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Peritoneal Disease and Sarcoma

​The NCCS is one of the most experienced centres in Asia for the clinical management of peritoneal-based malignancies and sarcomas, and is an “academic magnet” for clinicians and researchers to gain experience within a specialised oncology field with considerable international visibility. Through clinical trials and translational research, our multidisciplinary teams are dedicated to improving the management of patients with rare malignancies, such as peritoneal carcinomatosis and sarcomas, and seek to widen our clinical and scientific knowledge of these diseases to advance patient care.

PERITONEAL DISEASE
Peritoneal carcinomatosis (PC) is a common form of metastasis confined to the abdominal cavity and is a late manifestation of some terminal cancers, such as gastrointestinal and ovarian cancers. Up to 50% of patients with colorectal and gastric cancer develop peritoneal metastases during the course of their disease. An analysis of more than 10,000 patients with colorectal cancer clearly defined patients with peritoneal metastasis as having the worst prognosis when compared to those with liver or lung metastases. Cytoreductive surgery (CRS), combined with hyperthermic intra-peritoneal chemotherapy (HIPEC), has afforded prolonged survival in selected patients, with up to 50% attaining 5-year survival. Furthermore, approximately 20% of patients with colorectal peritoneal metastasis remain disease-free at 5 years. The peritoneal disease programme at the NCCS adopts a multidisciplinary approach combining scientific discovery of underlying tumour biology with state-of-the-art treatment modalities to augment the outcomes of patients with PC (Figure 1). 

MULTICENTRE COLLABORATIONS
Adj. Prof. Melissa Teo heads the team of surgical oncologists specialised in the management of complex intra-abdominal tumours, peritoneal malignancies, and sarcomas. She also leads the Asian Peritoneal Surface Malignancy Group (APSMG), a network of professionals and peritoneal treatment centres aimed at promoting learning opportunities and collaborations. This initiative seeks to improve the standards of management and survival of patients with peritoneal disease through patient education, physician training, and basic and clinical scientific research in the field of peritoneal disease. The APSMG creates a platform that facilitates cross-institutional collaboration and the exchange of ideas to incite potential translational projects. The network is currently organising the 2nd Peritoneal Surface Malignancy Course (PSMC) for June 2018, after a successful meeting the previous year.

PRACTICE CHANGING CLINICAL TRIALS
Dr. Grace Tan is close to completing a feasibility study of adjuvant HIPEC for high-risk colorectal cancers, and is in the midst of planning a multi-institutional, randomised, controlled trial to evaluate the efficacy of adjuvant HIPEC. This is to prevent the development of PC into high-risk colorectal cancers and will be the first trial of its kind in Asia. If effective, this trial could change the outcomes of colorectal cancers that are at a high risk of peritoneal recurrence, and alter the management policies of this disease.

Gastric peritoneal carcinomatosis, on the other hand, is believed to have a different tumour biology, and Dr. Claramae Chia aims to compare if bi-directional chemotherapy is superior to palliative chemotherapy in prolonging median overall survival in patients with this disease. Bi-directional chemotherapy works by the simultaneous delivery of intravenous and intraperitoneal
chemotherapy, thereby creating a diffusion gradient and creating a wider treatment area. Several bi-directional
chemotherapy regimens have been investigated and shown to be well tolerated, with up to 52% response rate. In addition, Dr. Chia also leads the prospective quality-of-life studies in patients who have undergone CRS and HIPEC.

In a similar vein, Dr. Clarinda Chua and Dr. Grace Tan are embarking on a collaborative, multi-centre, phase I clinical trial to ascertain the tolerability and safety of pressurised intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin in patients with gastrointestinal peritoneal metastases. PIPAC is a relatively novel technique of delivering intraperitoneal chemotherapy for patients with peritoneal disease. Using various cytotoxic agents at different doses, PIPAC has shown encouraging results in small series and early-phase studies. In most of these studies, the cytotoxic agents employed in PIPAC are dependent on the origin of the peritoneal metastasis, and generally include platinum drugs (such as oxaliplatin and cisplatin) and anthracyclines (such as doxorubicin). Whether there are optimal schedules, drug/drug combinations, and dosage for peritoneal metastases of different origins is less clear, and these aspects of the strategy require further evaluation.

Figure 1: Framework of the multidisciplinary approach of the NCCS in the management of peritoneal disease and sarcomas.

TRANSLATIONAL RESEARCH IN PC
Asst. Prof. Johnny Ong is investigating the molecular basis of how peritoneal disease arises and hopes to harness this knowledge to derive novel therapeutic strategies for patients with PC. His research seeks to elucidate the mechanism of paracrine signalling in PC. Such an understanding could provide insight into potential druggable targets that could be used as adjuncts to current chemotherapy regimens to enhance treatment outcomes for patients with PC. The laboratory of Applied Human Genomics, where this work is based, has also set up multiple collaborations within the SingHealth campus and with laboratories in the Cancer Science Institute (CSI) of Singapore.

SARCOMAS
Sarcomas are a group of malignant tumours that originate from connective tissues or other non-epithelial cells. Worldwide, the incidence is approximately 1% of all malignancies. Current treatment for sarcomas involves radical surgery, systemic chemotherapy, and radiation therapies. Only early-stage sarcomas, for which adequate surgical margins can be obtained, have a chance of cure. Outcomes are dismal in advanced or metastatic disease, where response rates to systemic treatments are poor. Despite advances in the systemic treatment of many cancers, many sarcomas remain difficult to treat, even in today’s era of modern medicine. Therefore, there is an urgent need to commit our efforts to provide answers to this unmet clinical concern.

TRANSLATIONAL RESEARCH IN SARCOMA
Scientific research into sarcomas is difficult due to the lack of reliable in vitro and in vivo models. Dr. Valerie Yang aims to develop better models of sarcoma by generating primary cell cultures and organoids representative of this disease. Patientderived models can be used in drug screens for individual patients to identify potential therapies, especially in patients who have failed to respond to conventional treatment. The identification of effective systemic treatments for individual patients can also help to inform the design of intelligent phase II clinical trials for specific sarcomas, which may accelerate the development of better systemic treatment options for sarcomas. Dr. Jason Chan is interested in elucidating the molecular pathogenesis of sarcomas. A unique group of soft tissue sarcomas have been observed to occur more frequently in patients with immunodeficiency. Apart from Kaposi sarcoma, an angioproliferative malignancy in which immunodeficiency and human herpes virus-8 have clear pathogenic roles, there is a lack of strong evidence for the contribution of oncogenic viruses to the development of other sarcoma subtypes. Recent epidemiological studies have demonstrated increased rates of leiomyosarcomas, angiosarcomas, and other sarcomas in individuals with HIV/AIDS as well as in organ transplant recipients, thus igniting interest in the exploration of novel oncoviral aetiologies. Using emerging 21st century technology, such as metagenomic “shotgun” sequencing, Dr. Chan hopes to accelerate the discovery of these oncoviruses. From a diagnostic perspective, Dr. Nagavalli is exploring the use of an assay that can detect circulating tumour DNA in plasma samples from patients with gastrointestinal stromal tumours. This exciting field is evolving rapidly and, once validated, can be used to diagnose and monitor the clinical status and progress of patients with gastrointestinal stromal tumours.

RADIOTHERAPY’S EVOLVING ROLE IN SARCOMAS
The role of radiotherapy in sarcoma is constantly evolving. Traditionally administered post-operatively with wide fields and for limb preservation, preoperative radiation therapy has now become a standard of care in many centres. Treatment fields and radiation doses have also been reduced to decrease the incidence of late toxicities in our patients. There is also increasing evidence for the use of proton therapy in several sarcoma subtypes, especially in the pediatric population and for tumours at the base of skull, spine, and pelvis. More research is needed to maximise the benefits of radiotherapy and decrease its potential late side effects. In this aspect, Dr. Wen Long Nei aims to optimise radiotherapy treatment, such as with the use of Intensity Modulated Proton Therapy (Figure 2).

Figure 2: Comparative dosimetric plans using Pencil Beam Proton Therapy (left) and conventional radiotherapy (right).

COST EFFECTIVENESS STUDIES AND PRACTICE
CHANGING TRIALS
Dr. Mohamad Farid is interested in understanding the role of decision analysis in the treatment of sarcoma. Decision analysis may have a unique role in rare cancers like sarcomas where epistemic uncertainty (the lack of reliable information about probabilities and parameter values) is particularly acute. Far from providing a single, unassailable answer to knotty clinical issues, their primary goal is to unveil underlying assumptions and premises, providing a means to challenge and refine them. Crucially, these analyses are not attempts to “save money” but, instead, aid to make more optimal and value-congruent decisions. They may be most impactful when used to address critical questions in diagnosis, early management, and survivorship, perhaps more so than in the evaluation of complex therapies in late-stage disease. With the aim to reduce recurrence and improve overall survival in patients with recurrent sarcomas, Asst. Prof. Johnny Ong is actively involved in an early-phase clinical study to evaluate the use of HIPEC in highrisk recurrent retroperitoneal sarcoma to prevent local recurrence and improve patient outcomes.

CANCER GENETICS FOR SARCOMA
Dr. Joanne Ngeow is particularly interested in understanding the associations of sarcoma and heritable cancer syndromes, and the implication of genetic predisposition in sarcoma development. For instance, Li-Fraumeni syndrome, an autosomal dominant cancer susceptibility disorder associated with germline TP53-deficiency, is characterised by early-onset cancers, predominantly sarcoma. In a study of young sarcoma patients, 10% harboured germline mutations regardless of family history, as determined using nextgeneration sequencing, which implies an unexpectedly greater role for genetic predisposition in Asian sarcomas. Using wholegenome sequencing, Dr. Ngeow’s team also identified a novel germline deletion of the CDKN2A-CDKN2B locus in a patient with malignant peripheral nerve sheath tumour, and functionally demonstrated loss of CDKN2A-encoded tumour suppressor p14ARF in the sarcoma lesion pheno-copied TP53-deficiency, which is observed in Li-Fraumeni syndrome patients. Detection of cancer predisposition syndromes in sarcoma patients will not only enable optimisation of treatment strategies to reduce toxicity and facilitate interventional surveillance but also allow for genetic counselling and testing of family members at risk of cancer.

YOUNG INVESTIGATORS
Dr. Valerie Yang is currently a Senior Resident with the Department of Medical Oncology at the NCCS. She received
the National Science Scholarship from the Agency for Science, Technology and Research (A*STAR), Singapore, which granted her a full scholarship to read Medicine and a PhD in the UK. She graduated from the Royal Free and University College Medical School with Distinction in Preclinical Medicine, as well as First Class Honours for a Bachelor of Science (BSc) in Molecular Medicine. She was conferred the Cluff Memorial Prize and the Goldberg-Schachmann and Freda Becker Memorial Award, and joined the A*STAR Chairman’s Honours List for her Preclinical Medicine and BSc achievements. Dr. Yang then continued with Clinical Medicine at the University of Cambridge, where she was accepted into the prestigious MB/PhD Programme. Her PhD was supervised by Prof. Ronald Laskey, CBE, FRS, where she studied DNA replication, cell cycle regulation and embryonic stem cell pluripotency. Her PhD work won her the first prize in Cambridge University’s Graduate Research Symposium, a competition among all Life Science PhD candidates in the university. This work also led to several publications, as well as oral presentations, including the Cold Spring Harbour Laboratory Conference and the Sylvia Lawler Prize Meeting at the Royal Society of Medicine. She was also invited as a speaker to the Chromatin, Chromosomal Stability and Genome Maintenance Conference held in Copenhagen. She also held a teaching position in the Cambridge University School of Medicine as an Associate Clinical Supervisor. Upon her return to Singapore, Dr. Yang commenced life as a busy house officer, resident, then senior resident. She received postgraduate training in Internal Medicine and was accepted to the Membership of the Royal College of Physicians (MRCP), UK, before commencing specialty training in Medical Oncology at the NCCS. Throughout her postgraduate training in Singapore, she has taken on roles in teaching and mentoring as an invited lecturer to PhD students, as well as a Clinical Lecturer to medical students at the Yong Loo Lin School of Medicine. She was the Chairman of the Residents’ Research Subcommittee, National University Health System (NUHS), and was selected for the Academic Development Programme at NUHS. She was conferred the Nurturing Clinician-Scientists Scheme Award (NCSS) by SingHealth for her research work. Dr. Yang aspires to be a full-time clinician-scientist: formulating solutions beyond conventional chemotherapeutics with sound scientific translational research.

Assistant Professor Johnny Ong is currently an Associate Consultant in the Division of Surgical Oncology at the NCCS. He graduated from the Yong Loo Lin School of Medicine in 2004 and was conferred the Dean’s list award for the 2nd Professional MBBS exam. He undertook his clinical training as a junior doctor between 2005 and 2008. During this period, he was exposed to various disciplines of medicine, where he saw that more could be done beyond routine clinical care. This led to his decision to pursue post-graduate studies in translational research under the mentorship of Professor Rebecca Fitzgerald in Cambridge, UK. This was funded by the National Medical Research Council (NMRC), which granted him a full scholarship to pursue his PhD in the UK. His PhD work led to several publications in many high-impact factor journals, and his work has been presented in numerous international conferences, winning the best poster presentation at the British Society of Gastroenterology conference in 2013 and an overseas travel grant from the United European Gastroenterology Week in 2013. Socially, he was the captain of the Cambridge University volleyball team and led the team to promotion to Division 1. Upon the completion of his PhD training, Asst. Prof. Ong continued his training as a surgical trainee and became a fellow of the Royal College of Surgeons of Edinburgh in 2016. He was also conferred the Best Registrar Award in 2016 for his excellent work ethics and clinical dedication. During this time, he also laid the foundations for a career as a clinician-scientist by performing experiments in the Laboratory of Applied Human Genetics under the mentorship of Prof. Oi Lian Kon. His research work was recognised by the senior management and he was
awarded the Strategic Surgeon-Scientist Start-up (S4G) grant in 2013 and the SingHealth Young Researcher Award in 2016. The preliminary results he gathered from his experiments as a surgical registrar also allowed him to be successfully awarded the Transition Award from the NMRC in 2017. Academically, Asst. Prof. Ong is passionate about teaching the next generation of medical students and scientists. His dedication to teaching was recognised by the Yong Loo Lin School of Medicine and he was awarded the Dean’s Excellence Award for teaching and Special Recognition Award for being a role model for medical students in 2017. Asst. Prof. Ong’s aspiration is to solve oncological problems that the surgical blade fails to do.

Researchers:

​Dr. Jason CHAN​Dr. Claramae CHIA​Dr. Clarinda CHUA​Dr. Mohamad FARID
​Dr. Wen Long NEI​Dr. Joanne NGEOW​Assistant Prof Johnny ONG​Dr. Nagavalli D/O
SOMASUNDARAM
​Dr. Grace TAN​Adj Prof Melissa TEO​Dr. Valerie YANG