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Ongoing programs

Selected Clinical trials:

Stereotactic Body Radiotherapy (SBRT) for organ-confined prostate cancer

There is evidence from radiobiological studies that prostate cancer is more sensitive to radiation damage compared to the surrounding normal tissues when radiotherapy is given in large doses per treatment. We thus hypothesize that delivering the radiotherapy in an vastly reduced number of highly accurate, focused high-dose treatments will be as safe and efficacious as the current standard of a 37-treatment course. The radiation therapy is to be delivered using intensity modulated radiotherapy (IMRT) with the aid of volumetric image guidance to ensure accuracy. The primary aim is to assess the acute and late toxicity and secondarily Prostate Specific Antigen (PSA), clinical and quality of life outcomes of an extreme hypofractionated regimen delivered using stereotactic techniques for low risk prostate cancer.

Androgen Deprivation Therapy and High Dose Radiotherapy With or Without Whole-Pelvic Radiotherapy in Unfavorable Intermediate or Favorable High Risk Prostate Cancer: A Phase III Randomized Trial

The proposed study will determine whether when higher doses of radiation is given there is a benefit to WPRT when treating unfavorable-intermediate to favorable high-risk patients. It is estimated that such patients have a risk of lymph node involvement > 15% but are not as likely to harbor occult distant metastasis as unfavorable high risk men (GS=8-10 and T3 and PSA >20) [Kattan 2003]. In addition, such patients are more likely to sustain long-term local control with high dose radiotherapy using IMRT, PPI, or boost. The primary objective is to demonstrate that prophylactic neoadjuvant androgen deprivation therapy (NADT) and whole-pelvic radiation therapy (WPRT) will result in improvement in overall survival (OS) in patients with “unfavorable” intermediate risk or “favorable” high risk prostate cancer compared to NADT and high dose prostate and seminal vesicle (SV) radiation therapy (P + SV RT) using intensity modulated radiotherapy (IMRT) or EBRT with a high dose rate (HDR) or a permanent prostate (radioactive seed) implant (PPI) boost.

Somatostatin receptor imaging in nasopharyngeal cancer

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 (sst2) in about 75% of patients. This opens up potential therapeutic and diagnostic applications for somatostatin receptor imaging and radionuclide therapy in NPC. Current methods for investigation of NPC utilize computer tomography (CT), magnetic resonance imaging (MRI) and fusion imaging using (18)F-fluorodeoxyglucose (FDG) with positron emission tomography and CT (PET/CT). Though these investigations have high sensitivity and specificity, in pre-treatment cases, in the post-irradiated setting difficulty often arises in detecting both local and regional recurrences. This is due to the similar imaging appearances of inflammatory tissues and recurrent tumour in the head and neck region.

Octreotate is a somatostatin analogue found to be useful in the imaging of neuroendocrine tumors when combined with Galium-68 through a linker DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Mainly used in the imaging of neuroendocrine tumors, Galium-68-DOTATATE imaging may be useful in overcoming several of the current imaging difficulties in NPC and in addition has the potential to be used in peptide receptor radionuclide therapy as well. With Ga-68-Dotatate imaging, it may be possible to select patients with recurrent/metastatic tumors with high levels of SST2 that may have the option of peptide receptor radionuclide therapy using Lutetium-177 Dotatate. This is currently being done and found to be very effective in neuroendocrine tumors.

Randomized 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 can 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.

Using plasma Epidermal Growth Factor Receptor (EGFR) DNA to monitor treatment responses in lung cancer patients treated with radical radiotherapy

Monitoring treatment responses of lung cancer post-radical radiotherapy is often complicated by uncertain radiological changes, leading to delays in further treatments strategies. Recently the use of cell-free plasma DNA to detect and monitor cancer has gained growing interest. The use of qualitative plasma EGFR DNA has shown good mutation concordance with lung cancer tissue and recent studies report it to be useful in monitoring patients undergoing treatment with EGFR tyrosine kinase inhibitors (TKIs). The value of quantitative evaluation has been less studied. We hypothesize that detectable post-radiotherapy plasma EGFR DNA will predict for a poorer tumour control. Our primary aim is to look for treatment response in plasma EGFR DNA after radical lung radiotherapy (+/-chemotherapy) and to study its correlation with local & overall tumour control and survival on follow-up imaging.

Radiation for Chordomas and Chondrosarcomas

Chordomas are malignant tumours arising from the embryonic notochord remnant with the majority of these tumours occur along the craniospinal axis: 50% grow in the sacrococcygeal regions, 35% in the base of the skull and 15% in the spine. Chondrosarcomas are malignant tumours that arise from cartilaginous structures, typically in the bones of the shoulders and pelvis but can also affect the limbs. About 5% of chondrosarcomas arise in the clivus, parasellar area and cerebella-pontine angle. These are rare tumours and there are no randomized clinical trials and no large prospective series that define the optimal treatment for either disease. Literature reviews of small retrospective series support a combined modality approach using maximal surgical resection and radiation therapy (RT). However, conventional photon radiotherapy in the treatment of chondrosarcomas has shown poor results in terms of local control. The maximum delivered dose ranges from 50 to 60 Gy using such techniques because of the sensitivity of critical organs surrounding the target. Advance RT techniques have improved on spatial selectivity, inverse dose profile with steep dose gradients makes it possible to deliver treatment dose to the tumour while preserving the surrounding organs at risk. The present prospective study aims to study patients with chordomas or chondrosarcoma with respect to treatment toxicity, clinical outcomes, quality of life (QOL) and comparative effectiveness including costeffectiveness of the different treatment strategy.

Outcomes Research in DRO Cancer Care

Individualized 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.

18F-FMISO PET guided dose escalation in nasopharyngeal carcinoma – a feasibility and planning study

Nasopharyngeal carcinoma, primarily treated with radiotherapy is highly prevalent in Asia. Local recurrence is the predominant pattern of failure in advanced stage and devastating as there are limited salvage options. Tumor hypoxia is well known to result in resistance to radiotherapy and postulated to result in recurrence. Therefore we envisage to adapt radiotherapy according to the tumor hypoxia status. 18F-FMISO-PET has been shown to correlate with the tumor oxygenation status. Dose escalation targeted to areas of increased radio-resistance guided by hypoxia imaging using 18F-FMISO PET presents an attractive treatment strategy. We hypothesize that the use of 18F-FMISO PET can identify hypoxic subvolume for dose escalation in NPC and consequentially improve local control without significant increase in toxicities.

Specific aims include:

  1. Establish hypoxia imaging in NPC patients
  2. Investigate the dynamics of tumor hypoxia before and during chemoradiation
  3. Learn how to integrate hypoxia imaging into radiation treatment planning protocols
  4. Design hypoxia adapted radiation schedules
  5. Identify candidate hypoxia biomarkers

Significance: We envisage to translate the findings from this feasibility study into future phase II/III studies of hypoxia-adapted radiochemotherapy, with photon or proton therapy.

Monitoring of Respiratory Pattern during Thoracic Radiotherapy

Lung tumours are known to move during respiration. In our department, 4D CT simulation scans are done using the Varian RPM system; this generates a patient’s respiratory waveform by tracking the movement of a block positioned on the patient’s xiphoid region. The movement of the tumour can then be visualised and accounted for with appropriate ITV margins during radiotherapy planning. However, this process is not repeated during daily set-up and treatment. As such, it is not known whether there have been any changes in the patient’s respiratory pattern, and whether the ITV margins are truly adequate for proper coverage of the tumour. The aims of this study are twofold. Firstly, to evaluate the respiratory pattern of patients during a course of radical lung treatment, and attempt to quantify the differences (if any). We hope to identify and measure inter- and intra-fraction differences, as well as differences between simulation and treatment. These will then be correlated back to the planning margins. Secondly, to determine and establish an appropriate monitoring protocol as part of a quality assurance and improvement initiative.

Intratumoral PD-L1 expression and Tumour infiltrating lymphocyte density in Oesophageal cancer treated with Neoadjuvant chemoradiation (PLuTON)

Oesophageal cancer is the eighth most common 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.

Selected Radiation technology research:

Small Field Dosimetry and Monte Carlo Simulation studies for Lung SBRT

Small field dosimetry is important in stereotactic RT. This includes perturbation effects caused by charge disequilibruium condition especially in heterogeneous medium like lung. The use of TLD with correction factors for small field lung treatment is being studied via experimental measurement and EGSnrc Monte Carlo Simulation. Other studies include the optimal prametrization of a MC simulation model against the golden beam data using the gamma analysis approach and the accuracy of AAA and AcurosXB algorithms against a moving respiratory target in a lung medium.

Comparative Study of Advanced Algorithms for Lung SBRT – AAA, AcurosXB and EGSnrc Monte Carlo Simulation

The commissioning of new advanced dose algorithms need to be studied carefully before being used for clinical treatment. The current clinical dose algorithm is the AAA model. A new model, based on the deterministic linear Boltzmann transport equations approach, is the AcurosXB. It is expected that AcurosXB will be more accurate for small fields and heterogeneous medium. This research project starts with a retrospective study of the 2 dose calculation algorithms on a set of clinical treatment data of at least 20 patients with previous Lung SBRT treatment using AAA. The data will highlight the major similarities and differences in the 2 algorithms. EGSnrc Monte Carlo simulation will be used to model some of the key dose differences between AAA and AcurosXB. Key differences may arise from tumor-lung interface, motion or out of field doses.

Stoichiometric CT Calibration study for Proton Therapy

Proton Therapy treatment planning requires careful calibration of the CT using a stoichiometric approach to obtain a set of stopping power ratios (SPR) against CT HU units. However sources of uncertainties exist, which requires further study. The use of CT calibration phantoms for organic and inorganic materials, standard CT protocols, and theoretical models for SPR and actual CT measurements are some of the key areas for the study. This study should result in a better understanding of PT range uncertainties due to CT calibration and for preparing the treatment planning system for proton planning studies.

Development of 4D-CT QA techniques with Quasar Phantom

Motion management is a very important part of modern radiation therapy techniques. 4DCT plays a major role in motion management in identifying the internal target volume or ITV. Hence the importance of understanding of 4DCT techniques and developing methods to QA the system is involved. Current in-house developed QA techniques that are undergoing validation include: 1) QA of the RPM system in terms of its detection of breathing frequency and amplitude, using MatLab programming. 2) QA of our 4DCT simulator image acquisition fidelity under fast, slow, and irregular breathing patterns. Another project also involves developing a software to help quantify patient breathing regularity. This will aid the radiation therapists to coach the patient in breathing control when they prepare the patient for 4DCT. It may also help filter out patients who are not suitable to 4DCT.

Imaging tumour heterogeneity with a multimodality functional approach in primary oesophageal cancer

This 3 year preclinical and clinical project will assess the application of PET/CT & PET/MRI and texture feature analysis to assess tumour heterogeneity in primary oesophageal cancer. In animal models, differences in the heterogeneity of PET tracer uptake (18F-FDG (metabolism), 18F-FLT (proliferation), and 62Cu-ATSM (hypoxia)) and MRI parameters (DW-MRI and BOLD-MRI) will be assessed in controls and those treated with chemotherapy +/-antiangiogenics, and compared to 02 probe measurements and immunohistochemistry (Pimonidazole, HIF-1, Glut-1, VEGF, CD34, CD105). In a phase 1 study, the feasibility of 62Cu-ATSM to demonstrate reversible hypoxia will be investigated with 62Cu-ATSM PET/perfusion CT and Carbogen, to refine patient selection for radiotherapy. The prognostic and predictive value of PET/CT texture analysis in oesophageal cancer will be investigated in the neoadjuvant and definitive chemoradiation settings. The prognostic and predictive value of multiparametric MRI following neoadjuvant chemotherapy and definitive chemoradiation in primary oesophageal cancer will be assessed in a single-centre prospective clinical trial. The primary end-points will be disease-free and overall survival.