Pressurised intraperitoneal aerosolised chemotherapy (PIPAC) for gastric cancer with peritoneal metastases: A systematic review by the PIPAC UK collaborative.

INTRODUCTION: Gastric cancer with peritoneal metastases (GCPM) carries a poor prognosis. Pressurised Intraperitoneal Aerosolised Chemotherapy (PIPAC) offers pharmacokinetic advantages over intravenous therapy, resulting in higher chemotherapy concentrations in peritoneal deposits, and potentially reduced systemic absorption/toxicity. This review evaluates efficacy, tolerability and impact on quality of life (QOL) of PIPAC for GCPM. METHODS: Following registration with PROSPERO (CRD42021281500), MEDLINE, EMBASE and The Cochrane Library were searched for PIPAC in patients with peritoneal metastases, in accordance with PRISMA standards RESULTS: Across 18 included reports representing 751 patients with GCPM (4 prospective, 11 retrospective, 3 abstracts, no phase III studies), median overall survival (mOS) was 8 - 19.1 months, 1-year OS 49.8-77.9%, complete response (PRGS1) 0-35% and partial response (PRGS2/3) 0-83.3%. Grade 3 and 4 toxicity was 0.7-25% and 0-4.1% respectively. Three studies assessing QOL reported no significant difference. CONCLUSION: PIPAC may offer promising survival benefits, toxicity, and QOL for GCPM.

SCOPE 2 - Still Answering the Unanswered Questions in Oesophageal Radiotherapy? SCOPE 2: a Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients with Oesophageal Cancer Treated with Definitive Chemoradiation with an Embedded Phase II Trial for Patients with a Poor Early Response using Positron Emission Tomography/Computed Tomography.

The SCOPE 2 trial of definitive chemoradiotherapy in oesophageal cancer investigates the benefits of radiotherapy dose escalation and systemic therapy optimisation. The trial opened in 2016. The landscape of oesophageal cancer treatment over the lifetime of this trial has changed significantly and the protocol has evolved to reflect this. However, with the recent results of the Dutch phase III ART DECO study showing no improvement in local control or overall survival with radiotherapy dose escalation in a similar patient group, we sought to determine if the SCOPE 2 trial is still answering the key unanswered questions for oesophageal radiotherapy. Here we discuss the rationale behind the SCOPE 2 trial, outline the trial schema and review current data on dose escalation and outline recommendations for future areas of research.

The Promise of Proton Beam Therapy for Oesophageal Cancer: A Systematic Review of Dosimetric and Clinical Outcomes.

AIMS: Due to its physical advantages over photon radiotherapy, proton beam therapy (PBT) has the potential to improve outcomes from oesophageal cancer. However, for many tumour sites, high-quality evidence supporting PBT use is limited. We carried out a systematic review of published literature of PBT in oesophageal cancer to ascertain potential benefits of this technology and to gauge the current state-of-the-art. We considered if further evaluation of this technology in oesophageal cancer is desirable. MATERIALS AND METHODS: A systematic literature search of Medline, Embase, Cochrane Library and Web of Science using structured search terms was carried out. Inclusion criteria included non-metastatic cancer, full articles and English language studies only. Articles deliberating technical aspects of PBT planning or delivery were excluded to maintain a clinical focus. Studies were divided into two sections: dosimetric and clinical studies; qualitatively synthesised. RESULTS: In total, 467 records were screened, with 32 included for final qualitative synthesis. This included two prospective studies with the rest based on retrospective data. There was heterogeneity in treatment protocols, including treatment intent (neoadjuvant or definitive), dose, fractionation and chemotherapy used. Compared with photon radiotherapy, PBT seemed to reduce dose to organs at risk, especially lung and heart, although not for all reported parameters. Toxicity outcomes, including postoperative complications, were reduced compared with photon radiotherapy. Survival outcomes were reported to be at least comparable with photon radiotherapy. CONCLUSION: There is a paucity of high-quality evidence supporting PBT use in oesophageal cancer. Wide variation in intent and treatment protocols means that the role and 'gold-standard' treatment protocol are yet to be defined. Current literature suggests significant benefit in terms of toxicity reduction, especially in the postoperative period, with comparable survival outcomes. PBT in oesophageal cancer holds significant promise for improving patient outcomes but requires robust systematic evaluation in prospective studies.

Comparative Dosimetric Analysis and Normal Tissue Complication Probability Modelling of Four-Dimensional Computed Tomography Planning Scans Within the UK NeoSCOPE Trial.

AIMS: NeoSCOPE is a trial of two different neoadjuvant chemoradiotherapy regimens for resectable oesophageal cancer and was the first multicentre trial in the UK to incorporate four-dimensional computed tomography (4D-CT) into radiotherapy planning. Despite 4D-CT being increasingly accepted as a standard of care for lower third and junctional oesophageal tumours, there is limited evidence of its benefit over standard three-dimensional computed tomography (3D-CT). MATERIALS: Using NeoSCOPE 4D-CT cases, we undertook a dosimetric comparison study of 3D-CT versus 4D-CT plans comparing target volume coverage and dose to organs at risk. We used established normal tissue complication probability models to evaluate the potential toxicity reduction of using 4D-CT plans in oesophageal cancer. RESULTS: 4D-CT resulted in a smaller median absolute PTV volume and lower dose levels for all reported constraints with comparable target volume coverage. NTCP modelling suggests a significant relative risk reduction of cardiac and pulmonary toxicity endpoints with 4D-CT. CONCLUSION: Our work shows that incorporating 4D-CT into treatment planning may significantly reduce the toxicity burden from this treatment.

Driving developments in UK oesophageal radiotherapy through the SCOPE trials.

BACKGROUND: The SCOPE trials (SCOPE 1, NeoSCOPE and SCOPE 2) have been the backbone of oesophageal RT trials in the UK. Many changes in oesophageal RT techniques have taken place in this time. The SCOPE trials have, in addition to adopting these new techniques, been influential in aiding centres with their implementation. We discuss the progress made through the SCOPE trials and include details of a questionnaire sent to participating centres. to establish the role that trial participation played in RT changes in their centre. METHODS: Questionnaires were sent to 47 centres, 27 were returned. RESULTS: 100% of centres stated their departmental protocol for TVD was based on the relevant SCOPE trial protocol. 4DCT use has increased from 42 to 71%. Type B planning algorithms, mandated in the NeoSCOPE trial, were used in 79.9% pre NeoSCOPE and now in 83.3%. 12.5% of centres were using a stomach filling protocol pre NeoSCOPE, now risen to 50%. CBCT was mandated for IGRT in the NeoSCOPE trial. 66.7% used this routinely pre NeoSCOPE/SCOPE 2 which has risen to 87.5% in the survey. CONCLUSION: The results of the questionnaires show how participation in national oesophageal RT trials has led to the adoption of newer RT techniques in UK centres, leading to better patient care.

Nab-paclitaxel in combination with gemcitabine for the treatment of metastatic pancreas cancer: the South Wales experience.

The prognosis of pancreatic cancer remains very poor, with a 5-year survival rate of around 3%. There has been little impact from various chemotherapy regimens on improving outcome for several decades. Gemcitabine has been the mainstay chemotherapy for around two decades with little improvement in overall survival (OS) for patients with advanced disease. However, more recently, there has been a paradigm shift in treatment options for these patients. Reported in 2011, combination therapy with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) showed a long awaited but modest improvement in survival, but is reserved only for a small proportion of very fit patients due to concerns over its toxicities. In 2013, the landmark phase III international study MPACT demonstrated an improvement in OS with the combination of nab-paclitaxel and gemcitabine (GEMBRAX) for the treatment of patients more akin to the real-world population. In the United Kingdom (UK), it was first made widely available on the National Health Service (NHS) in Wales in September 2014 and only recently received a final positive appraisal by NICE (National Institute of Clinical Excellence) for England in 2017. In this paper, we present our data on the use of this treatment for patients in South Wales and compare real-life practical experience with the MPACT data and reflecting the impact of this paradigm shift.

Role of chemoradiotherapy in oesophageal cancer -- adjuvant and neoadjuvant therapy.

Despite low postoperative mortality rates, the long-term outcomes from surgical-based treatment for oesophageal cancer remain poor. Chemoradiotherapy (CRT), either given before surgical resection as neoadjuvant therapy or after resection as adjuvant therapy, has been postulated to improve these outcomes. This systematic review examines the evidence for these approaches. The evidence for postoperative radiotherapy is limited and conclusions are difficult, but it may have a role in patients at high risk of local relapse (positive margins). The addition of chemotherapy is recommended when possible. Patient selection is important due to the associated toxicities. The evidence for neoadjuvant treatment is stronger and based on the current evidence neoadjuvant CRT can be recommended as a treatment approach in T2-T4, N1-3 oesophageal cancer for both adenocarcinoma and squamous cell carcinoma, but further work is needed to establish its superiority over neoadjuvant chemotherapy alone, particularly for adenocarcinoma. We recommend that further studies divide the two histologies and they should be treated as two separate diseases.

Oesophageal Chemoradiotherapy in the UK--current practice and future directions.

The SCOPE 1 trial closed to recruitment in early 2012 and has demonstrably improved the quality of UK radiotherapy. It has also shown that there is an enthusiastic upper gastrointestinal clinical oncology community that can successfully complete trials and deliver high-quality radiotherapy. Following on from SCOPE 1, this paper, authored by a consensus of leading UK upper gastrointestinal radiotherapy specialists, attempts to define current best practice and the questions to be answered by future clinical studies. The two main roles for chemoradiotherapy (CRT) in the management of potentially curable oesophageal cancer are definitive (dCRT) and neoadjuvant (naCRT). The rates of local failure after dCRT are consistently high, showing the need to evaluate more effective treatments, both in terms of optimal local and systemic therapeutic components. This will be the primary objective of the next planned UK dCRT trial and here we discuss the role of dose escalation and systemic therapeutic options that will form the basis of that trial. The publication of the Dutch 'CROSS' trial of naCRT has shown that this pre-operative approach can both be given safely and offer a significant survival benefit over surgery alone. This has led to the development of the UK NeoSCOPE trial, due to open in 2013. There will be a translational substudy to this trial and currently available data on the role of biomarkers in predicting response to therapy are discussed. Postoperative reporting of the pathology specimen is discussed, with recommendations for the NeoSCOPE trial. Both of these CRT approaches may benefit from recent developments, such as positron emission tomography/computed tomography and four-dimensional computed tomography for target volume delineation, planning techniques such as intensity-modulated radiotherapy and 'type b' algorithms and new treatment verification methods, such as cone-beam computed tomography. These are discussed here and recommendations made for their use.

Improving radiotherapy quality assurance in clinical trials: assessment of target volume delineation of the pre-accrual benchmark case.

As the complexity of radiotherapy (RT) trials increases, issues surrounding target volume delineation will become more important. Some form of outlining assessment prior to trial entry is increasingly being mandated in UK RT trials. This document produced by the Outlining and Imaging Subgroup (OISG) of the National Cancer Research Institute will address methods to reduce interobserver variation in clinical trials and how to conduct an assessment of outlining through a pre-accrual benchmark case. We review currently available methods of describing the variation and identify areas where further work is needed. The OISG would encourage ongoing discussion with chief investigators in order to provide advice on individual aspects of benchmark case assessment for current and future trials.

Prognostic significance of total disease length in esophageal cancer.

BACKGROUND: This study tested the hypothesis that endoluminal ultrasound (EUS) defined total length of disease (including both the primary tumor and the position and number of proximal and distal lymph nodes-ELoD) and the associated EUS lymph node metastasis count (ELNMC) are better predictors of outcome than endoscopic esophageal cancer (OC) length and radiological tumor node metastasis stage in patients who undergo potentially curative treatment with surgery or definitive chemoradiotherapy (dCRT). METHODS: A total of 645 consecutive patients diagnosed with OC and managed by a multidisciplinary team were staged by CT and EUS. The primary outcome measure was survival from date of diagnosis. RESULTS: A total of 323 patients received surgery (208 neoadjuvant chemotherapy), and 322 who were deemed unsuitable for surgery received dCRT. Univariable analysis revealed that survival was related to EUS T (p < 0.0001), N (p < 0.0001), EUS primary tumor length (p = 0.037), ELoD (p = 0.011), ELNMC (p < 0.0001), and treatment type (p = 0.001). Multivariable analysis revealed two factors: ELoD (hazard ratio (HR), 0.961; 95 % confidence interval (CI), 0.925-0.998; p = 0.041) and ELNMC (HR, 1.08; 95 % CI, 1.015-1.15; p = 0.016) were independently associated with survival. CONCLUSIONS: ELoD and ELNMC should become part of routine OC radiological staging to optimize stage-directed therapeutic outcomes.

Image-guided radiotherapy for rectal cancer: a systematic review.

Radiotherapy for rectal cancer is becoming more conformal. Both the rectum and the mesorectum are mobile structures and the use of image-guided radiotherapy techniques may improve treatment delivery. Studies up to 2008 have previously been reviewed; rectal motion was mostly studied in bladder and prostate cancer cases. Large variations were seen in both the rectal volume and rectal wall displacement during the treatment course. We reviewed the literature on primary rectal cancer. A systematic review was conducted using Medline and Embase databases using the keywords 'rectal, radiotherapy, IGRT, image guided, organ motion, internal margin, target shape/volume'. Nine studies looked at both inter- and intrafractional motion of the gross tumour volume, rectum, mesorectum and the clinical target volume using a variety of imaging modalities. There was significant movement in the upper mesorectum. There was a strong relationship between rectal filling and mesorectal motion. Differences according to gender and body mass index have been reported. One study showed adequate dose to the rectum despite rectal motion and deformation. Current margin recipes may not apply to deformable structures. Suggested margins for the clinical target volume to planning target volume expansion are between 1 and 3.5cm. There may be a role for re-imaging and re-planning during a treatment course. From the available data, electronic portal imaging devices should continue to be used to match for bony anatomy. Additional information on internal motion can be obtained by cone beam computer tomography or tomotherapy and if available its use should be considered. Individualised anisotropic margins may be required. Further work is required to assess the optimal imaging modality, whether to match to bone or soft tissue, and to assess if internal motion affects treatment outcome.

Imaging for target volume delineation in rectal cancer radiotherapy--a systematic review.

The global move towards more conformal radiotherapy for rectal cancer requires better imaging modalities that both visualise the disease accurately and are reproducible; to reduce interobserver variation. This review explores the advances in imaging modalities used in target volume delineation, with a view to make recommendations for current clinical practice and to propose future directions for research. A systematic review was conducted using MEDLINE and EMBASE. Articles considered relevant by the authors were included. Planning with orthogonal films is being replaced by computed tomography (CT) simulation. This is now considered the 'gold standard' and allows conformal three-dimensional planning. Magnetic resonance imaging (MRI) has been shown to overcome some of the limitations of CT and can be used either as a diagnostic image to visually aid planning, or as a 'planning' MRI carried out in the treatment position and co-registered with the planning CT. The latter approach has been shown to change the treated volumes compared with CT and in prostate cancer patients has been shown to reduce interobserver variation. There are remaining issues with four-dimensional motion that are yet to be fully appreciated or overcome. 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography/CT co-registered with planning CT results in smaller volumes than CT alone and also reduces interobserver variation, but requires further validation before routine implementation. Experimental work utilising novel positron emission tomography tracers and diffusion-weighted MRI shows promise and requires further evaluation. Rigorous quality assurance is important with processing of newer imaging modalities. Further work needs to be conducted into both interobserver variation and the formal evaluation of the clinical benefits of newer imaging modalities. Developments in image-guided radiotherapy are also required to ensure that improvements in target definition at the planning stage are reproducible throughout treatment.

Definitive chemoradiation for oesophageal cancer--a standard of care in patients with non-metastatic oesophageal cancer.

AIMS: A retrospective analysis was carried out of 291 cases of oesophageal cancer treated with definitive chemoradiotherapy (dCRT) at a single UK cancer centre between 1995 and 2009. Our protocol consisted of two cycles of neoadjuvant platinum-based chemotherapy followed by two further cycles given concurrently with 50Gy of external beam radiotherapy delivered in 25 fractions over 5 weeks. MATERIALS AND METHODS: Demographic, patient and outcome data were recorded prospectively through an electronic health record and retrospectively analysed, using appropriate statistical tools. RESULTS: Data on 266 patients were available for analysis. The median age was 66.6 years, 53% were adenocarcinomas. dCRT was used instead of surgery because of age/co-morbidity in 44% and disease extent in 39%. Ninety-three per cent of patients completed treatment according to protocol. Grade 3 and 4 toxicities were seen in 42 and 7%, respectively. Median survival was 20.6 months; 2, 3 and 5 year survival rates were 43.6, 32.9 and 19.5%, respectively. Advanced disease was associated with a worse outcome. Shorter disease length was associated with a better median survival, but some patients with disease >10cm had long-term disease control. The effect of other patient- and disease-related factors was also analysed. CONCLUSION: We present data showing that dCRT is well tolerated and should be considered as an alternative to surgery for all patients with locally advanced oesophageal cancer, not only those with co-morbidity. Furthermore, the benefits of dCRT are not confined to carcinomas with squamous histology.

Prognostic significance of age in the radical treatment of oesophageal cancer with surgery or chemoradiotherapy: a prospective observational cohort study.

AIMS: To compare the outcomes of stage-directed surgical therapy and chemoradiotherapy (CRT) for oesophageal cancer and to determine if a significant age-treatment interaction exists to guide therapy. MATERIALS AND METHODS: Five hundred and eight consecutive patients with oesophageal cancer suitable for radical treatment based on radiological stage and performance status were studied (275 surgery; 93 surgery alone, 131 neoadjuvant chemotherapy, 51 neoadjuvant CRT and 233 definitive CRT). The primary measure of outcome was survival. RESULTS: Thirty-day mortality rates and 2-year survival after surgery and CRT in patients<70 years were 2.4 and 57.5%, respectively, compared with 0 (P=0.207) and 47.3% (P=0.011), respectively. Thirty-day mortality rates and 2-year survival after surgery and CRT in patients>or=70 years were 7.0 and 45.1%, respectively, compared with 0 (P=0.029) and 46.3% (P=0.992), respectively. Multivariate analysis including only surgical patients in the model revealed three factors to be independently and significantly associated with survival; endoscopic ultrasound (EUS) T stage (P=0.033), EUS lymph node metastasis count (>or=2 versus 0: hazard ratio 1.67, 95% confidence interval 1.06-2.92, P=0.026), and age>or=70 years (hazard ratio 1.51, 95% confidence interval 1.05-2.16, P=0.025). CONCLUSION: Overall survival for patients treated with surgery was strongly age dependent around the age of 70 years, and patients>or=70 years with oesophageal cancer should be aware that outcomes after CRT are similar to those after surgery.

Respiratory movement of upper abdominal organs and its effect on radiotherapy planning in pancreatic cancer.

AIMS: Radiotherapy for pancreatic cancer is complicated by the frequent overlapping of the planning target volume (PTV) and the organ at risk (OAR), limiting the dose that can be safely delivered to the tumour. Individualising the margins applied to the clinical target volume (CTV) may reduce OAR irradiation without increasing the risk of geographical miss. We quantified the movement of the pancreas with respiration and evaluated whether individualised margins based on this motion reduced the dose to OARs. MATERIALS AND METHODS: Planning computed tomography scans were acquired in quiet breathing, held expiration and held inspiration. Organ motion was evaluated from displacement of a reproducible point within the pancreas in all directions. Two sets of plans (standard plan: P(stan); individualised plan incorporating movement data: P(ind)) were generated for each patient. The PTV and doses to OARs were evaluated for both sets of plans. RESULTS: The mean (standard deviation) movement of the pancreas in the superior-inferior, lateral and anterior-posterior directions were 15.3 mm (4.3), 5.2 mm (3.5) and 9.7 mm (6.1), respectively. The use of individualised margins reduced the mean PTV volume by 33.5% (9.8) (P=0.0051). The proportional reductions in the percentage of kidney receiving >10 Gy, small bowel >45 Gy and liver >30 Gy were 63.7% (P=0.0051), 29.3% (P=0.0125) and 29.2% (P=0.0107), respectively. For the same level of OAR constraints, individualised margins allowed dose escalation in six of the 10 patients to a mean dose of 63.2 Gy. CONCLUSIONS: The present study shows a simple way of incorporating organ motion into the planning process and can be adopted by any centre without major strain on healthcare resources. The use of individualised margins reduced PTV volume and the dose to OARs. This may offer an opportunity for dose escalation to try and further improve local control.