Combination treatment of HCC with SBRT and immune checkpoint inhibition.

The treatment of unresectable or metastatic HCC has been significantly advanced in recent years by developments in both radiotherapy and systemic cancer therapies. Independently, both Stereotactic Ablative Body Radiotherapy (SBRT) and Immune Checkpoint Inhibitors (ICIs) are licensed for the treatment of these tumours. Building on the successes seen in other solid tumours, there is significant interest in exploring combination treatments. In this review article we briefly present the evidence base for the use of these treatments in patients with HCC. With reference to our current understanding of the immuno-oncology and radiobiology of HCCs, we demonstrate why combining these two modalities is of interest. Finally, we discuss the clinical trials that are currently underway or planned and the direction that future research may take.

Conformal 3D computed tomography planned endoluminal brachytherapy for the local control of esophageal cancer.

PURPOSE: To outline the toxicity, tolerability, and efficacy of a 3D conformal computed tomography planned endoluminal brachytherapy (ELBT) treatment for esophageal adenocarcinoma (OAC) or squamous cell carcinoma (OSCC). METHODS AND MATERIALS: A retrospective single-center analysis of toxicity, tolerability, and outcomes for 65 consecutive patients with OAC/OSCC who received 6-8Gy in one fraction or 12-16Gy in two fractions of high-dose-rate ELBT as salvage postchemoradiotherapy (n = 7 and n = 14 respectively), or as a boost to external beam radiotherapy (n = 14 and n = 30, respectively). RESULTS: Median overall survival from the first brachytherapy application was 7.4 (IQR 5.0-14.7) months for the boost cohort and 9.2 (IQR 5.8-20.1) months for the salvage cohort. In a univariate analysis, use of a higher, fractionated dose of radiotherapy was associated with longer overall survival. At least one-third (33%; n = 7) of the salvage cohort and 28% (n = 12) of the boost cohort exhibited a local recurrence prior to death. Overall, 66.7% of the salvage and 56.8% of the boost cohort experienced odynophagia. Swallow function stabilized or improved early after treatment, with only 11.6% of the boost and 14.3% of the salvage cohort demonstrating a long-term decline in dysphagia score. CONCLUSIONS: 3D conformal planned ELBT is safe and tolerable. Most patients exhibit an early and sustained stabilization or improvement in their swallow function and greater survival is seen with higher brachytherapy doses. Further research is required to determine the place of brachytherapy in the management of esophageal cancer, particularly when planned using contemporary conformal approaches.

British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma.

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.

Can Concurrent Chemoradiotherapy Add Meaningful Benefit in Addition to Induction Chemotherapy in the Management of Borderline Resectable and Locally Advanced Pancreatic Cancer?: A Systematic Review.

OBJECTIVES: The role of concomitant chemoradiotherapy or radiotherapy (RT) after induction chemotherapy (IC) in borderline resectable and locally advanced pancreatic ductal adenocarcinoma is debatable. This systematic review aimed to explore this. METHODS: We searched PubMed, MEDLINE, EMBASE, and Cochrane database. Studies were selected reporting outcomes on resection rate, R0 resection, pathological response, radiological response, progression-free survival, overall survival, local control, morbidity, and mortality. RESULTS: The search resulted in 6635 articles. After 2 rounds of screening, 34 publications were selected. We found 3 randomized controlled studies and 1 prospective cohort study, and the rest were retrospective studies. There is consistent evidence that addition of concomitant chemoradiotherapy or RT after IC improves pathological response and local control. There are conflicting results in terms of other outcomes. CONCLUSIONS: Concomitant chemoradiotherapy or RT after IC improves local control and pathological response in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. The role of modern RT in improving other outcome requires further research.

Neoadjuvant Management of Adenocarcinoma of the Esophagus and Esophagogastric Junction: Review of Randomized Evidence and Definition of Optimum Treatment Algorithm.

BACKGROUND: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) are accepted standards of care for the management of adenocarcinoma of the esophagus and gastroesophageal junction. SUMMARY: The MRC-OEO2 study established the role of 2 cycles of neoadjuvant cisplatin/fluoropyrimidine. More recently, the FLOT-AIO4 study demonstrated the superiority of perioperative FLOT chemotherapy (5FU, oxaliplatin, and docetaxel) compared to ECX (epirubicin, cisplatin, and capecitabine) regime. The results from the pivotal CROSS study established neoadjuvant CRT as a new standard of care in OG cancer. The survival benefits observed in FLOT and CROSS studies are similar [FLOT - hazard ratio 0.75 (0.62-0.92); CROSS - 0.741 (0.55-0.98)]. KEY MESSAGES: Both nCT and nCRT have been shown to be associated with survival benefit compared to surgery alone. We have performed a comprehensive review of the available evidence to define the optimum treatment algorithm and identify specific patient sub-groups who may be appropriate for the use of one or more of these neoadjuvant options.

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.

Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: the UK consensus position.

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.

The Potential Role of Radiotherapy in the Management of Hepatoid Carcinomas of the Stomach: A Case Report.

INTRODUCTION: Hepatoid adenocarcinoma (AC) of the stomach (HAS) represents a rare variant of conventional gastric AC characterised by poor prognosis. They are usually managed with surgery (localised disease) and chemotherapy. CASE REPORT: We present the first case report of a patient with HAS who presented with weight loss, poor appetite, general clinical deterioration (performance status [PS] = 3), and active gastrointestinal bleeding who was treated with fractionated palliative radiotherapy (RT) using 30 Gy in 10 fractions. The use of RT was associated with excellent symptomatic and radiological response and facilitated surgery secondary to significant improvement in general fitness and PS. CONCLUSION: RT may have a role in the multimodality management of hepatoid AC of the stomach.

Respiratory-gated (4D) contrast-enhanced FDG PET-CT for radiotherapy planning of lower oesophageal carcinoma: feasibility and impact on planning target volume.

BACKGROUND: To assess the feasibility and potential impact on target delineation of respiratory-gated (4D) contrast-enhanced 18Fluorine fluorodeoxyglucose (FDG) positron emission tomography - computed tomography (PET-CT), in the treatment planning position, for a prospective cohort of patients with lower third oesophageal cancer. METHODS: Fifteen patients were recruited into the study. Imaging included 4D PET-CT, 3D PET-CT, endoscopic ultrasound and planning 4D CT. Target volume delineation was performed on 4D CT, 4D CT with co-registered 3D PET and 4D PET-CT. Planning target volumes (PTV) generated with 4D CT (PTV4DCT), 4D CT co-registered with 3D PET-CT (PTV3DPET4DCT) and 4D PET-CT (PTV4DPETCT) were compared with multiple positional metrics. RESULTS: Mean PTV4DCT, PTV3DPET4DCT and PTV4DPETCT were 582.4 ± 275.1 cm3, 472.5 ± 193.1 cm3 and 480.6 ± 236.9 cm3 respectively (no significant difference). Median DICE similarity coefficients comparing PTV4DCT with PTV3DPET4DCT, PTV4DCT with PTV4DPETCT and PTV3DPET4DCT with PTV4DPETCT were 0.85 (range 0.65-0.9), 0.85 (range 0.69-0.9) and 0.88 (range 0.79-0.9) respectively. The median sensitivity index for overlap comparing PTV4DCT with PTV3DPET4DCT, PTV4DCT with PTV4DPETCT and PTV3DPET4DCT with PTV4DPETCT were 0.78 (range 0.65-0.9), 0.79 (range 0.65-0.9) and 0.89 (range 0.68-0.94) respectively. CONCLUSIONS: Planning 4D PET-CT is feasible with careful patient selection. PTV generated using 4D CT, 3D PET-CT and 4D PET-CT were of similar volume, however, overlap analysis demonstrated that approximately 20% of PTV3DPETCT and PTV4DPETCT are not included in PTV4DCT, leading to under-coverage of target volume and a potential geometric miss. Additionally, differences between PTV3DPET4DCT and PTV4DPETCT suggest a potential benefit for 4D PET-CT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier - NCT02285660 (Registered 21/10/2014).

Phase I trial of radiation therapy and sorafenib in unresectable liver metastases.

BACKGROUND AND PURPOSE: To determine maximum tolerated dose (MTD) and toxicities of sorafenib combined with stereotactic radiotherapy (SBRT) or whole liver radiotherapy (WLRT) in patients with liver metastases. MATERIAL AND METHODS: Eligible patients had unresectable liver metastases. Sorafenib dose was escalated in 2 strata: I - SBRT: effective liver volume irradiated (Veff)<80% (30-60Gy in 6 fractions); II - WLRT: Veff>80% (21.6Gy in 6 fractions). Four weeks of sorafenib, with radiotherapy during weeks 2-3, was delivered at 3 escalating dose levels (200-400mg twice daily). Dose limiting toxicity was defined as any grade 3+ liver toxicity, or grade 4+ treatment-related toxicity. RESULTS: Thirty-three patients were treated: 18 in stratum I (median dose 42Gy), 15 in stratum II. The MTD was not reached. Grade 3+ toxicity was seen in 33% of patients, at a median of 10days. Two deaths from non-classic liver toxicity occurred post WLRT in stratum II. The median overall survival was 22.3 and 5.7months for strata I and II respectively. CONCLUSIONS: Sorafenib and 21.6Gy in 6 fraction WLRT resulted in unacceptably high rates of liver toxicity. Although sorafenib combined with SBRT was tolerable, the observed efficacy does not merit further clinical evaluation.

Phase 1/2 Study of the Addition of Cisplatin to Adjuvant Chemotherapy With Image Guided High-Precision Radiation Therapy for Completely Resected Gastric Cancer.

PURPOSE: Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. METHODS AND MATERIALS: Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m2/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m2) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. RESULTS: Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m2 cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. CONCLUSION: Cisplatin can be safely delivered with 5-FU-based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.

Metastatic melanoma: a regional review and future directions.

AIMS AND BACKGROUND: . The incidence of malignant melanoma has risen steadily over recent decades. NCI data from 2005-2007 have suggested that 1.93% of individuals born today in the US will develop melanoma at some stage. Approximately 15% of patients with MM either present with metastatic disease or develop metastases during the course of their illness. Unfortunately, metastatic MM remains a challenge with limited treatment options, and median overall survival is 6-9 months. METHODS: We reviewed our data for the treatment of metastatic MM over a period of four years. Data from all patients with metastatic MM treated with systemic therapy without clinical trials from 2006 to 2009 were reviewed. Response rate was determined as per RECIST criteria. RESULTS: Sixty four patients were treated with one or more lines of cytotoxic therapy. Median age was 62 years (range, 23-82) with 53% males. Primary site of the disease was the skin in 75%, mucosal in 12.5%, ocular in 9.4% and nodal with an occult primary in 3.1%. Visceral metastases were present in 75% of patients at the start of treatment, including pulmonary (39.6%) and hepatic (34.4%). All patients were screened for brain metastases, which were present in 26.5% of patients. ECOG performance status was 0 in 7.8%, 1 in 68.7%, 2 in 9.4% and undocumented in the remaining 14%. Patients without brain metastases received single agent DTIC as first line; those with brain metastases received temozolomide. Response rate was 7% for DTIC and 28% for temozolomide, with median progression-free survival of 2.4 and 3.2 months, respectively. Seven patients who received DTIC are alive on follow-up, 2 have ongoing stable disease post-DTIC at 41 months and 18 months. Second line therapy with vinblastine was given to 21 patients (32%), with a response rate of 9.5% and median progression-free survival of 3.4 months. Median overall survival from initiation of therapy was 7.7 months for DTIC and 3.6 months for patients with brain metastases receiving temozolomide. A performance status of 2 was associated with shorter median overall survival (2.0 months). CONCLUSIONS: . Our results are comparable to published data. Malignant melanoma is a disease with rising incidence and limited treatment options. These patients are best treated in the context of clinical trials as new targeted therapies are promising as future strategies.

Occult lung malignancy presenting with finger pain: a case report.

INTRODUCTION: Lung cancer is currently one of the most common malignancies in the world. Early detection is an important prognostic factor. Unfortunately, initial symptoms may be vague and a substantial proportion of cases present with the effects of metastases. CASE PRESENTATION: We discuss a case of occult lung malignancy in a 61-year-old man. The only symptom at presentation was pain in the right ring finger due to metastasis from the lung primary. CONCLUSION: This case highlights the need for vigilance when a patient presents with unusual or unexplained symptoms, especially if they have known risk factors for cancer.