DVH-based approach provided the highest embedded doses for all target diameters and patient example with modest increases in R50%, achieved by decreasing MLC segment size while increasing MU. These results suggest that embedding doses > 220% of tumor margin dose is feasible, potentially improving TCP for solid tumors.

4D liver tumor localization using cone-beam projections and a biomechanical model.

PURPOSE: To improve the accuracy of liver tumor localization, this study tests a biomechanical modeling-guided liver cone-beam CT (CBCT) estimation (Bio-CBCT-est) technique, which generates new CBCTs by deforming a prior high-quality CT or CBCT image using deformation vector fields (DVFs). The DVFs can be used to propagate tumor contours from the prior image to new CBCTs for automatic 4D tumor localization. METHODS/MATERIALS: To solve the DVFs, the Bio-CBCT-est technique employs an iterative scheme that alternates between intensity-driven 2D-3D deformation and biomechanical modeling-guided DVF regularization and optimization. The 2D-3D deformation step solves DVFs by matching digitally reconstructed radiographs of the 3D deformed prior image to 2D phase-sorted on-board projections according to imaging intensities. This step's accuracy is limited at low-contrast intra-liver regions without sufficient intensity variations. To boost the DVF accuracy in these regions, we use the intensity-driven DVFs solved at higher-contrast liver boundaries to fine-tune the intra-liver DVFs by finite element analysis-based biomechanical modeling. We evaluated Bio-CBCT-est's accuracy with seven liver cancer patient cases. For each patient, we simulated 4D cone-beam projections from 4D-CT images, and used these projections for Bio-CBCT-est based image estimations. After Bio-CBCT-est, the DVF-propagated liver tumor/cyst contours were quantitatively compared with the manual contours on the original 4D-CT 'reference' images, using the DICE similarity index, the center-of-mass-error (COME), the Hausdorff distance (HD) and the voxel-wise cross-correlation (CC) metrics. In addition to simulation, we also performed a preliminary study to qualitatively evaluate the Bio-CBCT-est technique via clinically acquired cone beam projections. A quantitative study using an in-house deformable liver phantom was also performed. RESULTS: Using 20 projections for image estimation, the average (±s.d.) DICE index increased from 0.48 ±â€¯0.13 (by 2D-3D deformation) to 0.77 ±â€¯0.08 (by Bio-CBCT-est), the average COME decreased from 7.7 ±â€¯1.5 mm to 2.2 ±â€¯1.2 mm, the average HD decreased from 10.6 ±â€¯2.2 mm to 5.9 ±â€¯2.0 mm, and the average CC increased from -0.004 ±â€¯0.216 to 0.422 ±â€¯0.206. The tumor/cyst trajectory solved by Bio-CBCT-est matched well with that manually obtained from 4D-CT reference images. CONCLUSIONS: Bio-CBCT-est substantially improves the accuracy of 4D liver tumor localization via cone-beam projections and a biomechanical model.

Impact of Socioeconomic Status on Pretreatment Weight Loss and Survival in Non-Small-Cell Lung Cancer.

PURPOSE: Socioeconomic status (SES) influences health care outcomes, but the influence of primary payer on cancer-associated wasting is unknown. We hypothesized that primary payer as an indicator of SES would influence pretreatment cancer-associated weight loss and treatment outcomes. MATERIALS AND METHODS: Retrospective review of medical records identified 1,366 patients with non-small-cell lung cancer (NSCLC) consecutively treated at a tertiary care health system between January 1, 2006 and December 31, 2013. Insurance status was obtained from an institutional tumor registry. Cancer-associated weight loss was based on the validated international consensus definition of cachexia. Multivariable regression analyses were used to identify prognostic factors of pretreatment cancer-associated weight loss and survival. RESULTS: The cohort included a representative group of patients with a median age at diagnosis of 64 years, 47% females, and 33% patients of nonwhite race. Pretreatment cancer-associated weight loss was present at the time of NSCLC diagnosis in 17%, 14%, 32%, and 38% of patients with stage I, II, III, and IV disease, respectively. Pretreatment cancer-associated weight loss was associated with increasing age at diagnosis, black race, single marital status, tobacco use, and disease stage. Compared with private insurance, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42 to 3.30) and lack of insurance (odds ratio, 2.32; 95% CI, 1.50 to 3.58) were associated with pretreatment cancer-associated weight loss. Among cachectic patients, comorbidity, histology, tumor grade, and disease stage were prognostic of survival on multivariable analysis; however, primary payer was not. CONCLUSION: Pretreatment cancer-associated weight loss is common in patients with NSCLC, and its presence is significantly associated with lower SES. However, among patients with pretreatment cancer-associated weight loss, SES was not predictive of survival. Early use of cancer cachexia-directed therapies may improve outcomes, and further study on the biologic mechanisms of cancer cachexia will provide novel therapeutic avenues.

Prevalence and Survival Impact of Pretreatment Cancer-Associated Weight Loss: A Tool for Guiding Early Palliative Care.

PURPOSE: Cancer-associated weight loss is associated with poor prognosis in advanced malignancy; however, its pretreatment prevalence and survival impact are inadequately described in large cohorts. Such data, stratified by tumor type and stage, may facilitate the optimal and timely allocation of complementary care, leading to improvements in patient survival and quality of life. METHODS: We performed a retrospective cohort study of 3,180 consecutively treated adult patients with lung or GI (including colorectal, liver, and pancreatic) cancer. Pretreatment cancer-associated weight loss was based on the international consensus definition of cachexia. Prevalence and survival impact of pretreatment cancer-associated weight loss were evaluated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Cancer-associated weight loss was observed at the time of cancer diagnosis in 34.1% of patients. Pretreatment weight loss was documented in 17.6%, 25.8%, 36.6%, and 43.3% of stage I, II, III, and IV cancers, respectively. Wasting was common regardless of tumor type, with prevalence at diagnosis ranging from 27.3% in patients with colorectal cancer to 53.4% in patients with gastroesophageal cancer. Pretreatment weight loss was associated with reduced overall survival after adjusting for stage, size, grade, comorbidity, age, sex, and tobacco history (hazard ratio, 1.26; 95% CI, 1.13 to 1.39). CONCLUSION: Pretreatment cancer-associated weight loss is common, even in early-stage disease, and is independently associated with reduced survival. Minimal weight loss represents a clinically distinct entity with an associated overall survival intermediate to that of no weight loss and overt wasting. Early diagnosis and treatment of cancer-associated wasting offers a novel therapeutic avenue for reducing cancer mortality.

Race- and Sex-Based Disparities in the Therapy and Outcomes of Squamous Cell Carcinoma of the Anus.

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2-T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17-1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47-1.73, men vs women), race (HR, 1.51; 95% CI, 1.34-1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82-0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.

A Phase I Dose-Escalation Trial of Single-Fraction Stereotactic Radiation Therapy for Liver Metastases.

BACKGROUND: There is significant interest in the use of stereotactic ablative radiotherapy (SABR) as a treatment modality for liver metastases. A variety of SABR fractionation schemes are in clinical use. We conducted a phase I dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR. METHODS: Patients with liver metastases from solid tumors, for whom a critical volume dose constraint could be met, were treated with single-fraction SABR. Seven patients were enrolled to the first group, with a prescription dose of 35 Gy. Dose was then escalated to 40 Gy in a single fraction, and seven more patients were treated at this dose level. Patients were followed for toxicity and underwent serial imaging to assess lesion response and local control. RESULTS: Fourteen patients with 17 liver metastases were treated. There were no dose-limiting toxicities observed at either dose level. Nine of the 13 lesions assessable for treatment response showed a complete radiographic response to treatment; the remainder showed partial response. Local control of irradiated lesions was 100 % at a median imaging follow-up of 2.5 years. Two-year overall survival for all patients was 78 %. CONCLUSIONS: For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy is tolerable and shows promising signs of efficacy at intermediate follow-up.

Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome.

PURPOSE: To evaluate differences in overall survival in patients with hepatocellular carcinoma (HCC) after the establishment of a multidisciplinary clinic (MDC) for HCC. METHODS: Patient demographic and tumor characteristics of 355 patients diagnosed with HCC were collected between October 2006 and September 2011. Patients diagnosed after the initiation of the HCC MDC on October 1, 2010, were compared to patients diagnosed in the 4 years before. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the groups. RESULTS: A total of 105 patients were diagnosed in the time period after HCC MDC initiation compared to 250 patients in the previous 4 years. Patients diagnosed with HCC after the HCC MDC had fewer symptoms at presentation (64 vs. 78 %, p = 0.01) and earlier stage of tumor presentation [Barcelona Clinic for Liver Cancer (BCLC) A stage, 44 vs. 26 %, p = 0.0003; tumor, node, metastasis classification system stage 1, 44 vs. 30 %, p = 0.003) compared with patients diagnosed before MDC formation. The median time to treatment after diagnosis in the later period was significantly shorter than in the earlier time period (2.3 vs. 5.3 months, p = 0.002). On multivariate analysis, being seen in the HCC MDC remained independently associated with better overall survival (hazard ratio 2.5, 95 % confidence interval 2-3), after adjusting for BCLC stage and recipient of curative treatment. Patients diagnosed after HCC MDC initiation had a median survival of 13.2 months compared to the 4.8 months observed in patients diagnosed before MDC formation (p = 0.005). CONCLUSIONS: The implementation of a MDC for the evaluation and treatment of patients with HCC is associated with improved overall survival.

Partial depletion of regulatory T cells does not influence the inflammation caused by high dose hemi-body irradiation.

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4(+) T cells, CD8(+) T cells, Treg cells, B cells, NK cells, NK1.1(+) T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.