Issue No. 10 • MICA (P) 149/10/2009
AN NCCS BI-MONTHLY PUBLICATION May / June 2010
...HELPING R E A DERS TO ACHIEV E GOOD HE A LTH Salubris is a Latin word which means healthy, in good condition (body) and wholesome.
CATALYST FOR THE GOOD AND BAD
In Other Words
May / June 2010
In popular fiction, the typical plot often would portray heroes with unique abilities who can inflict a crippling blow to the antagonist. Wishfully, this thought may cross the mind if only the battle against cancer is this straightforward.
ndeed, working hard to make this wish come true is what Prof Kanaga Sabapathy is doing in his approach to advancing the treatment outcomes for cancer. The Principal Investigator from the Laboratory of Carcinogenesis at NCCS is studying the origins of cancer and how it develops by understanding the basic cellular mechanisms. He then introduces suitable ‘heroes’, or catalysts, to save the ailing cells. For the record, he has made inroads in his study on cancer-related proteins and how they have been responsible for promoting tumour cell growth. One of the main focus of his research is studying the master tumour suppressor protein p53, and its related form p73, to shed further light on their traits and how they can be modulated for better or for worst.
Essentially, p73 exists in two forms - TAp73 which has tumoursuppressing properties like the p53; and DNp73 which has oncogenic properties and promotes growth of cancer cells (opposite to TAp73), by inhibiting p53 and TAp73. “One could not hope for a better mentor than Prof Sabapathy. His enthusiasm and passion for research can be quite contagious...” Mr Iqbal Dullo
In his study which was documented ‘The anti-apoptotic Delta Np73 is degraded in a c-Jun-dependent manner upon genotoxic stress through the antizyme-mediated pathway’ in the Proceedings of the National Academy of Science of the United States of America (PNAS), Prof Sabapathy discovered that genotoxic insult such as exposure to chemotherapeutic drug doxorubicin, which stabilises and activates TAp73, is also able to reduce the levels of tumour-promoting DNp73 in cancer cells. Together with his team, they probed into how DNp73 levels are regulated under this scenario so as to better understand the mechanisms which can subsequently be utilised to modulate its expression in cancer cells.
In Other Words
May / June 2010
They discovered that c-Jun, a protein that is typically induced by a variety of stress signals was a key player. Further testing provided strong evidence that c-Jun was indeed capable of inducing the degradation of DNp73 via the non-classical polyamineantizyme pathway, an outcome that was needed to reduce the proliferation and survival of cancerous cells. These findings gave a new and unexpected insight into why cancers, which have high levels of DNp73, are resistant to some chemotherapy regimes. Prof Sabapathy explained that it all boils down to knowing the abilities of cancer cells. “We seek to understand why cancer cells behave the way they do, how they work in order to know how to deal with them. We can then work with our translational research counterparts to determine how to treat them, whether it is through drug development or other treatment forms.” Although the discovery brings plenty of hope for cancer patients and research, Prof Sabapathy explained that there is still more to be done. “We will now test for compounds which will inevitably kill cancer cells through the regulation of DNp73, whether they are toxic and bring harm to normal cells. The findings will be useful to identifying bases to develop drugs.” To ensure that no efforts are spared, the team will have a strenuous task of testing hundreds of compounds each time. Although the work may be likened to looking for a needle in a haystack, Prof Sabapathy believes that it adds to the value chain for patients. “Our work is important for pharmaceutical companies as it helps them in the development of new drugs,” he said.
As a sweetener to his work, research funds are ample, though they come at no small cost. Over the years, Prof Sabapathy has been constantly soliciting for research funds through publishing scientific papers and presenting notable research work. To date, he has published more than 50 papers and the influence that comes from them helps him to secure research grants. “When a scientist publishes a paper, recognition will come when the paper contains good information for the field. Our productivity also hinges on how many papers we have published and how impactful they are.” As part of his work at NCCS, Prof Sabapathy has been mentoring a team of PhD and Masters students who are also research officers, such as Mr Iqbal Dulloo who has been working on the DNp73 project. Commenting on the calibre of his mentees, he said that their stint at NCCS has put them in good stead. “It is about sharing my knowledge and experience and guiding them. Although the standard between the PhD and Masters Students vary somewhat, I believe they are equally capable. I am also confident that the PhD students will endure in the field, even if they work in the West.” Mr Dulloo has benefited much from Prof Sabapathy’s guidance. He said: “One could not hope for a better mentor than Prof Sabapathy. His enthusiasm and passion for research can be quite contagious. His guidance and openness to discussion had undoubtedly helped me get the most out of my years in the lab as well as my PhD study. The knowledge, training and scientific achievements that I have made under his mentorship are the perfect building blocks for a career in the ever-so competitive world of medical research.”
Prof Sabapathy works with a multinational team, which he considers “a challenging yet rewarding experience for the team as they also gain cultural insights which will be valuable when they work in the US or Europe.“ With so much on his plate, it is little wonder that the father of a teenage son values the little family time he gets. He interacts with his 14-year-old during morning drives to school, going for short walks together when time permits and annual vacations.
Hence, Prof Sabapathy has no regrets in taking this arduous and rugged route.
“I have not had second thoughts about what I have done so far. I love Science and knew that there is nothing else I would do apart from research.”
By Veronica Lee
May / June 2010
LOOKING AHEAD… Cancer Opens My Eyes to the Beauty Around Me
To be diagnosed with breast cancer at a young age is never easy to accept. It’s even more difficult when life until then has been plain sailing. Even so, when the news broke, like a bolt out of the blue, Ms Yvonne Boon accepted her fate bravely. She cast a positive look on the future, to survive.
t age 35, Yvonne had a life that every woman wished for, namely, a loving husband, career satisfaction and three intelligent, beautiful young children. She led a fulfilling life as an active volunteer in church and spend her weekends and evenings indulging in her favourite activities like doing sports and having meals with her family. When diagnosed with her illness, the obvious came to mind: the end of life was near. She remembered her sister who succumbed to breast cancer because she failed to receive treatment. But it was different for her. She could count on her immediate family to give her the support she needed. She had her husband and three children to live for. Before long, Yvonne came to terms with her condition. She decided not to let cancer take her life away. She told herself that she had to be strong. She went through a lumpectomy and eventually mastectomy, chemotherapy and hormonal therapy. These took more than a year to complete. “It is amazing to be alive!” she gushed. “When I was healthy in the past, I took so much for granted. I used to push myself to multi-task too much, not listening to my body when I was tired. I think I’m very blessed as I have support from my husband, family and friends and I was also well covered by insurance.” For Yvonne, survival began at the point of diagnosis. It was the time when cancer patients are forced to confront their own mortality and begin to make adjustments that will be part of their immediate and long term future. “My plight opened my eyes to more important things, like family and friends. Work and material things just don’t matter as much any more and I am no longer petty about small issues. I have also become more understanding and generous towards others. I am also making changes to my priorities. Being diagnosed with cancer gives me a chance to do things better the second time round.” There were times when doubts crossed her mind and coping with them got tough. The side effects of treatment took a toll on her. “There were times when it seemed hard to move on and I wanted to give up. But when I look at my children, they reaffirmed my will to fight on and live for them. Whenever I fall into negative mode, I remind myself to look at all the positive things such as my children and my faith.” The experience has made her see life with a different purpose. “Cancer does not simply end at remission. Life will change in unexpected ways. Some have made their lives more meaningful, while others and their loved ones have responded negatively. As for me, finding meaning is one way to understand my cancer experience. It made me realise the greater purpose behind my illness and what it means for me and my family.”
Part of her greater purpose was also to help others make sense of cancer. Yvonne explained, “The fear of death that permeates most people when they are diagnosed often leads me to think about what I will leave behind and what I would like to do with the time I have left. I want to make sure I do my best while I still have the strength. I want to teach my children to be independent, to be kind and loving towards one another. Most important, I want them to support one another should the day come when I am no longer around. I want to help as many as I can to make sense of their sickness, to embrace it and to live their lives as meaningful as possible.”
On how she has made sense of the sickness herself, Yvonne has a refreshing perspective:
“Cancer has been the most beautiful experience in my life. Initially there was a reason to survive, then a purpose in helping others. It has enriched my life and made me not take life for granted. I am a survivor and can now watch my children grow and help others learn to see the beauty of life.”
BISPHOSPHONATES IN ONCOLOGY: OLD DOGS, NEW TRICKS
The advances made in recent years in treating solid tumours like Breast, Lung and Prostate Cancer and other cancers like Multiple Myeloma have extended survival times significantly. However with this progress has come the added risk of skeletal related events (SREs) such as intractable bone pain requiring opiod analgesics or palliative radiation therapy, pathological fractures, spinal cord compression, hypercalcemia etc. Though Bisphosphonates were first synthesised in the 1860s and were being used in the fertilizer, textiles and oil industries and as descaling agents, it was only almost a 100 years later in 1968 that it was shown that they effectively inhibit osteoclast-mediated bone resorption. Since then they have been widely used in several conditions including Osteoporosis and cancer induced bone disease. Bone is a fertile soil for metastatic tumour growth. Under normal circumstances, bone homeostasis is achieved through balanced resorption and formation by osteoclasts and osteoblasts. Metastatic bone disease alters the normal bone remodelling process by causing osteolytic bone destruction and abnormal bone formation often with one process more dominant than the other. Although historically, bone metastasis from breast cancer and MM have been characterized as osteolytic and prostate cancer metastasis as osteoblastic, in reality both bone processes are present in many patients.
The observation that osteoclast activation is the central event in the pathogenesis of skeletal â€“ related events in cancer has led to the development of therapies targeted to block osteoclast development and function.
Bisphosphonates are analogues of pyrophosphate that have a high affinity for bone mineral. They preferentially bind to bone at sites of active metabolism and inhibit osteoclast activity and survival. Variable side chains determine the potency and side effect profile of each agent. These compounds can be grouped into two classes according to their chemical structure and molecular mechanism of action: The newer nitrogen containing second or third generation compounds including Alendronate, Ibandronate, Pamidronate, Risedronate and Zoledronic Acid; the older non Nitrogen containing first generation bisphosphonates such as Clodronate, Etridronate and Tiludronate.
Under The Microscope
May / June 2010
By Dr Manju Chandran, MD, FACP, FACE, FAMS
Consultant and Director Osteoporosis and Bone Metabolism Unit Department of Endocrinology Singapore General Hospital
USE OF BISPHOSPHONATES IN ESTABLISHED BONE METASTASIS IN VARIOUS CANCERS: Breast Cancer: Multiple Clinical trials have shown that bisphosphonates reduce the occurrence of skeletal complications in patients with breast cancer and bone metastasis. Treatment Guidelines from the American Society of Clinical Oncology (ASCO) as well as the National l Comprehensive Cancer Network (NCCN) recommend either IV Pamidronate (90mg) or IV Zoledronic Acid (4mg) every 3 to 4 weeks for patients with radiographic evidence of bone destruction.
Prostate Cancer: According to consensus guidelines from the NCCN, bisphosphonate therapy should be considered for all patients with Hormone Refractory Prostate Cancer. Several bisphosphonates have been evaluated in patients with hormone refractory prostate cancer and metastatic bone disease but only Zoledronic Acid has been shown to decrease SREs. Long term data from the PR05 (men with metastasis) and PR04 (men without metastasis) trials have however shed some encouraging light on the survival benefit offered by the use of oral clodronate â€“ a first generation bisphosphonate in hormone sensitive metastatic prostate cancer. Exploratory analyses of these trials in fact suggest greater relative benefit with prompt initiation of clodronate for men with poorer prognostic features such as raised alkaline phosphatise and creatinine.
Lung Cancer and other Solid Tumours: Consensus guidelines for the use of bisphosphonates for patients with lung cancer or other solid tumours other than breast or prostate cancer are not available. Zoledronic Acid 4 mg IV every 3 weeks for 21 months has been shown to significantly reduce the proportion of patients developing at least one SRE including hypercalcemia of malignancy and delay the onset of skeletal complications in patients with lung cancer (small cell and non small cell) and renal cell carcinoma. Ibandronate 6 mg IV administered every 4 weeks for 9 months in patients with metastatic bone disease from colorectal cancer has been shown to significantly reduce the proportion of patients who experienced SREs and to delay the time to the first SRE by at least 6 months. Continued on page C2.
Under The Microscope
May / June 2010
BISPHOSPHONATES IN ONCOLOGY: OLD DOGS, NEW TRICKS
Continued from page C1.
Multiple Myeloma: The longâ€“term efficacy and safety of bisphosphonate therapy for prevention of SREs in patients with advanced multiple myeloma and osteolytic lesions are well established. Recently released guidelines from ASCO recommend treatment with either Pamidronate 90 mg IV or Zoledronic Acid 4mg IV every 3-4 weeks for a period of 2 years for MM patients who have radiographic evidence of osteolytic bone destruction or spinal compression. Less frequent dosing (every 12 weeks) is being evaluated for IV Zoledronic Acid.
Duration of therapy: A consensus has not been reached regarding the appropriate duration of bisphosphonate therapy in skeletal disease associated with cancers. ASCO recommends the continuation of bisphosphonates in patients with breast cancer metastatic to bone until evidence of a progressive decline in performance status develops. In MM with osteolytic metastasis, two years of bisphosphonate therapy is recommended. After two years, treatment can be discontinued if the MM is responding to therapy or is stable.
Monitoring: Serum and urine bone turnover markers like N telopeptide of type 1 collagen (NTX) have been evaluated to see whether they can help identify patients likely to respond to bisphosphonate therapy. Urinary NTX normalization with pamidronate treatment has been linked to delays in bone disease progression and a trend towards fewer fractures. However there is a dearth of sufficient prospective trials regarding this and so currently the use of bone turnover markers to monitor bisphosphonate therapy in cancer is not recommended in routine clinical practice.
BISPHOSPHONATES AND THEIR ROLE IN PREVENTION OF CANCER TREATMENT INDUCED BONE LOSS: Breast Cancer Treatment Induced Bone Loss: Premenopausal women with breast cancer are at risk of accelerated bone loss due to premature ovarian failure and treatments such as chemotherapy and ovarian suppression based endocrine therapy such as with goserelin, tamoxifen and anastrozole. In post menopausal women with breast cancer, aromatase inhibitor therapy which is standard in the adjuvant treatment has been shown to precipitate significant bone loss and increase fracture incidence. The greatest experience in the prevention of aromatase inhibitor induced bone loss is with Zoledronic acid (ABCSG-12 study, Z-FAST, ZO-FAST and E-ZO-FAST studies). However there are also ongoing studies of aromatase inhibitors and oral bisphosphonates such as the SABRE study and the ARIBON study. These trials have demonstrated that bisphosphonates in doses used to treat Osteoporosis are also effective in the prevention of aromatase inhibitor-induced bone loss. Expert panel guidelines from Europe and the United Kingdom recommend that in post menopausal women with breast cancer treated with Aromatase inhibitors, bisphosphonate therapy is indicated if the T score falls below -2 or the rate of bone loss exceeds 4% per year in women with pre-existing osteopenia. Patients over the age of 75 years with one or more risk factors for Osteoporotic fracture should receive a bisphosphonate irrespective of BMD. In premenopausal patients receiving ovarian suppression plus an aromatase inhibitor, bisphosphonate therapy should commence if the T score is less than -1.
Prostate Cancer and Androgen Deprivation Therapy (ADT) induced bone loss: Bone loss is increasingly recognized as a common occurrence in men receiving androgen deprivation therapy for prostate cancer. Bisphosphonates in particular Zoledronic Acid have been shown to improve BMD at both the spine and the hip in men with PSA relapse of prostate cancer receiving therapy with a Gn-RH agonist given with or without an antiandrogen. Presently there is no consensus regarding guidelines for monitoring bone loss in patients treated with ADT. It would seem prudent to monitor patients with baseline evaluation of BMD before starting ADT and periodic follow up assessments at intervals. Men with Osteoporosis before starting ADT should be treated with a bisphosphonate. Intermittent Zoledronic Acid is a reasonable choice. Measurement of BMD should be repeated at 12 months to assess response to therapy.
Potential antitumor Efficacy of Bisphosphonates: There has been a wealth of exciting preclinical studies demonstrating a direct antitumor effect for bisphosphonates. Bisphosphoanates have been shown to induce tumour cell apoptosis and inhibit tumour cell adhesion, invasion, proliferation and angiogenesis. Of significant clinical interest, bisphosphonates may potentially enhance the antitumor activity of cytotoxic drugs. This use of bisphosphonates in the adjuvant setting may open up exciting clinical strategies whereby modifying the bone microenvironment may interrupt the disease course by delaying or preventing the development of bone metastasis and inhibiting the survival of dormant tumour cells that may subsequently metastasize to extra skeletal sites.
Under The Microscope
May / June 2010
Potential Side Effects:
Intensive treatment with potent Nitrogen containing bisphosphonates have been associated with the relatively new phenomenon of Bisphosphonate Associated Osteonecrosis of the Jaw (BRONJ) characterized by exposed bone in the maxillofacial region lasting more than 8 weeks. An ONJ frequency of 1% has been reported in breast cancer patients with metastatic bone disease receiving IV bisphosphonates with, higher cumulative dose, the use of more potent bisphosphonates, poor oral health and dental extractions being risk factors. Consensus guidelines still do not exist on the management of this relatively uncommon condition.
Lipton A. Treatment of bone metastasis and bone pain with bisphosphonates. Support Cancer Ther.2007;4(2):92-100
Kohno N et al. Zoledronic Acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastasis from breast Cancer: a randomized placebo-controlled trial. J Clin Oncol.2005:23(15):3314-3321
Hortobagyi GN et al. For the Protocol 19 Aredia Breast Cancer Study Group. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastasis. N Engl J Med. 1996;335 (24):1785-1791
Body JJ et al. Intravenous Ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastasis. Ann Oncol. 2005;14(9):1399-1405
Body JJ et al. Oral Ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from 2 randomised, placebocontrolled phase 111 studies. Br J Cancer. 2004; 90(6):1133-1137
Saad F et al. Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst.2004;96(11):879-882
Dearnaley DP et al. Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol. 2009; 10(9):872-876
Rosen LS et al. Zoledronic Acid versus placebo in the treatment of skeletal metastasis in patients with lung cancer and other solid tumours: a randomized, phase 111, double-blind, placebo-controlled trial. Cancer. 2004; 100(12):2613-2621
Heras P et al. Ibandronate is effective in preventing skeletal events in patients with bone metastasis from colorectal cancer. Eur J Cancer Care. 2007;16(6):539-542
Hilner BE et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol.2003;21(21):4042-4057
The NCCN Breast Cancer clinical Practice Guidelines in Oncology (version 2.2008). Available at: http://www.nccn.org
Gnant M et al. Adjuvant endocrine therapy plus Zoledronic Acid in premenopausal women with early stage breast cancer: 5-year follow-up of the ABCSG -12 bone mineral density sub study. Lancet Oncol. 2008;9:840-849
Smith MR et al. Zoledronic Acid increases bone mineral density in men undergoing androgen deprivation therapy for prostate cancer. 3rd North American Symposium on Skeletal complications of malignancy. April 25-27, 2002
Winter MC et al. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response-exploratory evidence for direct antitumor activity in breast cancer. Cancer Res 2009; 69(Suppl2):5101
CONCLUSION: Bisphosphonates significantly reduce skeletal related events in metastatic bone disease. In the prevention of cancer treatment induced bone loss, bisphosphonates are the treatment of choice. In the adjuvant setting, there may be a potential disease modifying role of bisphosphonates. Both preclinical and emerging clinical evidence suggest that bisphosphonates exhibit direct antitumor effects. Results from ongoing metastasis prevention adjuvant trials must be derived to fully determine the impact and role of bisphosphonates in the adjuvant setting.
May / June 2010
THE ESSENCE OF PALLIATIVE CARE
It is paradoxical that the name of this publication is Salubris, a word from Latin meaning health. Many people may question whether palliative care can help patients achieve good health. Does health imply the absence of disease or is health about vitality and well-being even when disease is present? I would argue that the goals of palliative care are consistent with promoting a sense of well-being. But this cannot be achieved just by prescribing treatment or medications that provide good symptom control. When faced with life-threatening illness, the patient and family are jolted into a new reality. There are different priorities. Relationships become very important. Questions arise about the meaning of life. There is loss of control. There is uncertainty about outcomes. Decisions must be made despite this uncertainty. Questions are asked. Am I going to get better? What can you do for me now? How long have I got?
By Dr Rosalie Shaw
Palliative Care Physician
The ways in which these questions are answered and the discussions that follow are critical. Hope and trust can be destroyed, not only by a harsh truthful answer, but also by evasion or false reassurances. We are often afraid of upsetting the person who has asked the questions and our body language can betray our discomfort. If we hesitate, look away briefly or shift our posture, the patient or their family member senses that we are not being honest and the conversation closes down. An opportunity for sharing information and feelings is then lost. On the other hand, a simple response given with kindness, allows the patient to voice fears and concerns. These are the moments when healing begins. The relationship changes and the patient becomes a person who is grappling to make meaning of his unique life journey. At this time our role as listener is not to offer solutions but to give full attention as the story unravels. It is only in the context of the patientâ€™s story that appropriate treatment decisions can be made. However, it is important to remember that our compassionate listening may be more important to well-being than the treatment we prescribe. It is often thought that working in palliative care must be depressing. We are asked how we can bear to see so much suffering. But we also see suffering lessen as patients forgive, express gratitude and say goodbye to family and friends. Being able to let go of the burden of grievances, responsibilities and possessions often brings a great sense of relief and an upwelling of joy. Patients do not wish to be labelled as dying. While there is breath there is still the precious gift of life to be lived as fully as possible. Communication is at the heart of palliative care. As one Vietnamese doctor said to me, â€œPlease teach me so I do not have to lie to my patientsâ€?. If we are able to put away our fear of talking about dying we do not need to lie to our patients. It is not often we will talk about death but it is our fear that inhibits the conversations that may lead to this topic. Patients do think about death. They fear pain or lack of control over bodily functions more than they fear death itself. It is often very reassuring to be given information about the process of death so that unrealistic fears are allayed.
We cannot be taught how to communicate effectively by reading books or attending lectures. The best way to learn is to be present when these conversations are taking place. Mentoring is one of the major responsibilities of the palliative care team. Trust and intimacy are built up over time during the many interactions that occur between staff and patients. Mentoring occurs when staff observe the physician or nurse demonstrating consistent and genuine interest in the patient as a unique human being. There are times when we close the curtain to create an intimate space that excludes others. However, it is important that, whenever possible and appropriate, junior members of staff are invited to be present. Conversations when the patient is sharing his story can be transformative. These are moments of magic when healing and health take on a new meaning and the sick person becomes more than just a failing body. Medicine has made remarkable advances over the past few decades and much can now be done to prolong life. It is easy to forget that death is still the inevitable outcome for us all.
LOOK FEAR IN THE FACE
May / June 2010
Eleanor Roosevelt, known famously for her involvement in human rights issues, once said: “You gain strength, courage, and confidence by every experience in which you really stop to look fear in the face. You are able to say to yourself, ‘I have lived through this horror. I can take the next thing that comes along.’... You must do the thing you think you cannot do.”
ndeed, cancer survivors must be applauded for having walked the long and arduous journey bravely. Family members and caregivers who have accompanied their love ones through cancer treatment would know that they did not have it easy.
So what happens after beating cancer into remission? “Physical, emotional, and financial hardships often persist for most of them years after diagnosis and treatment. They may also face challenges such as employment problems, psychological struggles and the strain on personal relationships and, not to mention, the fear of recurrence,” shared Dr Yap Swee Peng, acting Director for Public Education and Patient Support Unit of National Cancer Centre Singapore (NCCS). “Hence, family support and seeking timely professional help from counsellors, medical social workers, among others, are essential in helping patients get back on their feet.”
Despite the many challenges cancer survivors have to face, a majority of them live a fulfilling life and is a source of inspiration for those around them. One such brave individual is Mr Ezzy Wang, the epitome of survivorship. Despite losing his right lower limb to cancer, he endured in his exercise regime, which includes cycling 50km around Singapore. To honour all who have fought a hard battle with cancer, the NCCS will host a day of fun and adventure for more than 400 cancer survivors, including their families, friends and the healthcare providers at the Singapore Zoo on Saturday, 26th June 2010 from 8.30am to 1pm. The event not only serves as an opportunity for cancer survivors to meet and spur each other to live better but also to equip them with the knowledge of doing so. Participants can partake in an exciting Zoomanji Adventure or visit the carnival game stalls and snack booths when hunger strikes. Mr Wang will also be there to share some tips on challenging negative thoughts.
After all, surviving cancer boils down to three key elements - knowledge, hope and inspiration!
By Carol Ang
May / June 2010
NCCS ON TRACK IN ITS FOCUS ON CUTTING-EDGE CANCER RESEARCH
Singapore is laying a strong foundation for its cancer research programme with the growing number of doctors returning from overseas training stint to put their knowledge to good use by conducting research and conducting clinical trials. Veronica Lee reports.
s clinical trials are fundamental to cancer research, the expertise of these doctors may see more translational research that would contribute to the development of a strong cancer research base at the National Cancer Centre Singapore. Two doctors who recently returned to join the talent pool at the NCCS are Dr Daniel Tan and Dr Iain Tan, both of whom are Registrars from the Department of Medical Oncology. While at the UK’s Royal Marsden Hospital on a National Medical Research Council (NMRC) fellowship, Dr Daniel Tan was the primary fellow in charge of a trial that tested for the safety and toxicity of a novel agent used for the first time in human bodies. He supervised the administration of the trial and monitored a maiden group of patients in the UK receiving these drugs and coordinated multiple investigations that were indicators of intended efficacy. The trial was selected for oral presentation in the Developmental Therapeutics session at the recent American Society of Clinical Oncology (ASCO) annual meeting, and Dr Tan was conferred a Merit Award by ASCO for his efforts.
The trial was to determine a safe and tolerable dose of the new agent targeting the mTOR pathway – a promising therapeutic pathway in cancer, as well as find the best techniques of administering it to patients. The drug in question is an improved design compared to the mTORC1 inhibitors currently used in clinical practice. In these early studies, it is reassuring that some of the biomarker analyses suggest that the agent was hitting its intended target within the schedules explored. On what contributed to the success of the trial, Dr Daniel Tan said, “Phase 1 trials are typically challenging. They require tremendous coordination of clinical care, logistics and administration. I am thankful for the dedication of the trial team.” He also expressed gratitude to Professor Stan Kaye and Dr Johann De Bono from the Royal Marsden Hospital, both leaders in the field of drug development who have provided “invaluable guidance and mentorship.”
Traditionally, the attrition rate is high with many compounds from the drug development pipeline failing to make it past a Phase 1, 2 and 3 Trial. However, the odds are now improving with an increasing incorporation of biomarkers that determine the best way to use the drug. In the case of this trial, it exhibited encouraging results when the agent showed that it was hitting its intended target, with some patients actually responding well to the agent. Dr Daniel Tan attributed this to a paradigm shift in drug development. “As majority of modern drugs are created and modelled purposefully rather than through serendipitous findings, early phase trials are now expanding from dose titration safety studies to include more information that can provide potential insights to drug effect, resistance and even disease biology. We see an increasing number of patients reap benefits even at an early stage, as evidenced in recent Phase 1 trial findings on PARP and BRAF inhibitors published in the New England Journal of Medicine.” “The positive outcomes from such early trials certainly help in the development of specific novel therapeutics, and determine a suitable patient base. Most importantly, it will accelerate the approval of useful drugs so that patients can benefit’, Dr Tan added.
May / June 2010
It was also found that the two intrinsic subtypes of gastric cancers respond differently to drugs that are presently being used in the treatment of gastric cancer. They also displayed strikingly different patterns of genetic aberrations that provided a reason for further development of subtype-specific targeted therapies. The findings were recently presented at the American Association of Cancer Research annual meeting, where he was awarded the meritorious scholarin-training award. Dr Iain Tan (far left) and Dr Daniel Tan (left).
Many patients with advanced stage cancer at diagnosis had predominantly been the targeted group for trials. These patients are ideal candidates for clinical trial as they are usually at the end of their journey for a cure. One such group is patients suffering from gastric cancer. Gastric Cancer is the second leading cause of global cancer mortality and is particularly common in Asia. It is a difficult cancer to treat as symptoms appear late. At diagnosis, many patients already have stage four cancer for which surgery is no longer possible. Among patients who do undergo surgery upon early detection, the disease can recur. There are several effective palliative treatment options available and whilst these are unable to completely eradicate the disease, they can control the cancer, prolong survival and most importantly, provide much needed symptom relief for patients. Patients can however experience varied responses to the available treatment regimens. Hence, choosing the right regimen for each patient is important because achieving initial control of the cancer leads to an improved clinical outcome and many patients will be unfit for subsequent attempts at treatment if their cancer degenerates early.
The lack of reliable tests to select the most appropriate treatment regimen for individual patients has been the impetus behind Dr Iain Tan’s research into understanding the biology of gastric cancer. Working under the supervision of his clinical Head of Department, Dr Toh Han Chong and his scientific supervisor, A/P Patrick Tan from Duke-NUS Graduate Medical School, Dr Iain Tan studied more than 400 cancer samples derived from patients in four countries. The study revealed that whilst there was indeed substantial molecular complexity and heterogeneity at a fundamental level, each gastric cancer conformed to one of two major molecular patterns which the team termed as ‘intrinsic signatures’.
After demonstrating effectiveness in predicting treatment responses in the controlled laboratory environment, the next step was to evaluate if it could be translated to the clinic. Dr Iain Tan then developed a research proposal to leverage upon cutting edge genomic tools to correlate tumor genetic profiles with patient treatment outcomes so as to rapidly and efficiently obtain a timely answer to his scientific enquiry. For conceiving this cutting-edge approach with the potential of providing direct benefit to patients, Dr Iain Tan received the ASCO Young Investigator Award and was the only recipient from an institution outside of North America to receive the award. Predicting good outcomes with specific chemotherapeutics had been the driving force to Dr Iain Tan’s research. With an aim to be a physician scientist in gastrointestinal cancer, the field will be given a boost and will definitely become one of the major pillars of clinical expertise at NCCS.
The achievements of NCCS oncologists, winning worldwide recognition for their work, is another step in the right direction for NCCS to achieve its mission to become the leading global cancer centre.
ARE YOU HAPPY?
May / June 2010
If there is such a thing as the secret to happiness, it is this: Happiness comes from within.
ast year, Singapore was placed in an unremarkable 49th out of 140 countries in The Happy Planet Index. As a materially wealthy nation, the results unleashed much soul-searching about the way Singaporeans truly view life and happiness. The common connotation is that the stresses of living in a society that focused on materialism have made Singaporeans less happy than their peers in many other countries. Concerned with the rising levels of stress in Singapore, Philip Merry - founder of the Philip Merry Consulting Group, organised the 1st Asian Happiness and Well-Being Conference that led the search for Singapore’s happiest person last year in 2009. “If you have people who love you, good health, food on the table and a stable job, you are already happier than nine in 10 people on earth,” he said. “Essentially, happiness comes from having meaning (contributing to something outside of yourself), authenticity (being your true self) and connection (having friends and family) in our life.” Philip is currently planning the 2nd Happiness Conference, this time focusing on Resilience & Courage. This year’s theme is linked to the economic downturn and centred on how resilience skills can help people thrive in difficult times. National Cancer Centre Singapore (NCCS) is the healthcare partner for this year’s conference.
Editorial Advisors Dr Kon Oi Lian Prof Soo Khee Chee Executive Editors Ms Carol Ang Ms Veronica Lee Mr Sunny Wee
Resilience is the positive behaviour we show when facing adversity that allows us to bounce back, and courage is our ability to confront our fears and problems. When things go wrong – such as the loss of health, relationships, jobs, savings or hope in a better future, resilience can be another opportunity for learning effective coping strategies. When asked for the reason behind NCCS partnering this meaningful conference, Eugene Sng, Programme Director of NCC Foundation, NCCS shared: “Cancer patients and caregivers face difficulties with resilience every day. NCCS is happy to be the healthcare partner of Resilience & Courage as we believe resilience skills will add a huge value to the lives of our patients, caregivers and staff.”
Contributing Editor Dr Wong Nan Soon
Medical Editor Dr Richard Yeo
Members, Editorial Board Ms Audrey-Anne Oei Ms Sharon Leow Ms Flora Yong
Members, Medical Editorial Board Ms Lita Chew Dr Mohd Farid Dr Melissa Teo Dr Teo Tze Hern Dr Deborah Watkinson
In enabling our healthcare practitioners to benefit from this talk, two lunch seminars were held at Singhealth, where Philip shared his secrets to building resilience in life and at work. Resilience & Courage is a community outreach effort that will help bring out the true meaning of resilience, and help people recognise that resilience is already within us. A search for Singapore’s resilient heroes will also be conducted later this year.
As Philip says, “If this conference can make just one person’s life better and happier, we will be happy,”
For more information about Resilience & Courage, please visit www.simply-happy.com
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