Selected Clinical trials/clinical studies:
Somatostatin receptor imaging in Nasopharyngeal cancer, Epstein-Barr Virus related cancers and other rare tumors
Recently, there have been reports of the expression of somatostatin receptors in nasopharyngeal cancer. Somatostatin is a peptide that functions as a neurotransmitter in the central nervous system and acts as a regulator of endocrine and gastrointestinal functions. Somatostatin receptors are not only found in normal tissues, but are over expressed in certain tumour tissues such as neuroendocrine tumours. Interestingly, NPC has been found to have moderate to high expression of somatostatin-receptor-2 (SSTR2) in about 75% of patients (2). We have also found increased expression of sstr2 in other EBV related cancers (Lymphoepithelialoma like lung carcinoma (LELC) and there are some reports that EBV viral proteins LMP1 and EBNA2 are able to increase transcription of sstr2. (3,4) This opens up potential theragnostic applications for radionuclide therapy in EBV related cancers.
The aim of our study is to first describe the avidity of this novel tracer in the locally advanced, metastatic and locally recurrent setting and to determine the proportion of patients with high somatostatin receptor density (SUVmax >10) that may benefit from future somatostatin targeted therapeutic trials plans. We also seek to image other EBV related cancers to determine the presence of sstr2.
Randomised Phase II and Phase III Studies of Individualized Treatment for Nasopharyngeal Carcinoma Based on Biomarker Epstein Barr Virus (EBV)
Deoxyribonucleic Acid (DNA) (NRG-HN001)
Plasma EBV-DNA have been used to monitor recurrence after definitive therapy and multiple studies have demonstrated poorer prognosis in patients with persistently detectable post-radiation plasma EBV-DNA. The current proposal seeks to use plasma EBV-DNA as a biomarker to select the most appropriate candidates for adjuvant chemotherapy after concurrent chemoradiation.
In this proposed trial, post-chemoradiation plasma EBV DNA will be used for risk stratification, and patients will be randomized to different treatments based on their risk. Those who have an undetectable post-treatment EBV DNA level are considered good risk and will be randomized to either observation or the current standard cisplatin and 5-FU. The aim is to see if omitting adjuvant chemotherapy for a group of patients at low risk for treatment failure will compromise overall survival (OS). Patients whose EBV DNA is detectable will be randomized to receive current standard adjuvant cisplatin and 5-FU versus gemcitabine and paclitaxel to test whether the latter regimen can further improve PFS in this high-risk population.
Outcomes Research in DRO Cancer Care
Individualised medicine based on the twin tenets of Multi-Disciplinary Care (MDC) and Evidence Based Medicine (EBM) has been instrumental in advancing oncology care in the last half-century. However, outcomes research supporting these philosophies of oncologic care is scarce which is ironic as we are neither individualizing it to the Singaporean population nor do we have local evidence in support of the success of this practice.
We aim to create a centre-wide database of all cancer patients treated with radiotherapy in NCCS to ascertain the outcomes of these patients and to benchmark ourselves against other Global leading cancer centres. This database will be updated in perpetuity so that changes in epidemiology, outcomes and impact of various intervention programmes can be tracked. This database will provide up to date information for medical practitioner, policy maker, healthcare administrator, decision maker and educator to make informed decisions on healthcare practise, policies and programmes.
Intratumoral PD-L1 expression and Tumour infiltrating lymphocyte density in Oesophageal cancer treated with Neoadjuvant chemoradiation (PLuTON)
Oesophageal cancer is the eighth commonest cancer in the world and is associated with poor survival even after curative treatment. Preoperative chemoradiation has been shown to improve survival compared to surgery alone. Nonetheless, disease relapse occurs in a significant proportion of patient after chemoradiation and surgery. Early evidence suggests that oesophageal cancer expresses a protein called the PD-L1 receptor which could be a related to poorer outcome in this disease. Immunotherapy such as anti-programmed death 1 (PD1) therapy has improved outcomes in melanoma and non-small cell lung cancer, and may have similar therapeutic benefit in oesophageal cancer. However, preoperative chemoradiation and chemotherapy seem to exert an opposite effect on PD-L1 expression in oesophageal cancer. Besides PD-L1 expression, white blood cells within the cancer called the tumour infiltrating lymphocytes (TILs) is also an indicator of tumour immunogenicity. Hence, we aim to evaluate the changes in PD-L1 expression and TIL density after preoperative chemoradiation in oesophageal cancer as these have the potential to direct future use of immunotherapy in this setting. Patients who are planned for preoperative chemoradiation followed by surgery for resectable oesophageal cancer will be approached for this study. Pre-treatment oesophageal biopsies and resected tumour specimens will be obtained for analysis and stained for the following protein markers: PD-L1, CD4, CD8 and FOXP3. The PD-L1 scores, and TIL density will be assessed by experienced pathologists. Pre-treatment and post-treatment values will be compared and correlated with pathological tumour response. This pilot study will provide valuable information if adjuvant immunotherapy has a role in the management of localised oesophageal cancer in our local population.
Continuous positive airway pressure (CPAP) for respiratory motion management in radical lung radiotherapy
Lung radiotherapy is challenging due to tumour motion from respiration as well as radiotherapy dose limitations due to lung volume constraints. We aim to study the use continuous positive airway pressure (CPAP) during radiotherapy CT simulation in reducing treatment volumes and normal tissue doses thus improving on the radiotherapy treatment plans.
It is important to deliver accurate and precise doses during lung radiotherapy to reduce normal tissue toxicities. There is no optimal standard to deliver lung radiotherapy. Several methods are available, but these can be technically complicated and expensive to implement. CPAP is inexpensive and easy to operate and has been safely used for many conditions. Its use in lung radiotherapy is not well characterized. This study is important as it will help determine if CPAP is beneficial for lung radiotherapy and assess which patients are most likely to gain from its use
Novel Functional Imaging Technique with FLT-PET/MRI For Staging, Response Assessment and Radiation Treatment Planning in Cervix Cancer
This pilot study aims to monitor early tumour response based on [18F] FLT-PET/MRI scans and to determine the feasibility of personalised radiotherapy to spare active bone marrow areas identified by [18F] FLT-PET/MRI.
Phase 2 study of Dose-Reduced Consolidation Radiation Therapy in Patients with Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL), the most common type of NHL and comprises of a heterogeneous group of neoplasms with multiple morphologic variants and subtypes described in the current WHO classification.
As long-term outcomes in DLBCL are becoming more favorable, decreasing the risk of late effects is critical. The risk of complications related to RT, including cardiac disease and secondary cancers, appear to be related to both dose and volume. The rationale would be to lower the dose to maintain efficacy and lower toxicity.
The aim of this phase 2 study is to evaluate whether a reduction in the dose of consolidation RT in patients who achieve a negative post-chemotherapy PET-CT scan following 3 to 6 cycles of chemoimmunotherapy, will be associated with a low risk of in-field failure. The goal of this approach is to maintain excellent control rates while minimizing the risk of acute and late toxicity.
Randomised prospective phase 2 trial in multiple brain metastases comparing outcomes between Hippocampal Avoidance Whole Brain Radiotherapy with or without Simultaneous Integrated Boost
Recently, the evidence supports hippocampal avoidance with WBRT (HA-WBRT) as the recommended option in patients with good prognosis and multiple brain metastases as it gives better neurocognitive preservation compared to historical WBRT controls. There is however often poor tumour control with this technique due to the limited doses given. Stereotactic Radiosurgery (SRS) can be given in patients with minimal brain metastases to increase radiation doses to the tumor results in better target control. With improvements in radiation technology, we can now use advanced dose-painting techniques to simultaneously integrate boost (SIB) doses to lesions whilst minimizing doses to the hippocampus to potentially improve brain control and preserve cognitive outcomes (HA-SIB-WBRT). We believe that the SIB in HA-SIB-WBRT (experimental) will result in better functional and survival outcomes compared to HA-WBRT (control). Our primary objective is study the duration of brain tumour control. Our secondary objective is to study the change in cognitive function and quality of life (QoL) from baseline, survival outcomes and toxicity between the 2 arms.
Optimisation of radiotherapy doses to patients with primary central system lymphoma
Primary central nervous system lymphoma (PCNSL) is an aggressive disease. Consolidative whole brain radiotherapy (WBRT) is a key component of combined-modality treatment (CMT) following chemotherapy. However, there is a significant risk of neurotoxicity following WBRT especially in the elderly and for patients who do not achieve a complete response after chemotherapy. Strategies to optimise WBRT are thus needed to enhance the therapeutic ratio of CMT by optimising the radiotherapy doses in order to reduce neurocognitive toxicity.
We hypothesize that we can reduce neurotoxicity without compromising efficacy of treatment in patients with PCNSL who are undergoing consolidative WBRT, by reducing the dose to the whole brain in patients with an incomplete response to systemic therapy, and reducing the dose to the hippocampi in patients who have a complete response to systemic therapy.
Neoadjuvant Hypo-fractionated Radiotherapy for Retroperitoneal Sarcoma with At Risk Margins “NOVELS”
We hypothesize that short course RT (SCRT) followed by immediate surgery (following the model of rectal and pancreatic cancer) targeted to the posterior/medial/lateral wall in patients in whom clear margins are not anticipated is safe and efficacious. This serves to sterilise margins in borderline operable RPS and obviates the risk of progression during long course neoadjuvant treatment and avoids RT to more sensitive structures such as the small bowels, duodenum, and stomach.
We aim to recruit 6 patients with RPS to receive neoadjuvant SCRT to the posterior/medial/lateral wall with image-guided photon therapy in a dose escalation schema. These are patients in whom a positive margin after surgery is anticipated. The organs are these areas are mainly musculoskeletal or adipose tissue (e.g., ribs, retroperitoneal fats, vertebral foramina). Acute toxicities and perioperative outcomes will be measured. These patients will be followed up for 3 years to assess short term local control. Simultaneously, these patients’ radiotherapy plans will be compared against proton therapy, to assess for dose volume differences and if robustness algorithm can mitigate proton uncertainty and patient’s motion.
Safety of grid radiotherapy (GRID) applied to inoperable bulky Hepatocellular Carcinoma
The overall objective is to assess the safety of GRID in patients with inoperable HCC, presenting with a bulky primary lesion unsuitable for currently available liver-directed treatments. The specific aim is to establish the safe radiation dose level through a prospective dose escalation study, looking for dose limiting toxicity (DLT). A DLT is any Grade 3-5 toxicity, as defined under Common Terminology Criteria for Adverse Events version 4.0, occurring within 90 days of treatment.
By establishing the safety of GRID, we can then further investigate its efficacy as an alternative, cost effective and non-invasive treatment option that complements the limitations of the other liver-directed therapies. Going further, we will also investigate the role of GRID in combination with immunotherapy for possible synergistic effect.
Selected Medical Physics Research Programmes:
Simulation programme for Proton Therapy
The use of well-crafted physics or mathematics-based models to simulate how charged particles & photons transfer energy in a human body plays an important role in Proton Therapy. This, in turn, can lead to a better understanding of and thus improvements to the effectiveness of radiation treatments. In NCCS, this programme is initiated & directed by a team of Medical Physicists. The main computational toolkit is the GEANT4 Monte Carlo suite. Projects in this programme include simulation of charge collection of a new commercial Bragg Peak Chamber for commissioning of our Proton Therapy machine; Simulation studies to commission proton range shifters; Studies on the different models of radiobiological effectiveness (RBE) of Proton Therapy; Independent dose calculation tool to credential Commercial treatment Planning Systems.
Radiomics programme for clinical outcomes prediction
Radiation Oncology is a natural platform for acquiring huge volumetric patient imaging data. The most common form of imaging is CT, MRI and PET which is acquired during pre-treatment. Radiomics is a field focused on extracting multi-dimensional features from images and are subsequently used to build prognostic models to predict either survival, response or other clinical outcomes. It requires knowledge of data analytics, Machine Learning and Image Processing and Physics. There are two main directions to our radiomics research. The first involve collaborating with clinicians to use radiomics approach to predict outcome in brain, NPC and breast. The second focuses on the technical development of radiomics approach to improve the interpretability and robustness of the model.
SRS programme to quantify & enhance accuracies in Stereotactic Radiosurgery
In Stereotactic Radiosurgery (SRS), is a radiation therapy technique used to treat functional abnormalities and small tumours of the brain. It can deliver precisely-targeted high-dose radiation to target the diseased area, thus can help preserve healthy tissue. Its performance is analogous to surgery but non-invasive. On-going development projects to enhance SRS treatment in NCCS includes introducing the Elements treatment planning system for multiple brain metastasis treatments; integrating the use of 3D volumetric CBCT & 2D imaging with surface guided imaging to achieve high precision patient positioning while reducing imaging radiation to the patient; developing an in-house simulation software system to explore new techniques for SRS treatment.
Proton imaging programme for improved accuracies in Proton Therapy
Using protons to image a patient is set to become a standard of care in Proton Therapy. Currently treatment plans are calculated on X-ray based CT imaging which introduces inherent inaccuracies during calculations of energy losses in protons due to its inability to resolve elemental differences in materials. Imaging in the form of Proton CT or Proton Digital Tomosynthesis can significantly reduce such uncertainties. This programme leverages on software tools built from the Proton Therapy Simulation programme, together with its own hardware and firmware capabilities, to investigate & design novel detectors for proton imaging.
Clinical: Development of a 3D printed pseudo TPUS probe to improve consistency of treatment position during MRI
To establish a novel clinical workflow for prostate cancer patients undergoing stereotactic body radiotherapy (SBRT) by developing a 3D printed pseudo ultrasound probe to improve consistency of patient positioning during MRI to facilitate image fusion for contouring during radiotherapy treatment planning. Optimal image fusion with minimal impact from positioning uncertainties between MRI and CT simulation will provide the basis of future exploration of dose escalation for dominant intra-prostatic lesion. In addition, this will enable real-time monitoring of the prostate displacement for timely intervention by beam-holding during delivery (in the event of gross target displacement) of radiotherapy while sparing surrounding organ-at-risk (such as the bladder and rectum).
High throughput Motion Management Quality Assurance
Motion management is important for radiotherapy involving moving tumors such as in the lung, liver or pancreas. There are several strategies for motion management including breath-hold, fiducial marker tracking and phase gating. These advanced techniques could potentially reduce the amount of irradiated normal tissues but requires addition quality assurance to ensure equipment functionality. We have developed new QA tools to reduce the time for QA significantly so that more patients can benefit from these techniques.
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