Real world outcomes of neoadjuvant chemotherapy and radiotherapy for borderline resectable pancreatic cancer: a multicentre observational study.

BACKGROUND: Neoadjuvant therapy may increase the likelihood of complete (R0) resection for borderline resectable pancreatic cancer. The optimal approach is unknown and differs amongst treatment centres. METHODS: We identified patients with biopsy-proven borderline resectable pancreatic adenocarcinoma who commenced neoadjuvant therapy between January 2012 and June 2019 at three centres in Sydney, Australia. Patterns of care and outcomes of varying approaches were examined. RESULTS: Forty-eight patients were identified. Median age was 66 years (range: 41-84). Staging included endoscopic ultrasound in 98%, PET-CT scan in 77%, laparoscopy in 46%. Neoadjuvant regimens used were a combination of chemotherapy and chemo-radiation (58%), chemotherapy alone (13%) and chemoradiation alone (29%). Radiologic complete or partial response occurred in 33% and progression in 25%. Complete macroscopic surgical resection was achieved in 50%, and R0 resection in 38%. At median follow-up of 15 months, the 1-year and 2-year overall survival was 75% and 63% respectively, and the 1-year and 2-year progression-free survival was 50% and 29% respectively. Significant predictors of macroscopic resectability were radiologic response (p = 0.005) but not addition of radiotherapy to chemotherapy (OR 0.87, p = 0.81). Predictors of overall survival included baseline Ca19.9 level (p = 0.04) and a trend to the use of systemic chemotherapy (HR 0.51, p = 0.07), but not use of radiotherapy (HR 0.70, p = 0.47). CONCLUSION: There is high variability in staging and neoadjuvant approaches for borderline resectable pancreas cancer. Despite aggressive neoadjuvant therapies, R0 resection and prolonged survival are uncommon. The incremental benefit of neoadjuvant radiotherapy after neoadjuvant chemotherapy was not demonstrated in this observational study.

Impact of audiovisual biofeedback on interfraction respiratory motion reproducibility in liver cancer stereotactic body radiotherapy.

INTRODUCTION: Irregular breathing motion exacerbates uncertainties throughout a course of radiation therapy. Breathing guidance has demonstrated to improve breathing motion consistency. This was the first clinical implementation of audiovisual biofeedback (AVB) breathing guidance over a course of liver stereotactic body radiotherapy (SBRT) investigating interfraction reproducibility. METHODS: Five liver cancer patients underwent a screening procedure prior to CT sim during which patients underwent breathing conditions (i) AVB, or (ii) free breathing (FB). Whichever breathing condition was more regular was utilised for the patient's subsequent course of SBRT. Respiratory motion was obtained from the Varian respiratory position monitoring (RPM) system (Varian Medical Systems). Breathing motion reproducibility was assessed by the variance of displacement across 10 phase-based respiratory bins over each patient's course of SBRT. RESULTS: The screening procedure yielded the decision to utilise AVB for three patients and FB for two patients. Over the course of SBRT, AVB significantly improved the relative interfraction motion by 32%, from 22% displacement difference for FB patients to 15% difference for AVB patients. Further to this, AVB facilitated sub-millimetre interfraction reproducibility for two AVB patients. CONCLUSION: There was significantly less interfraction motion with AVB than FB. These findings demonstrate that AVB is potentially a valuable tool in ensuring reproducible interfraction motion.

Intravenous contrast-enhanced cone beam computed tomography (IVCBCT) of intrahepatic tumors and vessels.

PURPOSE: Liver tumors are challenging to visualize on cone beam computed tomography (CBCT) without intravenous (IV) contrast. Image guidance for liver cancer stereotactic body ablative radiation therapy (SABR) could be improved with the direct visualization of hepatic tumors and vasculature. This study investigated the feasibility of the use of IV contrast-enhanced CBCT (IV-CBCT) as a means to improve liver target visualization. METHODS AND MATERIALS: Patients on a liver SABR protocol underwent IV-CBCT before 1 or more treatment fractions in addition to a noncontrast CBCT. Image acquisition was initiated 0 to 30 seconds following injection and acquired over 60 to 120 seconds. "Stop and go" exhale breath-hold CBCT scans were used whenever feasible. Changes in mean CT number in regions of interest within visible vasculature, tumor, and adjacent liver were quantified between CBCT and IV-CBCT. RESULTS: Twelve pairs of contrast and noncontrast CBCTs were obtained in 7 patients. Intravenous-CBCT improved hepatic tumor visibility in breath-hold scans only for 3 patients (2 metastases, 1 hepatocellular carcinoma). Visible tumors ranged in volume from 124 to 564 mL. Small tumors in free-breathing patients did not show enhancement on IVCBT. CONCLUSIONS: Intravenous-CBCT may enhance the visibility of hepatic vessels and tumor in CBCT scans obtained during breath hold. Optimization of IV contrast timing and reduction of artifacts to improve tumor visualization warrant further investigation.

First clinical implementation of audiovisual biofeedback in liver cancer stereotactic body radiation therapy.

This case report details a clinical trial's first recruited liver cancer patient who underwent a course of stereotactic body radiation therapy treatment utilising audiovisual biofeedback breathing guidance. Breathing motion results for both abdominal wall motion and tumour motion are included. Patient 1 demonstrated improved breathing motion regularity with audiovisual biofeedback. A training effect was also observed.

Audiovisual biofeedback breathing guidance for lung cancer patients receiving radiotherapy: a multi-institutional phase II randomised clinical trial.

BACKGROUND: There is a clear link between irregular breathing and errors in medical imaging and radiation treatment. The audiovisual biofeedback system is an advanced form of respiratory guidance that has previously demonstrated to facilitate regular patient breathing. The clinical benefits of audiovisual biofeedback will be investigated in an upcoming multi-institutional, randomised, and stratified clinical trial recruiting a total of 75 lung cancer patients undergoing radiation therapy. METHODS/DESIGN: To comprehensively perform a clinical evaluation of the audiovisual biofeedback system, a multi-institutional study will be performed. Our methodological framework will be based on the widely used Technology Acceptance Model, which gives qualitative scales for two specific variables, perceived usefulness and perceived ease of use, which are fundamental determinants for user acceptance. A total of 75 lung cancer patients will be recruited across seven radiation oncology departments across Australia. Patients will be randomised in a 2:1 ratio, with 2/3 of the patients being recruited into the intervention arm and 1/3 in the control arm. 2:1 randomisation is appropriate as within the interventional arm there is a screening procedure where only patients whose breathing is more regular with audiovisual biofeedback will continue to use this system for their imaging and treatment procedures. Patients within the intervention arm whose free breathing is more regular than audiovisual biofeedback in the screen procedure will remain in the intervention arm of the study but their imaging and treatment procedures will be performed without audiovisual biofeedback. Patients will also be stratified by treating institution and for treatment intent (palliative vs. radical) to ensure similar balance in the arms across the sites. Patients and hospital staff operating the audiovisual biofeedback system will complete questionnaires to assess their experience with audiovisual biofeedback. The objectives of this clinical trial is to assess the impact of audiovisual biofeedback on breathing motion, the patient experience and clinical confidence in the system, clinical workflow, treatment margins, and toxicity outcomes. DISCUSSION: This clinical trial marks an important milestone in breathing guidance studies as it will be the first randomised, controlled trial providing the most comprehensive evaluation of the clinical impact of breathing guidance on cancer radiation therapy to date. This study is powered to determine the impact of AV biofeedback on breathing regularity and medical image quality. Objectives such as determining the indications and contra-indications for the use of AV biofeedback, evaluation of patient experience, radiation toxicity occurrence and severity, and clinician confidence will shed light on the design of future phase III clinical trials. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), its trial ID is ACTRN12613001177741 .

A randomized controlled trial of lorazepam to reduce liver motion in patients receiving upper abdominal radiation therapy.

PURPOSE: Reduction of respiratory motion is desirable to reduce the volume of normal tissues irradiated, to improve concordance of planned and delivered doses, and to improve image guided radiation therapy (IGRT). We hypothesized that pretreatment lorazepam would lead to a measurable reduction of liver motion. METHODS AND MATERIALS: Thirty-three patients receiving upper abdominal IGRT were recruited to a double-blinded randomized controlled crossover trial. Patients were randomized to 1 of 2 study arms: arm 1 received lorazepam 2 mg by mouth on day 1, followed by placebo 4 to 8 days later; arm 2 received placebo on day 1, followed by lorazepam 4 to 8 days later. After tablet ingestion and daily radiation therapy, amplitude of liver motion was measured on both study days. The primary outcomes were reduction in craniocaudal (CC) liver motion using 4-dimensional kV cone beam computed tomography (CBCT) and the proportion of patients with liver motion ≤5 mm. Secondary endpoints included motion measured with cine magnetic resonance imaging and kV fluoroscopy. RESULTS: Mean relative and absolute reduction in CC amplitude with lorazepam was 21% and 2.5 mm respectively (95% confidence interval [CI] 1.1-3.9, P=.001), as assessed with CBCT. Reduction in CC amplitude to ≤5 mm residual liver motion was seen in 13% (95% CI 1%-25%) of patients receiving lorazepam (vs 10% receiving placebo, P=NS); 65% (95% CI 48%-81%) had reduction in residual CC liver motion to ≤10 mm (vs 52% with placebo, P=NS). Patients with large respiratory movement and patients who took lorazepam ≥60 minutes before imaging had greater reductions in liver CC motion. Mean reductions in liver CC amplitude on magnetic resonance imaging and fluoroscopy were nonsignificant. CONCLUSIONS: Lorazepam reduces liver motion in the CC direction; however, average magnitude of reduction is small, and most patients have residual motion >5 mm.

Are visiting oncologists enough? A qualitative study of the needs of Australian rural and regional cancer patients, carers and health professionals.

AIM: Survival rates for patients with cancer who live in rural and regional areas are worse than in metropolitan areas. This may be due to geographical isolation, delayed diagnosis, inadequate transport, lower socioeconomic status and workforce shortages. We conducted a qualitative study of rural patients, carers and health professionals. It aimed to identify concerns about, and strategies to optimize cancer care from those with direct experience. METHODS: Focus groups and structured interviews were conducted in New South Wales, Australia at four rural and regional hospitals (Bega, Dubbo, Tamworth and Albury) and three metropolitan locations (in Sydney and the Jean Colvin Hostel) caring for rural patients. Sessions were audiotaped, transcribed and analyzed using thematic analysis. RESULTS: In total, 36 patients, 14 carers and 32 health professionals were interviewed in seven focus groups and 42 individual interviews. Concerns related to access to oncologists and other health professionals, and for services for investigation and treatment, the financial and social consequences of travel, unmet carer support needs and the hardships for health professionals. Strategies for improvement included comprehensive staffing and services coordinated in a hub and spoke model from adjacent larger centers, adequate reimbursement for travel and better carer support. CONCLUSION: We identified broad concerns about regional and rural cancer care in Australia. The Australian Federal Government commitment of $560 million to establish regional cancer centers is welcome; however, improvements must extend beyond infrastructure funding in large regional centers to comprehensive staffing in centers currently lacking resident oncologists, travel support and assistance for carers.

Phase I study of individualized stereotactic body radiotherapy of liver metastases.

PURPOSE: To report on the outcomes of a phase I study of stereotactic body radiotherapy (SBRT) for treatment of liver metastases. PATIENTS AND METHODS: Patients with liver metastases that were inoperable or medically unsuitable for resection, and who were not candidates for standard therapies, were eligible for this phase I study of individualized SBRT. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%). Additional patients were treated at the maximal study dose (MSD) in an expanded cohort. Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks. RESULTS: Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated. Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL). The highest RILD risk level investigated was safe, with no dose-limiting toxicity. Two grade 3 liver enzyme changes occurred, but no RILD or other grade 3 to 5 liver toxicity was seen, for a low estimated risk of serious liver toxicity (95% CI, 0 to 5.3%). Six (9%) acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) grade 4 toxicity (thrombocytopenia) were seen. The 1-year local control rate was 71% (95 CI, 58% to 85%). The median overall survival was 17.6 months (95% CI, 10.4 to 38.1 months). CONCLUSION: Individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.

Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

PURPOSE: To report outcomes of a phase I study of individualized stereotactic body radiotherapy treatment (SBRT) for unresectable hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHC). PATIENTS AND METHODS: Patients with unresectable HCC or IHC, and who are not suitable for standard therapies, were eligible for six-fraction SBRT during 2 weeks. Radiation dose was dependent on the volume of liver irradiated and the estimated risk of liver toxicity based on a normal tissue complication model. Toxicity risk was escalated from 5% to 10% and 20%, within three liver volume-irradiated strata, provided at least three patients were without toxicity at 3 months after SBRT. RESULTS: Forty-one patients with unresectable Child-Pugh A HCC (n = 31) or IHC (n = 10) completed six-fraction SBRT. Five patients (12%) had grade 3 liver enzymes at baseline. The median tumor size was 173 mL (9 to 1,913 mL). The median dose was 36.0 Gy (24.0 to 54.0 Gy). No radiation-induced liver disease or treatment-related grade 4/5 toxicity was seen within 3 months after SBRT. Grade 3 liver enzymes were seen in five patients (12%). Two patients (5%) with IHC developed transient biliary obstruction after the first few fractions. Seven patients (five HCC, two IHC) had decline in liver function from Child-Pugh class A to B within 3 months after SBRT. Median survival of HCC and IHC patients was 11.7 months (95% CI, 9.2 to 21.6 months) and 15.0 months (95% CI, 6.5 to 29.0 months), respectively. CONCLUSION: Individualized six-fraction SBRT is a safe treatment for unresectable HCC and IHC.

Neoadjuvant treatment for pancreatic cancer--a review.

Pancreatic cancer is associated with a poor prognosis. While surgical resection is the only treatment that holds the potential of cure, a minority of patients are surgical candidates. Despite surgery, the overall survival rates remain low. Neoadjuvant treatment has been investigated both in the setting of resectable disease at diagnosis, or in an attempt to downstage locally advanced disease for resection. Single institution studies of neoadjuvant chemoradiation have demonstrated favourable outcomes, compared to similar series of patients treated with surgery with or without adjuvant therapy. For unresectable disease, partial or complete responses have been observed which have allowed some patients to subsequently undergo resection. The reports of neoadjuvant therapy for pancreatic cancer are heterogeneous with regards to patient population, treatment methods and modalities, making comparisons of different regimens inherently flawed. To date, no randomized controlled trials of neoadjuvant therapy have been conducted, however given the positive outcomes of single institutional series of neoadjuvant therapy this approach is worthy of further study.