Ovarian cancer: the recognition and initial management of ovarian cancer This guidance updates and replaces recommendation 1.7.4 in ‘Referral guidelines for suspected cancer’ (NICE clinical guideline 27; published June 2005). Full Guideline April 2011 Developed for NICE by the National Collaborating Centre for Cancer Published by the National Collaborating Centre for Cancer (2nd Floor, Front Suite, Park House, Greyfriars Road, Cardiff, CF10 3AF) at Velindre NHS Trust, Cardiff, Wales. First published 2011 ©2011 National Collaborating Centre for Cancer No part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licenses issued by the Copyright Licensing Agency in the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page. 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More information on accreditation can be viewed at www.evidence.nhs.uk Contents Foreword iv Key priorities v Key research recommendations vii List of all recommendations ix Methodology xiii Algorithms xxiii 1 Epidemiology 1 1.1 Introduction 1 1.2 Data collection 1 1.3 Incidence 2 1.4 Mortality 5 1.5 Survival 9 1.6 Routes to diagnosis 12 1.7 Treatment 12 1.8 The findings of cancer peer review of gynaecology cancer teams in England 2004-2007 13 1.9 Summary 14 2 Detection in primary care 16 2.1 Awareness of symptoms and signs 16 2.2 Asking the right question - first tests 21 3 Establishing the diagnosis in secondary care 28 3.1 Tumour markers: which to use? 28 3.2 Malignancy indices 30 3.3 Imaging in the diagnostic pathway: which procedures? 32 3.4 Tissue diagnosis 34 4 Management of suspected early (stage I) ovarian cancer 40 4.1 The role of systematic retroperitoneal lymphadenectomy 40 4.2 Adjuvant systemic chemotherapy for stage I disease 46 5 Management of advanced (stage II-IV) ovarian cancer 55 5.1 The value of primary surgery 55 5.2 Intraperitoneal chemotherapy 61 5.3 Chemotherapy regimens 69 6 Support needs of women with newly diagnosed ovarian cancer 72 Appendices 1 A cost-utility analysis of diagnostic investigations in primary care for women with symptoms of ovarian cancer 75 2 Abbreviations 97 3 Glossary 98 4 Guideline scope 107 5 List of topics covered by each chapter 111 6 People and organisations involved in production of the guideline 112 iv Foreword These clinical guidelines review a number of clinical questions that involve the detection, diagnosis and initial management of ovarian cancer and which focus on areas of uncertainty or where there is a wide variation in clinical practice. The clinical questions were chosen using a consultative process that involved an array of stakeholders that included patient groups, representatives from relevant professional organisations and the pharmaceutical industry. For each chapter of the guideline, the Guideline Development Group (GDG) have made evidence-based recommendations concerning clinical practice and, where applicable, some recommendations on future research. The GDG are pleased that the focus of many of the clinical issues relate to an early stage in the patient pathway with particular relevance to patients and their families. In particular, identifying the first tests in primary care should help ensure women are directed onto the right clinical pathway in a timely fashion. The chair and lead clinician were aided and supported by a diverse and engaged GDG membership whose complementary skills and perspectives have been instilled in this guideline. Mr Sean Duffy Mr Charles Redman GDG Chair GDG Lead clinician v Key priorities Awareness of symptoms and signs 1. Carry out tests in primary care (see section 2.2 on page 21) if a woman (especially if 50 or over) reports having any of the following symptoms on a persistent or frequent basis – particularly more than 12 times per month 1 : • persistent abdominal distension (women often refer to this as ‘bloating’) • feeling full (early satiety) and/or loss of appetite • pelvic or abdominal pain • increased urinary urgency and/or frequency. 2. Carry out appropriate tests for ovarian cancer (see section 2.2. on page 21) in any woman of 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS) 2 , because IBS rarely presents for the first time in women of this age. Asking the right question – first tests 3. Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section 2.1 on page 16). 4. If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis. 5. For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound: • assess her carefully for other clinical causes of her symptoms and investigate if appropriate • if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent. Malignancy indices 6. Calculate a risk of malignancy index I (RMI I) score 3 (after performing an ultrasound; see section 3.3 on page 32) and refer all women with an RMI I score of 250 or greater to a specialist multidisciplinary team. Tissue diagnosis 7. If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not appropriate) in all but exceptional cases. 1 See also ‘Referral guidelines for suspected cancer’ (NICE clinical guideline 27; available at www.nice.org.uk/guidance/CG27) for recommendations about the support and information needs of people with suspected cancer. 2 See ‘Irritable bowel syndrome in adults’ (NICE clinical guideline 61; available at www.nice.org.uk/guidance/CG61). 3 See Box 3.1 for details of how to calculate an RMI I score. Ovarian cancer: the recognition and initial management of ovarian cancer vi The role of systematic retroperitoneal lymphadenectomy 8. Do not include systematic retroperitoneal lymphadenectomy (block dissection of lymph nodes from the pelvic side walls to the level of the renal veins) as part of standard surgical treatment in women with suspected ovarian cancer whose disease appears to be confined to the ovaries (that is, who appear to have stage I disease). Adjuvant systemic chemotherapy for stage I disease 9. Do not offer adjuvant chemotherapy to women who have had optimal surgical staging 4 and have low-risk stage I disease (grade 1 or 2, stage Ia or Ib). Support needs of women with newly diagnosed ovarian cancer 10. Offer all women with newly diagnosed ovarian cancer information about their disease, including psychosocial and psychosexual issues, that: • is available at the time they want it • includes the amount of detail that they want and are able to deal with • is in a suitable format, including written information. 4 Optimal surgical staging constitutes midline laparotomy to allow thorough assessment of the abdomen and pelvis; a total abdominal hysterectomy, bilateral salpingo-oophorectomy and infracolic omentectomy; biopsies of any peritoneal deposits; random biopsies of the pelvic and abdominal peritoneum and retroperitoneal lymph node assessment [Winter Roach BA, Kitchener HC, Dickinson HO (2009) Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database of Systematic Reviews, Issue 3: CD004706] vii Key research recommendations 1. Further research should be undertaken on the relationship between the duration and frequency of symptoms in women with ovarian cancer before diagnosis, the stage of disease at diagnosis and subsequent survival. Most women presenting with ovarian cancer have advanced disease and have had symptoms for months. Greater awareness among both women and healthcare professionals might result in women presenting earlier with less advanced disease, leading to better outcomes. There is insufficient understanding of the factors that influence earlier diagnosis in women with ovarian cancer, especially the relationship between duration of symptoms and stage at diagnosis. Data demonstrating benefits from earlier presentation will justify investment in raising awareness among women and healthcare professionals. This is likely to be a population-based study that records both the duration and frequency of symptoms. 2. Further research should be undertaken to determine the optimum RMI I threshold that should be applied in secondary care to guide the management of women with suspected ovarian cancer. Variation exists in the current evidence base with regard to the optimum RMI I threshold that should be applied in secondary care. The cut-off levels used will have implications for both the management options considered and the number of women who will be referred for specialist treatment. Therefore it is important to establish the relative sensitivities and specificities at the different levels. The research should be a prospective observational cohort study evaluating women referred with suspected ovarian cancer. Diagnostic accuracy, sensitivity, specificity and cost effectiveness should be examined at the different RMI I thresholds. 3. Large multicentre case–control studies should be conducted to compare the accuracy of CT versus MRI for staging and for predicting optimal cytoreduction in women with ovarian cancer. Currently most women with ovarian cancer will undergo a CT scan before surgery to assess the extent and resectability of disease. CT and MRI are complementary in their abilities to detect disease, but no adequate studies have been performed that compare their effectiveness in women with suspected ovarian cancer. No comparative studies have been undertaken evaluating surgical outcome. A prospective study in women undergoing primary surgery would be feasible. 4. A prospective randomised trial should be undertaken to evaluate the therapeutic effect, associated risks and cost effectiveness of systematic retroperitoneal lymphadenectomy in women with ovarian cancer whose disease appears to be confined to the ovaries. Ovarian cancer: the recognition and initial management of ovarian cancer viii Systematic retroperitoneal lymphadenectomy is an untested procedure but is likely to be more accurate than lymph node sampling, with a potential benefit for the woman of avoiding chemotherapy. However, increased risks are associated with it. Although there may be no overall survival advantage of this procedure, avoidance of chemotherapy and impact on quality of life may make it attractive to some women as a treatment option. In order to counsel women appropriately it is essential to understand fully the risks associated with this surgery as well as the benefits. Researchers should be encouraged to develop a prospective randomised trial with international collaboration to answer this question in a timely manner. 5. Research should be undertaken to determine the effectiveness of primary surgery for women with advanced ovarian cancer whose tumour cannot be fully excised. Most women with advanced ovarian cancer undergo surgery at some point. Previous studies have shown that surgery after the completion of chemotherapy has no therapeutic value. Studies are being performed to investigate whether the timing of surgery during primary chemotherapy influences outcome. No studies have evaluated whether primary surgery itself has any therapeutic value when compared with chemotherapy alone. The potential advantages of surgery have to be offset against the morbidity, occasional mortality and undoubted costs associated with it. This would be a prospective randomised clinical trial recruiting women who have biopsy-proven advanced ovarian cancer and who are fit enough to receive surgery and chemotherapy. Women would be randomised to either chemotherapy and surgery (conventional arm) or chemotherapy alone (experimental arm). Primary outcome measures would be survival at 1 and 5 years. ix List of all recommendations Chapter 2: Detection in primary care Awareness of symptoms and signs • Refer the woman urgently 1 if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids) 2 . • Carry out tests in primary care (see section 2.2 on page 21) if a woman (especially if 50 or over) reports having any of the following symptoms on a persistent or frequent basis – particularly more than 12 times per month 2 : • persistent abdominal distension (women often refer to this as ‘bloating’) • feeling full (early satiety) and/or loss of appetite • pelvic or abdominal pain • increased urinary urgency and/or frequency. • Consider carrying out tests in primary care (see section 2.2 on page 21) if a woman reports unexplained weight loss, fatigue or changes in bowel habit. • Advise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent. • Carry out appropriate tests for ovarian cancer (see section 2.2 on page 21) in any woman of 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS) 3 , because IBS rarely presents for the first time in women of this age. Asking the right question – first tests • Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see section 2.1 on page 16). • If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis. • If the ultrasound suggests ovarian cancer, refer the woman urgently 1 for further investigation 2 . • For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound: • assess her carefully for other clinical causes of her symptoms and investigate if appropriate • if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent. 1 An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks. 2 See also ‘Referral guidelines for suspected cancer’ (NICE clinical guideline 27; available at www.nice.org.uk/guidance/CG27) for recommendations about the support and information needs of people with suspected cancer. 3 See ‘Irritable bowel syndrome in adults’ (NICE clinical guideline 61; available at www.nice.org.uk/guidance/CG61). Ovarian cancer: the recognition and initial management of ovarian cancer x Chapter 3: Establishing the diagnosis in secondary care Tumour markers: which to use? • Measure serum CA125 in secondary care in all women with suspected ovarian cancer, if this has not already been done in primary care. • In women under 40 with suspected ovarian cancer, measure levels of alpha fetoprotein (AFP) and beta human chorionic gonadotrophin (beta-hCG) as well as serum CA125, to identify women who may not have epithelial ovarian cancer. Malignancy indices • Calculate a risk of malignancy index I (RMI I) score 4 (after performing an ultrasound; see section 3.3 on page 32) and refer all women with an RMI I score of 250 or greater to a specialist multidisciplinary team. Imaging in the diagnostic pathway: which procedures? • Perform an ultrasound of the abdomen and pelvis as the first imaging test in secondary care for women with suspected ovarian cancer, if this has not already been done in primary care. • If the ultrasound, serum CA125 and clinical status suggest ovarian cancer, perform a CT scan of the pelvis and abdomen to establish the extent of disease. Include the thorax if clinically indicated. • Do not use MRI routinely for assessing women with suspected ovarian cancer. Tissue diagnosis Requirement for tissue diagnosis • If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer, first obtain a confirmed tissue diagnosis by histology (or by cytology if histology is not appropriate) in all but exceptional cases. • Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without a tissue diagnosis (histology or cytology) only: • in exceptional cases, after discussion at the multidisciplinary team and • after discussing with the woman the possible benefits and risks of starting chemotherapy without a tissue diagnosis. Methods of tissue diagnosis other than laparotomy • If surgery has not been performed, use histology rather than cytology to obtain a diagnosis. To obtain tissue for histology: • use percutaneous image-guided biopsy if this is feasible • consider laparoscopic biopsy if percutaneous image-guided biopsy is not feasible or has not produced an adequate sample. Use cytology if histology is not appropriate. 4 See Box 3.1 for details of how to calculate an RMI I score. [...]... Approximately 4,300 women die from ovarian cancer each year in the UK which makes it the leading cause of death in gynaecological cancers (Cancer Research UK2) It accounts for 6% of all cancer deaths in women The reason for the high mortality rate in ovarian cancer 2 http://info.cancerresearchuk.org/cancerstats/index.htm 5 Ovarian cancer: the recognition and initial management of ovarian cancer may be because most... America and Northern Europe and lowest in some parts of Africa and Asia Figure 1.2 Worldwide estimated age-standardised incidence rate of ovarian cancer per 100,000 population; all ages (2008) Data source: GLOBOCAN 2008 (IARC) 3 Ovarian cancer: the recognition and initial management of ovarian cancer In comparison with other European countries, the UK is among those with the highest incidence rates of ovarian. .. Executive The list of reported errors from the pre-publication check and the responses from the NCC-C were subsequently published on the NICE website The final document was then submitted to NICE for publication on their website The other versions of the guideline (see below) were also discussed and approved by the GDG and published at the same time Other Versions of the Guideline This full version of the. .. of this guideline and includes current information regarding the epidemiology of ovarian cancer 1.2 Data collection Office of National Statistics (ONS) and cancer registries The data on incidence, mortality and survival of ovarian cancer for the United Kingdom is published by the ONS (2007) It is based on the data collated by 11 cancer registries covering England, Wales, Scotland and Northern Ireland... Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer Cochrane Database of Systematic Reviews issue 3: CD004706] xi Ovarian cancer: the recognition and initial management of ovarian cancer • xii Ensure that information is available about: • the stage of the disease, treatment options and prognosis • how to manage the side effects of both the disease and its treatments in order... surgery and chemotherapy.’ xiii Ovarian cancer: the recognition and initial management of ovarian cancer Involvement of stakeholders Key to the development of all NICE guidance is the involvement of relevant professional and patient/carer organisations that register as stakeholders Details of this process can be found on the NICE website or in the ‘NICE guidelines manual’ (NICE 2009) In brief, their... estimated age-standardised mortality rate of ovarian cancer per 100,000 population, all ages (2008) Data source: GLOBOCAN 2008 (IARC) Across Europe, the highest mortality rates are seen in Northern Europe and Ireland (Figure 1.10) This is similar to the high incidence rates seen in these regions 7 Ovarian cancer: the recognition and initial management of ovarian cancer Figure 1.10 Estimated age-standardised... compared to older women (>40) In women aged 15-39 years the one year and five year survival are 93% and 84% respectively compared to 31% and 14% in the 80-89 age group 9 Ovarian cancer: the recognition and initial management of ovarian cancer Figure 1.13 Age-standardised five year relative survival of ovarian cancer by age in England (2001-2006) Age standardised relative survival rate 90 80 70 60 50 Five-year... NICE and the NCC-C and the remit set by the DH • inform professionals and the public about the expected content of the guideline • provide an overview of the population and healthcare settings the guideline would include and exclude • specify the key clinical issues that will be covered by the guideline • inform the development of the clinical questions and search strategy Before the guideline development... ovarian cancer (Figure 1.3) Generally the highest rates are in the Northern and Eastern European countries of Lithuania, Latvia, Ireland, Slovakia and Czech Republic The lowest rates are in Southern European countries of Portugal and Cyprus Figure 1.3 Age-standardised incidence rates of ovarian cancer in the European Union (2008) United Kingdom The Netherlands Sweden Spain Slovenia Slovakia Portugal Poland . recognition and initial management of ovarian cancer, to include both surgery and chemotherapy.’ Ovarian cancer: the recognition and initial management of ovarian. Ovarian cancer: the recognition and initial management of ovarian cancer xvi Method From each of the key clinical issues identified in the scope the