O&G Newsletter Apr - Jun

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MICA (P) 082/06/2010 A Quarterly CME Apr - Jun 2010

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Screening For Ovarian Cancer – To Do Or Not To Do? Chemotherapy For Newly Diagnosed Ovarian Cancer

How Does Palliative Care Get Involved With Ovarian Cancer?

Hereditary Ovarian Cancers – Fast Facts The Pathophysiology and Staging of Ovarian Cancer Influenza A (H1N1) In Children – The Pandemic That Flu In Editorial Note Ovarian cancer remains difficult to treat, simply because a vast majority of patients present late and the response to treatment poor. It has the highest fatality-to-case ratio of all gynaecological cancers.

The need for early detection is clear. Survival statistics for early stage ovarian cancers are encouraging. Unfortunately there has not been a cost effective method for screening of ovarian cancers till date. Awareness of the condition and its symptomatlogy would go a long way in helping to reduce the incidence of advanced stage disease.

Women who have symptoms of bloatedness, indigestion, feeling full quickly and pelvic and abdominal pain that persist for a few weeks should see their doctors. The ovarian cancer awareness month will present an opportunity for more public education and better understanding of this dreaded disease by the public.

A/Prof Ho Tew Hong Senior Consultant Chief of Gynae Oncology Section Dept of Obstetrics & Gynaecology

DEPARTMENT OF OBSTETRICS & GYNAECOLOGY Tel: 6321 4667 / 6321 4668 / 6321 4651 & 6321 4675 Fax: 6225 3464 Obstetric Co-ordinator: 6326 5923 Endocrine / Climateric Co-ordinator: 6321 4330 Urogynaecology Co-ordinator: 6326 5929 Oncology Co-ordinator: 6436 8106

Appointment: 6321 4377 Centre for Assisted Reproduction (CARE): 6321 4292 Early Pregnancy Unit (EPU) Hotline: 6321 4516 Prenatal Diagnostic Centre (PDC): 6321 4516 http://www.sgh.com.sg

SCREENING FOR OVARIAN CANCER – Ovarian cancer is known to have an insidious onset, often presenting late when there is gross enlargement of the abdomen from the mass, ascites or symptoms from metastatic disease, such as pleural effusion. These often alert the woman to seek medical consultation. With the breakthrough of vaccination for cervical cancer prevention, the availability of mammograms for breast cancer and Papanicolau smear for cervical cancer, there is increased pressure to develop a screening strategy for this “silent killer”. This disease satisfies some criteria for disease screening proposed by the World Health Organisation – it is a major cause of death amongst gynaecologic cancers, early stage disease has a better prognosis and effective treatment (surgery) is available for early disease. However, there are certain points against screening for this disease. Firstly, the natural history of disease is unclear – whether cancer develops from pre-existing conditions such as endometriosis or benign ovarian cysts; whether it evolves from early stage to advanced stage or it arises as an advanced disease in the first place. Secondly, the screening tests do not have a high positive predictive value. High specificity is vital in screening strategies for ovarian cancer because a positive test result generally requires definitive surgical assessment. These factors make screening not cost-effective, and may even increase morbidity from surgical interventions for benign asymptomatic conditions. Current screening methods include pelvic examination, CA 125 levels, ultrasound pelvis, or a combination of modalities.

Pelvic Examination Very limited data exist on the usefulness of the bimanual pelvic examination.

Sensitivity of pelvic examination for detection of ovarian cancer is unknown; however, it is thought to be low due to the anatomic location of the ovary.

Cancers detected by pelvic examination are often advanced. There are many benign and non gynaecological causes of adnexal masses. It has been calculated that 10,000 routine pelvic examinations would be required to detect one early ovarian cancer in a population of asymptomatic patients.

CA 125 Levels CA 125 was first described by Bast et al in 1981 as an antigenic determinant on a high-molecular-weight glycoprotein recognized by the murine monoclonal antibody OC-125. It is the most thoroughly assessed serum biomarker for ovarian cancer. CA 125 level of 35 U/mL, representing the upper 1% of female healthy donors, is often accepted as the upper limit of normal in clinical practice. The use of CA 125 for screening however, is limited by its poor sensitivity in early stage disease; with CA 125 levels elevated in only 50% of patients with stage I disease, whereas levels are elevated in over 90% of patients with advanced disease.

The marker can also be elevated in other conditions, including other malignancies, medical conditions such as ascites, gastrointestinal disorders, liver disease and benign and physiological states, including pregnancy, endometriosis and menstruation, thereby limiting its specificity. The diagnostic accuracy of elevated CA 125 is higher in the post-menopausal group due to increased risk of disease with age as well as the reduced incidence of confounding conditions, such as fibroids and endometriosis.

Ultrasound of the Pelvis Routine ultrasound screening of asymptomatic women generates a high proportion of false-positive results, which often require laparoscopy or laparotomy to exclude malignancy. One study of 805 high-risk women yielded 39 laparotomies, 1 ovarian cancer, and 8 other tumors (2 borderline tumors, 1 caecal cancer, 5 cystadenomas). Another large study of 5,479 asymptomatic self-referred women reported the detection of 5 cancers in 14,594 transabdominal ultrasound screens performed over 3 years. Positively screened women (grossly abnormal ovaries or non-regressing masses) were referred for surgery. There were 338 positive screens. The positive predictive value for transabdominal ultrasound was 1.5%. Transvaginal ultrasound (TVUS) with Doppler studies may increase the sensitivity of this screening modality. In the largest study to date, annual TVUS screening was performed

CHEMOTHERAPY FOR NEWLY DIAGNOSED Ovarian cancer is the fourth highest-ranking cancer among women in Singapore and the leading cause of death from gynaecologic cancers.

Because of the non-specific nature of presentation, approximately 70% of these patients are diagnosed in the advanced stages (stages III or IV).

Despite its advanced presentation, surgery is the mainstay of treatment for ovarian cancer, in combination with platinum-based chemotherapy.

Aggressive surgical debulking for optimal cytoreduction has been shown to be a strong prognostic factor in advanced disease. Women with early stage ovarian cancer have excellent survival, with more than 85% living beyond 5 years. Surgical resection by a trained gynaecologistoncologist offers the best chance at optimal cytoreduction, and achieves comprehensive surgical staging to rule out occult advanced disease.

Systemic chemotherapy after surgery is indicated in patients with a high risk of relapse after primary surgical treatment.

Chemotherapy for Early-Stage Disease The benefit of adjuvant chemotherapy was demonstrated in 2 large trials, the Adjuvant Chemotherapy In Ovarian Neoplasms (ACTION) and International Collaborative Ovarian Neoplasm (ICON 1). When all the patients in both trials were combined, a significant improvement in 5-year overall survival (OS) from 74% in the observation arm to 82% in the chemotherapy arm was found. This was also true for recurrence-free

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survival. The National Comprehensive Cancer Network (NCCN) practice guidelines now recommend adjuvant chemotherapy for all patients with a clear cell carcinoma histology, poorly differentiated (Grade 3) or stage IC ovarian cancer. More recently, the Gynecologic Oncology Group (GOG) investigated if 3 or 6 cycles of carboplatin and paclitaxel was better in patients with grade 3 or stages IC and II ovarian cancer. Results revealed that the risk of recurrence was not significantly different in patients receiving 3 or 6 cycles of chemotherapy, although there was a trend towards a lower relapse rate in those receiving 6 cycles. It is thus concluded that the decision to give 3 or 6 cycles of chemotherapy is based on toxicity and the patient’s co-morbidities and tolerance.

Chemotherapy for Advanced-Stage Disease The availability of platinum in the early 1990s and subsequently taxane chemotherapy vastly improved outcomes in patients with advanced ovarian cancer. GOG 111 investigated the combination of paclitaxel and cisplatin chemotherapy as upfront treatment for patients with advanced ovarian cancer following suboptimal debulking. This regimen demonstrated significant improvement in overall response, progression-free survival (PFS) and median OS (38 months vs 24 months) over the then standard-of-care treatment of cyclophosphamide and cisplatin.

In view of concerns over the toxicity of cisplatin, GOG 158 studied, in a non-inferiority trial of patients with stage III

Dr Cindy Pang Associate Consultant Dept of Obstetrics & Gynaecology

TO DO OR NOT TO DO? on 25,327 women over a period of 9 years. The patients were asymptomatic aged above 50 or had a family history of ovarian cancer aged above 25 years old. 364 (1.4%) patients had surgical interventions for suspicious findings on ultrasound, with 35 invasive ovarian cancers and 28 patients having stage 1 disease. There were also 9 tumours of low malignant potential and 7 metastatic tumors detected. 9 patients had false negative results – developing cancer within 12 months of a negative screen. The positive predictive value of transvaginal scan in this series is 14.01%. The low positive predictive value of ultrasound is due to the commonality of benign pelvic lesions, even in postmenopausal women.

Multimodality Screening Combined CA 125 and TVUS tests have been used to increase the specificity of screening, by reducing false positives. Jacobs et al in 1999 randomized 22,000 postmenopausal women to be screened with 3 annual CA-125 measurements or to no screening. The positive predictive value was 20.7%. Repeat Ca125 measurements over time (longitudinal screening) appear to improve the estimation of the risk of ovarian cancer. Biostatistician Steven Skates developed the Risk of Ovarian Cancer (ROC) algorithm that incorporates serial measurements of CA 125 in the individual and validated it with a retrospective analysis of another large screening trial performed in London. A follow-up pilot prospective study of nearly 14,000 women, half screened and half not, produced sufficiently compelling data to launch the more definitive U.K. Collaborative Trial of Ovarian Cancer Screening, a randomized trial now underway, as discussed below.

Current Trials on Ovarian Cancer Screening: The UK Collaborative Trial of Ovarian Cancer Screening is a prospective randomised controlled trial which involves 202,638 postmenopausal women aged 50 to 74, randomized to annual screening using serum CA 125 using the ROC algorithm with transvaginal ultrasound (TVUS) as a second-line test, TVUS alone or no screening.

OVARIAN CANCER optimally debulked ovarian cancer, the substitution of cisplatin with the less toxic analogue, carboplatin. Results showed that the paclitaxel/carboplatin regimen was equivalent to paclitaxel/cisplatin with regards to PFS and overall survival, but with significantly less nephrotoxicity and emetogenic effects. This established the combination of paclitaxel and carboplatin as the new standard of care. Attempts to further improve outcomes of patients with advanced ovarian cancer include a recent randomized, phase III study of stages II to IV ovarian cancer by the Japanese Gynaecologic Oncology Group (JGOG).

The dose-dense weekly regimen of paclitaxel and carboplatin significantly improved 3-year OS and median PFS over the standard therapy given every 3 weeks, but at the expense of increased neutropenia and anaemia. Almost twice the number of patients in the dose-dense arm discontinued treatment due to toxicity compared to the control arm. Patients who are not surgical candidates at the time of presentation or in whom optimal cytoreduction cannot be achieved, neoadjuvant chemotherapy may be considered. In a recent EORTC-GCG/NCIC-CTG study presented in 2008 by Vergote et al, overall survival was equivalent in patients receiving neoadjuvant chemotherapy but with fewer complications.

Intraperitoneal Chemotherapy Ovarian cancer is a disease of the peritoneal cavity, with the bulk of disease typically found on the peritoneal surface and a unique pattern of spread

Results from the prevalence (initial) screen have been published. The sensitivity, specificity and positive predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8% and 43.3% for ROC screening, and 84.9%, 98.2% and 5.3% for USS, respectively. The results of ongoing screening are required before the effect of screening on mortality can be determined. Final results from this study will only be available in 2014.

The NIH Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) Study is a prospective, randomised controlled trial investigating ovarian cancer screening in over 78,237 women in USA. The participants were randomised to control (no screening) or to CA 125 and TVUS. Women with abnormal results (CA 125 >/= 35U/ml or abnormal TVUS) will be referred to a gynaecological oncologist for further management.

Preliminary data have been reported based on initial screening results in the group that received screening (n=28,816 women who received at least one test). The positive predictive value for invasive cancer was 3.7% for an abnormal CA 125, 1.0% for an abnormal TVS, and 23.5% if both tests were abnormal.

Results from four rounds of screening have very recently been published. The overall ratio of surgeries to screen detected cancers was 19.5:1 with 72% of the screen detected cancers, unfortunately, being stage 3 and above. Full results from the trial are not expected until after 2010.

Conclusion Ovarian cancer is a lethal disease. The options of using CA 125, ultrasound screening or a combination of both is an attractive concept when faced with an anxious patient worried regarding her risks of ovarian cancer.

However, review of the evidence suggests caution in adopting a screening strategy with the current available tests. None of the studies have shown a decrease in mortality from screening and may even prove to be harmful by increasing investigations, anxiety and unnecessary surgical interventions for asymptomatic patients.

Dr Lynette Ngo Associate Consultant Dept of Medical Oncology National Cancer Centre Singapore within the peritoneal cavity. Dedrick et al first proposed an approach to expose tumour to high concentrations of drugs without systemic toxicity by intraperitoneal (IP) administration of chemotherapy. However, it was not until GOG 172 that IP therapy demonstrated significant improvements in both PFS and OS. In this randomized phase III study, Armstrong et al reported a 16-month improvement in median OS for the IP arm, the longest median survival advantage ever reported in optimally debulked stage III patients to date. However, toxicity of IP therapy was a major problem, with only 42% of patients completing the planned course of treatment.

IP port-related complications included infections, malfunction and bowel perforations. The choice between upfront intravenous or intraperitoneal chemotherapy remains controversial. Careful patient selection is essential and the decision to give IP therapy should be guided by toxicity concerns.

Patients with poor performance status, co-morbidities, advanced age or previous bowel surgery are not ideal candidates for IP chemotherapy.

Conclusion Ovarian cancer is a disease best managed by a multi-disciplinary team with a combination of surgery and chemotherapy. We look forward to future studies incorporating molecular therapeutic agents and new surgical techniques such as laparoscopy in further improving survival and reducing treatment-related morbidity in patients with ovarian cancer.

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HOW DOES PALLIATIVE CARE GET INVOLVED WITH OVARIAN CANCER? Carol is a 46 year old lady who runs a small business and is married with teenage children. She presents with stage III ovarian disease with widespread peritoneal metastases and ascites. A decision is taken for primary chemotherapy since surgery is deemed to be high risk. She has symptoms of subacute bowel obstruction. The palliative care team is asked to help manage these medically whilst she receives the first few cycles of chemotherapy. The chemotherapy is very successful and after 3 months the peritoneal disease is considerably reduced and many of her symptoms have settled. She goes on to have surgery. The palliative care team stop active follow up.

Unfortunately, 9 months the later the disease returns and despite several lines of chemotherapy the disease progresses rapidly. Carol develops recurrent ascites, peripheral oedema and bowel obstruction. She wishes to die at home, close to her family. She is re-referred to the palliative care team.

Palliative care most often gets involved with patients who have stage 3 and 4 ovarian cancer. As with Carol, patients often present late in the course of the illness when the disease has spread throughout the peritoneal cavity.

This causes many symptoms but sometimes, as in her case, symptoms of sub-acute intestinal obstruction predominate. Where the palliative care team is part of the multidisciplinary team, it can help to manage these symptoms medically (see later) even whilst the patient is undergoing chemotherapy that may have a high chance of inducing remission. It can also offer support to the patient and family. If and when the patient goes into remission the symptoms often settle. Palliative care can then stop follow up until disease recurrence occurs.

Recurrent ovarian cancer will have a much lesser chance of responding to chemotherapy but various lines are often given with diminishing success with the intent to reduce symptoms and prolong life. During this period patients like Carol will often have a cluster of symptoms that can benefit from palliative care input.

There is, in fact, a paucity of literature on symptom and end of life issues in ovarian cancer and gynaecologic cancers generally, despite the fact that such patients are often very symptomatic and also have considerable psychosocial issues.

One of the few studies specifically looking at symptoms in advanced ovarian cancer was published in 2007.

The most common complications in the last six months of life were pain (85%), fatigue or weakness (75%), nausea or vomiting (71%), constipation (49%), peripheral oedema (44%), ascites (28%), bowel obstruction (12%) and pleural effusion (10%).

There were some limitations of this study especially in the way data was collected and classified. The figure for bowel obstruction is low since it usually occurs in 5-35% of patients with advanced ovarian cancer. Nevertheless, the study gives an idea of the kind of problems faced by these women. The symptoms are consistent with those from any advanced cancer but some are more specific to ovarian cancer.

Ovarian cancer tends to spread regionally in the form of scattered deposits of tumour on all surfaces of the peritoneal cavity. Morbidity and mortality as a direct result of this process are much more common than symptoms related to recurrence at the tumour site or from distant extra-abdominal sites.

Bowel obstruction often results from small volume peritoneal deposits either causing a functional obstruction due to impaired and chaotic peristalsis or mechanical obstruction from tumour deposits compressing or surrounding the bowel. The patient may describe early satiety initially but later this can progress. Obstruction can occur throughout the bowel. Sometimes large bowel obstruction will be at a single site allowing the simple formation of a 4

defunctioning stoma. More often there will be multiple levels of obstruction, especially when the small bowel is involved, and surgery is either unwise or impossible as the bowel cannot be mobilised and/or the obstruction would necessitate too high a stoma formation. If the usual conservative measures to “rest� the bowel fail, palliative medicine teams may be asked to be involved to manage the symptoms. For functional bowel obstruction a combination of analgesia and prokinetic agents given either intravenously or subcutaneously will help. For a more severe obstruction with colic, it is necessary to consider a combination of parenteral drugs including opioid analgesics, anticholinergics, antiemetics, sometimes octreotide (for large volume vomiting) and a trial of steroid medication. If large volume vomiting from high GI obstruction persists a venting NG or gastrostomy may be helpful. Occasionally the pain from bowel obstruction can be extremely severe and require rapid titration of analgesics and specialist drugs.

Deciding which patients should be considered for surgery to relieve obstruction is a challenge. This should ideally be decided in the context of a multidisciplinary team involving the surgeons, medical oncologists and palliative medicine specialists. Various features will guide the decision including the site(s) of obstruction, the presence of ascites and large omental deposits, the time since last chemotherapy as well as the current functional status of the patient.

Issues around nutrition can often be problematic. Patients with malignant bowel obstruction might be able to take very small amounts of food but the patient and relatives may worry about whether this is adequate and it will need careful handling to decide on the best action to be taken. There is very little evidence that TPN administered to a patient with advanced cancer will give any benefit in terms of survival or quality of life unless they are about to undergo surgery, intensive chemotherapy or radiotherapy. However, individual decision making is important and cost must be factored in to this.

The issue of adequate hydration, especially for patients being cared for at home is sometimes more tricky but can often be managed by delivering subcutaneous hydration.

Ascites is a common complication of ovarian cancer due to widespread peritoneal deposits. It can cause discomfort, pain, early satiety and breathlessness, as well as be disfiguring. The optimal management of this type of malignant ascites is poorly researched but it does not usually respond well to diuretics. It is better to drain the fluid either in single sittings or by placing a drain in situ and allowing intermittent drainage. Unlike cirrhotic ascites, it is often possible to drain quite high volumes without problems of hypotension and fluid shifts and without using albumin. Implanted drains left in situ may carry less risk of infection than non-implanted ones.

Peripheral oedema and lymphoedema in these patients is quite common secondary to lymphatic disease, extensive disease in the pelvic and peritoneal

Dr Deborah Watkinson Consultant in Palliative Medicine National Cancer Centre Singapore

cavity and ascites. Management may include diuretics, compression bandaging and specialist massage.

Ureteric obstruction from pelvic disease can also develop and also needs a careful assessment to decide on the best course of action depending on the patients overall condition and the disease progression. Treatment will involve either internal ureteric stenting or percutaneous drainage.

Clearly psychosocial issues may present in this group of patients. Carol is a relatively young woman with a husband and dependent children who will also have support needs. The help of a Medical Social Worker as well as the palliative care team can be invaluable.

Many of these patients will wish to be cared for at home. Even with bowel obstruction, it is usually possible to find a suitable combination of drugs that can be delivered by a small syringe driver subcutaneously. Home care palliative care teams can help to maintain and adjust the medications and offer support to the family to allow a comfortable home death.

So – how can palliative care help? The palliative care team is happy to work alongside the gynaecologists, medical oncologists and GPs, offering symptom control advice at any stage of the disease, as appropriate and necessary.

Patients can be supported as inpatients, seen in clinic or followed up at home with the hope of providing an integrated, seamless service throughout the course of the illness.

HEREDITARY OVARIAN CANCERS – FAST FACTS

Dr Elisa Koh Registrar Dept of Obstetrics & Gynaecology

➢ The majority of ovarian cancers are sporadic, with only 10% of cases being inherited. ➢ The average lifetime risk of developing ovarian cancer is 1 in 70. If a woman’s first degree relatives develop ovarian cancer, her risk of developing ovarian cancer is about 3 times as high as an average woman’s risk. ➢ In hereditary ovarian cancers, genetic mutations are carried by an individual resulting in a greatly increased risk of developing ovarian cancer and the possibility of transmitting this mutation to offspring.

Some common hereditary cancer syndromes associated with an increased risk of ovarian cancer include :

• Li-Fraumeni Syndrome.

• Ataxia-telengiectasia.

1) Hereditary Breast and Ovarian Cancer Syndrome (HBOC) • The genes affected are the tumour suppressor genes known as BRCA1 and BRCA2 genes.

• BRCA1 and BRCA 2 stand for breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2 respectively.

• The lifetime risk of developing ovarian cancer in those with a BRCA mutation in the general population is about 15-40%.

• Women carrying such gene mutations have an increased risk of developing breast and/or ovarian cancer before menopause, and often have a strong family history of these diseases.

It is more common in certain populations such as the Ashkenazi Jews, Dutch, Norwegian and Icelandic peoples.

Screening Criteria

2) Hereditary Non-Polyposis Colorectal Cancer (HNPCC) • HNPCC is commonly associated with a greatly increased risk of colorectal cancer of up to 80% and are at an increased risk for developing stomach and small bowel cancer, and also breast cancer.

• Women with HNPCC have a 9-12% risk of developing ovarian cancer.

The risk of uterine cancer is even higher, at 20-50%.

3) Peutz-Jeghers Syndrome • Features of this syndrome include the presence of multiple hamartomatous polyps in the gastro-intestinal tract which predisposes to colorectal cancer, as well as hyperpigmented spots on the face and hands.

• Women with this syndrome have a 20% risk of developing ovarian cancer.

• There is also an increased risk of developing breast, lung and uterine cancers.

Other rarer cancer syndromes resulting in an increased ovarian cancer risk : • Nevoid basal cell carcinoma syndrome (NBCCS), which predisposes to the development of fibrosarcoma of the ovary.

Currently there are no standard criteria for screening for ovarian cancers.

However, the risk of having a genetic mutation or cancer syndrome is increased in the following groups : ➢ Two first-degree relatives (mother, daughter, or sister) diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger ; ➢ Three or more first-degree or second-degree (grandmother or aunt) relatives diagnosed with breast cancer regardless of their age at diagnosis; ➢ A combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person) ; ➢ A first-degree relative with cancer diagnosed in both breasts (bilateral breast cancer) ; ➢ A combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis ; ➢ A first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis ; and ➢ Breast cancer diagnosed in a male relative.

Implications of Screening for Genetic Mutations • Pros and cons of screening for a genetic mutation such as BRCA must be discussed with the patient as test results can also affect personal choices, such as marriage and childbearing.

• There are also ethical issues surrounding the privacy and confidentiality of genetic test results, especially in the context of employment or insurance coverage.

• The risk of a false negative result must also be explained.

• For those who test positive for a genetic mutation, treatment options include prophylactic surgery, chemoprevention, and close surveillance. However, these measures have not been conclusively proven to detect early disease or improve survival rates for those who develop ovarian cancer.

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The Pathophysiology and Staging of Ovarian Cancer Ovarian cancer ranks as the fifth commonest cancer among Singaporean women, and the second commonest female genital tract cancer. As these ovarian tumours cannot be detected early in their development, they account for a disproportionate number of fatal cancers, being responsible for almost half of the deaths from cancer of the female genital tract. There are numerous types of ovarian tumours, both benign and malignant. About 80% are benign, and these occur mostly in young women between the ages of 20 and 45 years. The malignant tumors are more common in older women between the ages of 40 and 65 years.

Of the different types of ovarian cancers, epithelial ovarian cancer is the most common (80-90%), originating in the cells that cover the surface of the ovary, which are known as epithelial cells. Other rarer kinds of ovarian cancer include germ cell tumours, which generally occur in younger women and arise in the egg-producing cells of the ovary, and sex-cord and stromal cell tumors, which develop in hormone producing cells and cells which provide the support framework of the ovary.

Although it is not known exactly what causes ovarian cancer, certain traits make some women more susceptible than others to develop epithelial ovarian cancer. Each trait varies in significance for the individual.

The following risk factors may increase a woman’s risk of developing ovarian cancer :

Figure 1. Normal anatomy of the female genital tract, showing two ovaries on either side of the uterus

➢ Inherited genetic mutations, including mutations in the BRCA1, BRCA2, MLH1, MSH2, or MSH6 genes. The lifetime ovarian cancer risk for BRCA1 mutation carriers is 35 to 60%, and the risk for BRCA2 mutation carriers is between 10 to 27%. The Heriditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome (MLH1, MSH2 or MSH6 mutations) is associated with a 9 to 12% increased lifetime risk of ovarian cancer, and also a 40 to 60% lifetime risk of both uterine and colon cancer. ➢ A first degree relative (mother, sister, or daughter) with ovarian cancer, whereby the risk of developing cancer is 5 percent. ➢ A personal history of breast cancer prior to age 40. ➢ A personal history of breast cancer prior to age 50, and one or more close relatives with breast or ovarian cancer at any age. ➢ Two or more close relatives with breast cancer prior to age 50 or with ovarian cancer diagnosed at any age.

Lesser risk factors include any of the following : ➢ A history of infertility and/or use of assisted reproductive therapies, such as in vitro fertilization (IVF). ➢ A history of endometriosis (a condition in which tissue from the lining of the uterus grows outside of the uterus). ➢ A history of hormone replacement use for the management of symptoms related to menopause. ➢ A personal history of breast cancer diagnosed after age 40 with no family history of breast or ovarian cancer. ➢ Obesity. ➢ Nulliparity / low parity.

Although some of the specific tumors have distinctive features and are hormonally active, most are nonfunctional and tend to produce relatively mild symptoms until they have reached a large size. Malignant tumors have usually spread outside the ovary by the time a definitive diagnosis is made. Some of these tumors, principally epithelial ovarian cancers, tend to be bilateral. Abdominal pain and distention, urinary and gastrointestinal tract symptoms due to compression by tumor or cancer invasion, and abdominal and vaginal bleeding are the most common symptoms. These may be accompanied by weight loss, loss of appetite and progressive weakness. If cancer extends through the surface of the ovary to seed the peritoneal cavity, fluid containing exfoliated cancer cells can rapidly accumulate, resulting in massive abdominal swelling and discomfort. The pattern of peritoneal seeding in these cases is characteristic: small subcentimetre nodules of tumour are seeded over the external surfaces of various pelvic organs and tissue. The regional lymph nodes are often involved, and metastases may be found in the liver, lungs, gastrointestinal tract, and elsewhere.

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Figure 2. Ovarian cancer, composed of mainly solid tissue with an irregular surface.

Because there are no early signs or symptoms with ovarian masses, many of these tumours have spread by the time they are detected.

Dr Ivy Chew Associate Consultant Dept of Pathology Singapore General Hospital

Figure 3. Microscopic appearance of ovarian cancer, featuring pronounced finger like (papillary) projections covered by tumour cells.

Figure 4. Ovarian cancer. These tumours characteristically spread by “seeding” or “growing” along peritoneal surfaces

The stages of ovarian cancer include : Stage I Cancer cells are found in one or both ovaries. Cancer cells may be found on the surface of the ovaries or in fluid collected from the abdomen.

Stage II Cancer cells have spread from one or both ovaries to other tissues in the pelvis. Cancer cells are found on the fallopian tubes, the uterus, or other tissues in the pelvis. Cancer cells may be found in fluid collected from the abdomen.

Stage III Cancer cells have spread to tissues outside the pelvis or to the regional lymph nodes. Cancer cells may be found on the outside of the liver.

Stage IV Cancer cells have spread to tissues outside the abdomen and pelvis. Cancer cells may be found inside the liver, in the lungs, or in other organs.

Because ovarian carcinomas often remain undiagnosed until they are large, or present on the ovarian surface from where they readily spread to the pelvis, many patients are first seen with lesions that are no longer confined to the ovary. This is perhaps the primary reason for the relatively poor 5- and 10-year survival rates for these patients, compared with rates in cervical and endometrial carcinoma. Prevention of ovarian cancer remains an elusive goal, but both fallopian tubal ligation and oral contraceptive therapy are associated with significant reductions in relative risk. Screening strategies based on identifying women at risk (positive for BRCA mutations) and employing prophylactic oophorectomy are currently standard, but the long-term impact of these approaches on ovarian cancer death rates remains to be determined. ... continued from pg 8 mask when examining patients. Prevention is recommended through the administration of Panvax, the only pandemic H1N1 vaccine approved for use in children from 6 months and above, and available in Singapore. Medical practitioners are required to notify National Immunization Registry upon vaccine administration. The following dosing regime is recommended in children : • (Adults and) Children 10years old : single dose of 0.5 ml (15 mcg).

• Children aged 3-10 years old : 2 doses of 0.5 ml (15 mcg), given 4 weeks apart.

• Children aged from 6 months to 3 years : 2 doses of 0.25 ml (7.5 mcg), given 4 weeks apart.

Panvax® H1N1 vaccine Junior (CSL) is designed for use in children under 3 years old. It comes as a 0.25 ml single-dose pre-filled syringe which does not contain thiomersal or any preservative. Children over 3 years old are given Panvax® H1N1 vaccine (CSL) which comes in a multi-dose vial and does contain a small amount of thiomersal. The thiomersal preservative used in vaccines has had a very long safety record.

Results from a study in children showed that Panvax vaccine was generally well tolerated with a safety and tolerability profile consistent with that seen with seasonal flu vaccines. The most commonly reported side effects were injection site tenderness or pain, and flu-like symptoms. The majority were mild to moderate in intensity. In immune-compromised patients, the antibody response may be lower.

Contra-Indications and Adverse Effects of Vaccination Vaccination with Panvax® H1N1 vaccine is contra-indicated in patients with allergy to any of the ingredients in the vaccine or anaphylactic hyper-sensitivity to thiomersal (applicable only to the vaccine in vials), eggs, neomycin or

polymyxin, and in those who received another flu vaccine. Symptoms of an allergic reaction include : • shortness of breath, wheezing, difficulty in breathing.

• swelling of the face, lips, tongue or other parts of the body.

• skin rash, itching or urticaria.

Following vaccination, the commoner adverse events observed within 7 days were : • reaction around the injection site such as tenderness, bruising, redness, pain, swelling or the formation of hard lumps.

• flu-like symptoms, such as headache, tiredness, fever, sore throat, runny nose or blocked nose and sneezing, cough, chills.

• vomiting, nausea, diarrhoea.

• irritability / loss of appetite.

• Toothache.

• myalgia, arthralgia or back pain.

• tingling or numbness.

Rarely, the following adverse events may occur, requiring urgent attention : • allergic reactions.

• neuralgia, paraesthesiae or seizures.

• transient thrombocytopenia.

• severe stabbing or throbbing nerve pain, neck stiffness.

• Guillain-Barre syndrome.

Following review, MOH stepped down the flu alert status from DORSCON yellow to DORSCON green with effect from 12 February 2010. This was based on the declining activity and lack of increased virulence of the virus, as well as the availability of vaccines to the local community. It is important that all healthcare institutions and medical professionals continue to remain vigilant and exercise good care and infection control measures at all times against the influenza A (H1N1-2009).

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Dr Lian Wee Bin Senior Consultant Dept of Neonatal & Developmental Medicine

INFLUENZA A (H1N1) IN CHILDREN – THE PANDEMIC THAT FLU IN

Influenza A (H1N1-2009) first surfaced around April 2009, after which a pandemic was declared by WHO on 11 June 2009. Sometimes called swine flu, it spreads from person to person, much like the common flu. In reality, it carries a combination of genes from pigs, birds and humans. Although the number of infected individuals has declined since October 2009, it continues to be the predominant flu virus in circulation. Flu viruses are transmitted through droplets from infected persons that are spread during coughing, sneezing or talking, and sometimes through touching a surface/object with flu viruses on it followed by touching the mouth or nose.

Morbidity and Mortality The symptoms of influenza A (H1N1-2009) infection include fever, cough, sore throat, runny or stuffy nose, body aches, headache, chills and fatigue, and sometimes vomiting and diarrhea. Although a generally mild illness, they can sometimes be severe, especially in immuno-compromised persons, causing morbidity and mortality. High risk groups include the young (especially those <5 years) and old ( 65 years), pregnant women and those with chronic medical illnesses, such as : • Asthma or Chronic lung disease.

• Neurological / neuro-developmental conditions (such as cerebral palsy, epilepsy, stroke, significant developmental delay, muscular diseases or spinal cord injury).

• Heart disease (congenital heart disease, heart failure and coronary artery disease).

• Blood disorders.

• Endocrine disorders (such as diabetes mellitus).

• Kidney disorders.

• Liver disorders.

• Metabolic disorders.

• Lowered immunity (HIV/AIDS, cancer or those on chronic steroid therapy).

• People < 19 years old on long-term aspirin therapy.

The Ministry of Health (MOH) influenza biosurveillance program showed that as of 1 April 2010, the prevalence of Influenza A (H1N1-2009) ranged from 21 40% amongst patients with influenza-like illnesses in the community. Children and teenagers below 18 years comprised 21% of severely ill patients who required intensive care or who died.

Treatment Anti-viral treatment can potentially reduce morbidity and mortality. Medical practitioners need to exercise clinical judgment when deciding to prescribe anti-virals, balancing the patient’s risk of complications against the benefits/ risks of treatment. Anti-viral treatment with Tamiflu 2mg/kg/dose BD (up to maximum of 75mg BD) should be considered for those < 5 years and in highrisk groups. The duration of medical certificates is at the doctors’ discretion.

Children with signs of severe or increasing respiratory distress, hypoxemia, dehydration or altered mental status should be admitted to hospital for further management. Notification to MOH within 24 hours of diagnosis/death is required for influenza A (H1N1-2009) patients who are clinically suspected and seriously ill, have laboratory confirmation or who have died.

Prevention Infection control measures are important in preventing further spread of the influenza A (H1N1-2009) infection. Patients with influenza-like illness are best segregated while healthcare professionals should wear at least a surgical continued to pg 7 ... ..

Obstetrics and Gynaecology Head Dr Tan Hak Koon Senior Consultant Prof Charles Ng A/Prof Ho Tew Hong Dr Yu Su Ling A/Prof Tay Sun Kuie Dr Yong Tze Tein Dr Chua Hong Liang Dr Tan Lay Kok Dr Devendra K (Chief Editor, OGN) Dr Tan Poh Kok Consultant Dr Tan Wei Ching Dr Fong Kah Leng Associate Consultant Dr Hemashree Rajesh Dr Tan Eng Loy Dr Cindy Pang Registrar Dr Elisa Koh Dr Jason Lim Dr Renuka Devi Dr Ravichandran N

Services

Obstetric Services

Gynaecology Services

Pre-Pregnancy Counselling / Antenatal Classes Prenatal Diagnosis and Counselling • Fetal anomaly ultrasound scan • Amniocentesis, chorionic villus sampling, fetal blood sampling • Fetal therapy Down Syndrome screening, nuchal translucency ultrasound scan, first trimester and second trimester serum screening

General Gynaecology Gynaecological Oncology • Colposcopy & LEEP Clinic • Vulva Clinic • Cancer surgery • Inpatient and outpatient chemotherapy and radiotherapy Uro-gynaecology • Urinary incontinence and Pelvic Prolapse Clinic • Pelvic Floor Disorder Centre • Urodynamic assessment • Incontinence surgery including tension-free vaginal tape (TVT & TVT-O) Reproductive Medicine • Centre for Assisted Reproduction (CARE) • Intra-uterine insemination, in-vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), donor programs for oocyte, embryos and sperm • Fertility Augmentation Clinic • Andrology / Male Infertility Clinic • Sexual Dysfunction Clinic • Adolescent Gynaecology Clinic • Menopause Clinic • Ovarian Cryopreservation Mental-Health Clinic • Postnatal blues & postpartum depression • Climateric psycho-somatic problems • Psychiatric conditions in women Early Pregnancy Unit (EPU) • A one-stop centre for management of early pregnancy problems such as bleeding in early pregnancy (threatened miscarriage) and suspected ectopic pregnancies • Early appointments (often on the same day) can be obtained by calling the EPU hotline

High Risk Pregnancy Clinic Gestational Diabetes Mellitus Clinic Obstetric Day Assessment • Medical disorders in pregnancy (eg. autoimmune disease and renal disease) • Fetal wellbeing assessment • Maternal blood pressure monitoring and treatment Joint Cardiology-Obstetric Clinic • Congenital & valvular heart diseases • Ischaemic heart disease & cardiomyopathy • Pre-pregnancy counselling for known cardiac disease Obstetric Ultrasound Services • Early pregnancy scan • Fetal anomaly scan • Growth scan, Doppler studies • Placental evaluation Labour and delivery suites with full obstetric anaesthetic support

Neonatal and Developmental Medicine Head Dr Yeo Cheo Lian

Senior Consultant Prof Ho Lai Yun A/Prof Daisy Chan (Advisor, OGN) Dr Lian Wee Bin Dr Selina Ho

Consultant Dr Varsha Atul Shah Associate Consultant Dr Poon Woei Bing Registrar Dr Masitah Binte Ibrahim Staff Registrar Dr Imelda L. Ereno

Services Antenatal Counselling for High Risk Pregnancy Neonatal Intensive Care Neonatal High-Dependency and Normal Nursery Neonatal Screening Child health Screening Ambulatory Paediiatrics Universal Hearing Screening Developmental Screening