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.

Liver SBRT dose accumulation to assess the impact of anatomic variations on normal tissue doses and toxicity in patients treated with concurrent sorafenib.

BACKGROUND AND PURPOSE: Unexpected liver volume reductions occurred during trials of liver SBRT and concurrent sorafenib. The aims were to accumulate liver SBRT doses to assess the impact of these anatomic variations on normal tissue dose parameters and toxicity. MATERIALS AND METHODS: Thirty-two patients with hepatocellular carcinoma (HCC) or metastases treated on trials of liver SBRT (30-57 Gy, 6 fractions) and concurrent sorafenib were analyzed. SBRT doses were accumulated using biomechanical deformable registration of daily cone-beam CT. Dose deviations (accumulated-planned) for normal tissues were compared for patients with liver volume reductions > 100 cc versus stable volumes, and accumulated doses were reported for three patients with grade 3-5 luminal gastrointestinal toxicities. RESULTS: Patients with reduced (N = 12) liver volumes had larger mean deviations of 0.4-1.3 Gy in normal tissues, versus -0.2-0.4 Gy for stable cases (N = 20), P > 0.05. Deviations > 5% of the prescribed dose occurred in both groups. Two HCC patients with toxicities to small and large bowel had liver volume reductions and deviations to the maximum dose of 4% (accumulated 36.9 Gy) and 3% (accumulated 33.4 Gy) to these organs respectively. Another HCC patient with a toxicity of unknown location plus tumor rupture, had stable liver volumes and deviations to luminal organs of -6% to 4.5% (accumulated < 30.5 Gy). CONCLUSION: Liver volume reductions during SBRT and concurrent sorafenib were associated with larger increases in accumulated dose to normal tissues versus stable liver volumes. These dosimetric changes may have further contributed to toxicities in HCC patients who have higher baseline risks.

The Impact of Disease Progression on Health-Related Quality of Life Outcomes in Patients With Oligometastatic Disease at 12 Months Post Stereotactic Body Radiation Therapy.

PURPOSE: There is a paucity of published health-related quality of life (HRQOL) outcomes in patients with oligometastatic disease (OMD) who receive stereotactic body radiation therapy (SBRT) and no available data assessing the effect of disease progression post-SBRT on HRQOL in this patient population. METHODS AND MATERIALS: Patients with OMD who received SBRT in a phase II single-arm research ethics board approved study were included. HRQOL was a secondary outcome. This study hypothesized that there is a different pattern of change from baseline HRQOL in patients with OMD treated with SBRT that have disease progression by 12 months (progressors) compared with those that do not progress by 12 months (nonprogressors), as measured by the European Organisation of Research and Treatment in Cancer Quality of Life Questionnaire Core 30. RESULTS: A total of 107 patients were included in this analysis, 41 without progression and 66 with progression by 12 months; median time to progression was 7.7 (0.3-57) months. A statistically significant decline in the mean global health/quality of life (GHQOL) score (73 [SD, 21.8] to 67.2 [SD, 27.1]; P = .04) from baseline in the entire population at the 12-month follow-up was found. Mean GHQOL change score in nonprogressors was -0.8 and in progressors was -8.8 (P = .07). However, only progressors demonstrated a difference between baseline and 12-month mean GHQOL scores (71.2 vs 62.4; P = .01), which was both statistically and clinically significant (-8.8) in the range of small minimal clinically important difference. There was a higher proportion of patients who experienced a minimal clinically important difference deterioration in progressors compared with nonprogressors (37.4% vs 24.4%; P = .14). CONCLUSIONS: Patients who progressed by 12 months did not have a statistical or clinically significant difference in mean GHQOL change score compared with nonprogressors. However, there were signals to suggest that patients who progressed by 12 months post-SBRT experienced a different pattern of change compared with nonprogressors, which was worse compared with baseline.

Multimodal assessment of acute cardiac toxicity induced by thoracic radiotherapy in cancer patients. Study protocol.

BACKGROUND: Today, cancer ranks as one of the leading causes of death. Despite the large number of novel available therapies, radiotherapy (RT) remains as the most effective non-surgical method to cure cancer patients. In fact, approximately 50% of all cancer patients receive some type of RT and among these 60% receive RT-treatment with a curative intent. However, as occurs with any other oncological therapy, RT treated patients may experience toxicity side effects that range from moderate to severe. Among these, cardiotoxicity represents a significant threat for premature death. Current methods evaluate cardiotoxic damage based on volumetric changes in the Left Ventricle Ejected Fraction (LVEF). Indeed, a 10% drop in LVEF is commonly used as indicator of cardiotoxicity. More recently, a number of novel techniques have been developed that significantly improve specificity and sensitivity of heart's volumetric changes and early detection of cardiotoxicity even in asymptomatic patients. Among these, the Strain by Speckle Tracking (SST) is a technique based on echocardiographic analysis that accurately evaluates myocardial deformation during the cardiac cycle (ventricular and atrial function). Studies also suggest that Magnetic Resonance Imaging (MRI) is a high-resolution technique that enables a better visualization of acute cardiac damage. METHODOLOGY: This protocol will evaluate changes in SST and MRI in cancer patients that received thoracic RT. Concomitantly, we will assess changes in serum biomarkers of cardiac damage in these patients, including: high-sensitivity cardiac Troponin-T (hscTnT), N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) and Circulating Endothelial Cells (CECs), a marker of endothelial dysfunction and vascular damage. DISCUSSION: The presented protocol is to our knowledge the first to prospectively and with a multimodal approach, study serological and image biomarkers off early cardiac damage due to radiotherapy. With a practical clinical approach we will seek early changes that could potentially be in the future be linked to clinical mayor events with consequences for cancer survivors.

Radiological tumor response and histopathological correlation of hepatocellular carcinoma treated with stereotactic body radiation therapy as a bridge to liver transplantation.

PURPOSE: To assess the imaging findings of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) as a bridging therapy prior to liver transplantation (LT), with histopathological correlation at liver explant. METHODS: Our institutional review board approved this retrospective study. The study subjects included 25 HCC lesions in 23 patients (20 males; median age, 60 years; range 41-68 years) who underwent LT after SBRT for HCC as a bridge to LT in a single tertiary referral institution over a 12-year period. Target HCC lesions were assessed for imaging biomarkers on contrast-enhanced CT or MRI including change in HCC diameter and assessment of percentage necrosis. The radiologic response at pre-LT imaging was compared to explant pathology. RESULTS: There was a positive correlation between the tumor size (Spearman's ρ = 0.86; p < 0.001) and percentage necrosis (p < 0.001) on Pre-LT imaging and those on pathology. Partial response (PR), stable disease (SD), and progressive disease (PD) according to RECIST 1.1 were seen in 8 (32%), 15 (60%), and 2 (8%) lesions on pre-LT imaging, respectively. Of the 15 lesions with radiologic SD, 5/15 (33%) showed necrosis of more than 50% on post-SBRT imaging, while 9/15 (60%) showed necrosis of more than 50% at explant pathologic analysis, showing a tendency to underestimate the degree of tumor necrosis compared to pathology. CONCLUSION: RECIST 1.1 radiologic response criteria may underestimate the response to treatment with SBRT, and radiologic estimation of percent tumor necrosis was more closely correlated with pathologic percent tumor necrosis.

Stereotactic body radiation therapy for hepatocellular carcinoma with Macrovascular invasion.

BACKGROUND: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MVI) is associated with a poor prognosis. The purpose of this study is to describe long-term outcomes of patients with HCC and MVI treated with stereotactic body radiation therapy (SBRT). METHODS: Patients with HCC and MVI who were treated with SBRT from January 2003 to December 2016 were analyzed. Patients who had extrahepatic disease or previous liver transplant were excluded. Demographical, clinical, and treatment variables were analyzed. RESULTS: 128 eligible patients with HCC and MVI were treated with SBRT. Median age was 60.5 years (39 to 90 years). Baseline Child-Pugh (CP) score was A5 in 67%, A6 in 20%. Median SBRT dose was 33.3 Gy (range: 27 to 54 Gy) in 5 fractions. Local control at 1 year was 87.4% (95% CI 78.6 to 96.1%). Median overall survival (OS) was 18.3 months (95% CI 11.2 to 21.4 months); ECOG performance status > 1 (HR:1.85, p = 0.0138) and earlier treatment era (HR: 2.20, p = 0.0015) were associated with worsening OS. In 43 patients who received sorafenib following SBRT, median OS was 37.9 months (95% CI 19.5 to 54.4 months). Four patients developed GI bleeding possibly related to SBRT at 2 to 8 months, and 27% (31/112 evaluable patients) had worsening of CP class at three months after SBRT. CONCLUSIONS: SBRT was associated with encouraging outcomes for patients with HCC and MVI, especially in those patients who received sorafenib after SBRT. Randomized phase III trials of SBRT with systemic and/or regional therapy are warranted and ongoing.

What is the optimal radiotherapy utilization rate for lung cancer?-a systematic review.

Lung cancer is a major cause of morbidity and mortality globally. Although radiotherapy (RT) may be beneficial in the radical and/or palliative management of many lung cancer patients, it is underutilized worldwide. Population-level development of RT resources requires estimates of optimal radiotherapy utilization rates (ORUR) and actual radiotherapy utilization rate (ARUR). A systematic review of PubMed database for English-language articles from January 2009 to January 2019 was performed. Keywords included utilization, underutilization, demand, epidemiologic, benchmark, RT and cancer. Data abstracted included: study population, diagnosis, stage, year of diagnosis, timing of RT, intent of RT, ARUR, and ORUR. Eligible studies provided ARUR or ORUR for lung cancer, small cell lung cancer (SCLC), or non-small cell lung cancer (NSCLC). Included ARUR were based on at least 1,000 patients who were diagnosed or treated in 2009 or later. Included ORUR were based on evidence review or ARUR in 2009 or later. The initial search strategy yielded 1,627 unique abstracts. After review, 105 articles were determined appropriate for full-text review. From these, a final set of 21 articles met all inclusion criteria. In eight papers, ORUR was estimated. Estimated lifetime ORUR ranged from 61% to 82%. Methods for estimation included the evidence-based guideline model, Malthus model, and criterion-based benchmarking (CBB) model. The majority of estimates (6/8) used the evidence-based guideline model. Fifteen papers provided ARUR on lung cancer, inclusive of SCLC and NSCLC. ARUR within 9 months to 1 year of diagnosis ranged from 39% to 46%. Lifetime ARUR was an estimated 52% in Ontario, Canada. Palliative intent ARUR ranged from 12% in Central Poland to 46% in Ontario, Canada. RT is underutilized for lung cancer globally, and there is wide geographical variation in the level of underutilization.

Extensive Unpredictable Pancreas Cancer Inter-fraction Motion: A Case Report.

We present a case of locally advanced pancreatic cancer with duodenal invasion treated with consolidative chemoradiation, where extensive unpredictable interfraction motion was observed. Initially, two attempts were made to treat with volumetric modulated arc therapy technique. However, due to substantial interfractional motion of the pancreatic head mass relative to the regional nodal areas, the patient was eventually replanned and treated with a four-field box technique. This case highlights the difficulty in delivering conformal radiation to the pancreas and quantifies the movement of the target, the adjacent biliary stent, and regional nodes.

Imaging post-stereotactic body radiation therapy responses for hepatocellular carcinoma: typical imaging patterns and pitfalls.

Stereotactic body radiation therapy (SBRT) has increased utility in the management of hepatocellular carcinoma (HCC) ranging from local therapy in early-stage HCC not suitable for other focal therapies to end-stage HCC. As the indications for the use of SBRT in HCC expand, diagnostic imaging is being increasingly used to assess response to treatment. The imaging features of tumor response do not parallel those of other focal therapies such as radiofrequency ablation or trans-arterial chemoembolization that immediately devascularize the tumor. The tumor response to SBRT on imaging takes much longer and often shows gradual changes including the reduction of enhancement and size over several months. It is essential to recognize the typical imaging patterns of response, as well as the appearance of focal liver reaction in the non-target liver that can confound image interpretation. The timing of treatment response assessment imaging is fundamental to minimize the potential for false negative response. The purpose of this article is to review the variable post-SBRT imaging features of HCC and adjacent liver parenchyma and discuss the potential pitfalls of imaging evaluation after SBRT for HCC.

Quality of life changes after stereotactic ablative radiotherapy for liver metastases: A prospective cohort analysis.

PURPOSE: To report the changes in quality of life (QoL) after stereotactic ablative radiotherapy (SABR) in patients with liver metastases (LM). MATERIALS AND METHODS: A prospective cohort study was undertaken to measure the acute changes in QoL after SABR. Patients with 1-3 treated LM were eligible. Doses of 30-60 Gy in 3-5 fractions were delivered. Prospective QoL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires, Core 15 for Palliative Care (EORTC QLQ-C15-PAL) and liver metastases (LM21), at baseline, 1st week and last day of treatment, then 1, 6 and 12 weeks after SABR. The functional living index-emesis (FLIE) was collected at baseline, 1st week, last day and 1 week after treatment. Univariable and multivariable linear mixed modeling were performed as appropriate to assess changes in QoL over time. RESULTS: Sixty patients were included. The most common primary cancer was colorectal (42%). The global health score measured by QLQ-C15-PAL was significantly worse at treatment completion (p = 0.001), 1 week (p = 0.003) and 6 weeks (p = 0.002) after SABR but recovered by 12 weeks (p = 0.124). Nausea and constipation were worse at treatment completion (p < 0.05) but recovered 1 week after while fatigue recovered 6 weeks post-SABR. The majority of patients reported stable QoL at 12 weeks for all domains in the C15-PAL and LM21 questionnaires. CONCLUSION: SABR offers a non-invasive mean of ablating LM with minimal impact on acute QoL.

Perfusion imaging of colorectal liver metastases treated with bevacizumab and stereotactic body radiotherapy.

Stereotactic body radiotherapy (SBRT) and bevacizumab are used in the treatment of colorectal liver metastases. This study prospectively evaluated changes in perfusion of liver metastases in seven patients treated with both bevacizumab and SBRT. Functional imaging using dynamic contrast-enhanced CT perfusion and contrast-enhanced ultrasound were performed at baseline, after bevacizumab, and after SBRT. After bevacizumab, a significant decrease was found in permeability (-28%, p < .05) and blood volume (-47%, p < .05), while SBRT led to a significant reduction in permeability (-22%, p < .05) and blood flow (-37%, p < .05). This study demonstrates that changes in perfusion can be detected after bevacizumab and SBRT.

Radiation-Induced Liver Toxicity.

The advent of highly conformal radiation therapy (RT) has defined a new role for RT in the treatment of both primary and metastatic liver cancer. Despite major advances in how RT is delivered, radiation-induced liver disease (RILD) remains a concern. Classic RILD, characterized by anicteric ascites and hepatomegaly, is unlikely to occur if treating to doses of ≤30Gy in 2Gy per fraction in patients with baseline Child-Pugh A liver function. On the other hand, nonclassic RILD is a spectrum of liver toxicity, including a general decline in liver function and elevation of liver enzymes. It is less well defined and less predictable, especially in patients with underlying liver disease. Scoring and quantifying RILD remains a challenge. The Child-Pugh score has been the most consistently used parameter. Other scoring systems such as the albumin-bilirubin score provide further discrimination in patients with hepatocellular carcinoma, although their value in patients treated with RT remains to be established. Many serum and imaging biomarkers of liver function are currently being investigated, and they will provide further useful information in the future for local and global liver function assessment, for planning optimization, and for treatment adaptation. To date, no pharmacological therapies have provided consistent results in mitigating RILD once it has manifested clinically. Numerous promising treatment strategies including TGFß inhibition, Hedgehog inhibition, CXCR4 inhibition, hepatocyte transplantation, and bone marrow-derived stromal cell therapy, have potential to be helpful in the treatment of RILD in the future.

Squamous cell carcinoma of the conjunctiva with extraocular involvement: case report and literature review. / Carcinoma escamoso de la conjuntiva con compromiso extraocular: reporte de caso y revisión de la literatura.

Squamous cell carcinoma of the conjunctiva is the most frequent malignant tumor of the ocular surface. It is a rare disease with an incidence of 0.13 to 1.9 per 100,000 inhabitants, mainly affecting individuals between 50 and 75 years of age. It tends to have a slow, non-aggressive course. Treatment depends on the extent of the tumor. If there is intraocular involvement, enucleation is indicated, and in the presence of extraocular involvement the orbital exenteration is the standard treatment. We report and discuss the case of an 82 year old male patient having a conjunctival squamous cell carcinoma with intra and extraocular involvement, together with a review of the literature.

El carcinoma escamoso de la conjuntiva es el tumor maligno más frecuente de la superficie ocular. Constituye una enfermedad rara con una incidencia de 0,13 a 1,9 por 100 000 habitantes que afecta principalmente a individuos entre los 50 y los 75 años. Suele tener un curso lento y poco agresivo. El tratamiento depende de la extensión tumoral. En presencia de compromiso intraocular la enucleación está indicada y en presencia de compromiso extraocular la exanteración orbitaria es el tratamiento estándar. Reportamos el caso de un paciente de 82 años con carcinoma escamoso conjuntival con compromiso intra y extraocular, se discute el caso y se revisa la literatura.

Central nervous system metastasis secondary to colorectal cancer: a retrospective cohort study of 20 cases.

INTRODUCTION: Involvement of the central nervous system (CNS) secondary to colorectal cancer is infrequent and associated with a poor prognosis. Its treatment is extrapolated from metastases of other origins as the information available on this scenario is limited. The goal of this study is to assess the clinical characteristics of a series of patients and determine the results in terms of progression-free survival (PFS) and global survival. METHOD: The records of patients with CNS metastasis of colorectal origin who were treated in this facility between the years 2001 and 2016 were reviewed retrospectively. RESULTS: 20 patients with CNS lesions of this origin were identified. Of these, 45% were male and 55% were female (average age 65.5 years). The histology corresponded to tubular adenocarcinoma in 95% of cases. Around 85% of the patients showed a neurological deficit, and their recursive partitioning analysis (RPA) classifications were 1 in 20%, 2 in 55%, and 3 in 25% of the cases studied. The treatments provided were: holocerebral radiotherapy (45%), stereotactic radiosurgery (25%), surgery followed by holocerebral radiotherapy (25%), and exclusively palliative care (5%). The PFS was 2.6 months from treatment of the CNS lesion, while the median survival was 3.8 months. The survival times for patients receiving different treatments were as follows: surgery plus holocerebral radiotherapy 16.2 months, stereotactic radiotherapy 12 months, and holocerebral radiotherapy 2.4 months (p = 0.003). CONCLUSION: The prognosis for patients with metastasis of colorectal origin is poor. The patients treated with surgery or stereotactic radiotherapy can have a greater survival.