BGCS Guidelines for Epithelial Ovarian / Fallopian tube / Primary Peritoneal Cancer: Recommendations for Practice

Christina Fotopoulou, Marcia Hall, Sean Kehoe, Raji Ganesan, Derek Cruickshank, Cathy Hughes, Sudha Sundar, Hani Gabra, Raj Naik

The remit of this guideline is to collate and propose evidence-based guidelines for the management of ovarian cancer. This document covers all ovarian cancers of any histological type.

Recommendations are graded as per the Royal College of Obstetricians and Gynaecologists document. Clinical Governance Advice No. 1: Guidance for the Development of RCOG Green-top Guidelines (available on the RCOG website at https://www.rcog.org.uk/globalassets/documents/guidelines/clinical-governance-advice/clinical-governance-advice-1c.pdf

Hierarchy of evidence and recommendations grading scheme as defined by NICE (https://www.nice.org.uk/guidance/cg31/chapter/appendix-a-grading-scheme)

Level Type of evidence Grade Evidence

I Evidence obtained from a single randomised controlled trial or a meta-analysis of randomised controlled trials

A At least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence level I) without extrapolation

IIa Evidence obtained from at least one well-designed controlled study without randomisation

B Well-conducted clinical studies but no randomised clinical trials on the topic of recommendation (evidence levels II or III); or extrapolated from level I evidence

IIb Evidence obtained from at least one other well-designed quasi-experimental study

III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies

IV Evidence obtained from C Expert committee reports or opinions

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expert committee reports or opinions and/or clinical experiences of respected authorities

and/or clinical experiences of respected authorities (evidence level IV) or extrapolated from level I or II evidence. This grading indicates that directly applicable clinical studies of good quality are absent or not readily available

GPP Recommended good practice based on the clinical experience of the GDG.

Adapted from Eccles M, Mason J (2001) How to develop cost-conscious guidelines. Health Technology Assessment 5:16 and Mann T (1996) Clinical Guidelines: Using Clinical Guidelines to Improve Patient Care Within the NHS. London: Department of Health.

Evidence was searched in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE up to August 2010, registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.

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Topics - Epithelial ovarian cancer-

1 Introduction (Incidence / Prevalence)

2 Screening and Prevention

3 Secondary care and initial pre- treatment assessment

4 Pathology and genetics

5 Surgical management of early/late stage epithelial ovarian cancer

6 Chemotherapy treatment of early stage epithelial ovarian cancer

7 First-line chemotherapy for advanced epithelial ovarian cancer (includes neoadjuvant chemotherapy

8 Follow-up

9 Management of recurrent disease

10 Other epithelial ovarian cancers: low grade serous, mucinous, clear cell, low grade endometrioid, borderline tumours

11 Supportive care – patient needs

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Appendices

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1. INTRODUCTION

1.1. Incidence, prevalence and clinical presentation

Epithelial ovarian cancer (EOC) is the 5th most common cancer among women in the UK (2011), accounting for 4% of all new cases of cancer in females and for about 6% of all cancer deaths in women having so the highest mortality of all gynaecological cancers (Cancer research UK data). (http://www.cancerresearchuk.org/cancer-info/cancerstats/typFes/ovary/). A total of 7,116 new cases were reported in the UK in 2011 (Cancer research UK data). (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/ovary/). The crude incidence rate shows that there are 22 new ovarian cancer cases for every 100,000 females in the UK, with significantly higher rates in Wales and significantly lower in Northern Ireland compared with England. EOC occurs predominantly in post-menopausal women, peaking in the 60-64 years age group.

Despite the improvements in cancer detection, through increased use of imaging, more than 70% of the patients with newly diagnosed EOC will present with extrapelvic advanced disease (stage-III or IV).

Approximately 26% of EOC-patients in England present as an emergency with a significant proportion not receiving any therapy for cancer. (http://www.ncin.org.uk/publications/data_briefings/routes_to_diagnosis) Data from the National cancer Intelligence Network also show that 36% of patients will die within the first year of presentation. (Ref: Factors Affecting Short-term Mortality in Women With Ovarian, Tubal, or Primary Peritoneal Cancer. Population-Based Cohort Analysis of English National Cancer Registration Data. Matthew Barclay, Carolynn Gildea,, Jason Poole, Lynn Hirschowitz, MBBCh, Usha Menon, and Andrew Nordin).

1.2. Diagnosis

1.2.1. Presenting symptoms

Symptoms that have been shown to be significantly associated with ovarian cancer are persistent abdominal distension, abdominal bloating (early satiety) and/or loss of appetite, pelvic or abdominal pain, increased urinary urgency and/or frequency, particularly when present for <1 year and occurred more than 12 times per month. Other symptoms include postmenopausal bleeding, unexplained weight loss, fatigue or changes in bowel habit. Symptoms that suggest IBS in a woman over 50 may also be suggestive of ovarian cancer. 5

A number of case–control studies investigating symptoms in women with ovarian cancer and comparing them to symptoms in women without ovarian cancer demonstrate that patients with ovarian cancer are symptomatic for a variable period before diagnosis. 6

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1.2.2. Diagnostic methods - Current guidance

NICE guidance recommends sequential testing with CA125 and ultrasound in all women presenting to primary care with symptoms suggestive of ovarian cancer. This is particularly emphasized in women over the age of 50. Urgent referral to secondary care is indicated if both tests are abnormal or if women present to primary care with a pelvic or abdominal mass. (reference NICE guidance CG122) .

In the UK, recommendations for diagnosis and referral are based on National Institute for Health and Clinical Excellence (NICE) guidelines on the Recognition and Initial Management of Ovarian Cancer 5 and the Scottish Intercollegiate Guidelines Network guidelines on epithelial ovarian cancer.7

The Canadian Diagnosing Ovarian Cancer Early (DOvE) prospective study investigated whether open-access assessment would increase the rate of early-stage diagnosis of ovarian cancer. The analysis of 1455 women demonstrated that DOvE patients presented with less tumour burden than the general population patients did, had significantly lower CA125 and were associated with significantly higher complete tumor resection rates due to the lower tumor burden, even though no stage shifting was noted. The investigators concluded that due to the nature of carcinogenesis of high grade serous ovarian cancer being often extraovarian, early diagnosis programmes should ideally aim to identify low-volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. 8

References:

4. Factors Affecting Short-term Mortality in Women With Ovarian, Tubal, or Primary Peritoneal Cancer

Population-Based Cohort Analysis of English National Cancer Registration Data. Matthew Barclay, Carolynn Gildea,, Jason Poole, Lynn Hirschowitz, MBBCh, Usha Menon, and Andrew Nordin,

5. Recognition and Initial management of Ovarian Cancer: summary of NICE guidance Redman C, Duffy S, Bromham N and Francis S on behalf of the Guidelines Group BMJ 2011;342:d2073 doi: 10.1136/bmj.d20736. Bankhead CR, Kehoe ST and Austoker J (2005). Symptoms associated with diagnosis of ovarian cancer: a systematic review. BJOG. 112: 857-865.)

7. www.sign.ac.uk/guidelines/fulltext/75

8. Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project. Gilbert L1, Basso O, Sampalis J, Karp I, Martins C, Feng J, Piedimonte S, Quintal L, Ramanakumar AV, Takefman J, Grigorie MS, Artho G, Krishnamurthy S; DOvE Study Group. Lancet Oncol. 2012 Mar;13(3):285-91. doi: 10.1016/S1470-2045(11)70333-3. Epub 2012 Jan)

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2. Screening and prevention – Clinical pathways

Protective factors include:

Oral combined contraceptive use Pregnancy Sterilization/tubal ligation Hysterectomy

Risk factors include:

Family history associated with mutations in the BRCA1, BRCA2 or mismatch repair genes

Nulliparity or first birth after age 35 years Early menarche, late menopause

2.1. Primary care

Pelvic ultrasound scan (+/-TVS) and CA125 should be considered as initial investigations for post-menopausal women presenting with signs or symptoms of Ovarian Cancer (Level IIA, Grade B)

Women with an RMI of ≥250 should have further investigations and be referred to the specialist gynaecological centre MDT (Level IIA, Grade B)

There is currently no role for organized screening programmes in women considered at low risk of development of ovarian cancer. ( Level I, Grade A)

In women considered at >10% risk of development of Ovarian cancer, annual ultrasound and CA125 levels do not result in a stage shift in cancer diagnosis. (Level IIA, Grade B)

According to NICE, clinical examination and also serum CA125 should be considered in women with symptoms suggestive of ovarian cancer (NICE CG122, 2011). If serum CA125 is 35 IU/ml or greater or if a pelvic mass or abnormality is identified at examination, then an ultrasound scan of the abdomen and pelvis should be considered. 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 then:– Careful assessment for other clinical causes of her symptoms is required. The women should be advised to return to her GP if her symptoms become more frequent and/or persistent.

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The American Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial demonstrated that screening asymptomatic postmenopausal women with a single threshold value of CA125 does not result in reduction of mortality; an even after 13 years of long term follow up. 1,9

The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial randomised 200,00 women to observation alone, testing with an algorithm based on serial values of CA125 and multimodal testing or serial ultrasound, showed also no reduction in mortality in primary analysis but a possible reduction in mortality after exclusion of prevalent cases after 7 years of follow-up. Long-term data and cost-effectiveness data are still awaited. 2

About 1.3 percent of women in the general population will develop ovarian cancer sometime during their lives (4). By contrast, according to the most recent estimates, 39 percent of women who inherit a harmful BRCA1 mutation (5, 6) and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 yearsUp to 63% of women with a BRCA1 mutation and 27% of women with a BRCA2 mutation will develop ovarian cancer by age 70 years. 3 4 The UKFOCCS study evaluated a strategy of annual ultrasound and CA125 in 3653 women considered at >10% risk of development of Ovarian cancer. Positive and negative predictive values of incident screening were 25.5% (95% CI, 14.3 to 40.0) and 99.9% (95% CI, 99.8 to 100) respectively. The study highlighted a need for strict adherence to schedule in these patients. Ongoing trials evaluate a 4 monthly screening strategy with CA125 and ultrasound.5

Risk reducing salpingo-oophorectomy prevents development of epithelial ovarian cancer and reduces mortality in women at high risk for epithelial ovarian cancer. ( IIA, Grade B)

Prospective multicenter cohort studies have demonstrated that risk reducing salpingo-oopherectomy is associated with a lower risk of EOC, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality. However there still is a residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers.6,7 Ongoing studies evaluate the role of opportunistic salpingectomy in the prevention of ovarian cancer in low risk women. 8

Tumour markers and Malignancy indices

Tumour markers are not diagnostic but may be helpful in establishing diagnosis and showing baseline values that might be of use at follow up. (Ref: Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol 1990;97:922–9. Royal College of Obstetricians and Gynaecologists, Guideline no 34. Ovarian cysts in Postmenopausal women)New prospective evidence from the United Kingdom Collaborative Trial of Ovarian Cancer Screening Cancer (UKTOCS) in which 46,237 women were triaged by using the multimodal

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strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA), has shown that screening by using ROCA doubled the number of screen-detected EOCs compared with a fixed cut off of 35 IU/ml and that reliance on predefined single-threshold rules may result in biomarkers of value being discarded. This novel knowledge means that new standards of care might need to be defined in order to avoid giving false reassurance in women with one normal value of CA125 and focus more on serial measurements, associating so rather the serial trend than one absolute number of CA125 with the clinical picture and imaging findings. 10

References:

1. JAMA. 2011 Jun 8;305(22):2295-303. doi: 10.1001/jama.2011.766. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, Reding DJ, Greenlee RT, Yokochi LA, Kessel B, Crawford ED, Church TR, Andriole GL, Weissfeld JL, Fouad MN, Chia D, O'Brien B, Ragard LR, Clapp JD, Rathmell JM, Riley TL, Hartge P, Pinsky PF, Zhu CS, Izmirlian G, Kramer BS, Miller AB, Xu JL, Prorok PC, Gohagan JK, Berg CD; PLCO Project Team.)

2. Jacobs et al . Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet

DOI: http://dx.doi.org/10.1016/S0140-6736(15)01224-63. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation

carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56:265–71.

4. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998;62:676–89.

5. Rosenthal AN1, Fraser L, Manchanda R, Badman P, Philpott S, Mozersky J, Hadwin R, Cafferty FH, Benjamin E, Singh N, Evans DG, Eccles DM, Skates SJ, Mackay J, Menon U, Jacobs IJ. Results of annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight the need for strict adherence to screening schedule. J Clin Oncol. 2013 Jan 1;31(1):49-57. doi: 10.1200/JCO.2011.39.7638. Epub 2012 Dec 3.

6. Salpingo-oophorectomy and the Risk of Ovarian, Fallopian Tube, and Peritoneal Cancers in Women With a BRCA1 or BRCA2 Mutation.

Amy Finch, MS; Mario Beiner, MD; Jan Lubinski, MD, PhD; Henry T. Lynch, MD; Pal Moller, MD; Barry Rosen, MD; Joan Murphy, MD; Parviz Ghadirian, PhD; Eitan Friedman, MD; William D. Foulkes, MD; Charmaine Kim-Sing, MD; Teresa Wagner, MD; Nadine Tung, MD; Fergus Couch, PhD; Dominique Stoppa-Lyonnet, MD; Peter Ainsworth, MD; Mary Daly, MD; Barbara Pasini, MD; Ruth Gershoni-Baruch, MD; Charis Eng, MD; Olufunmilayo I. Olopade, MD; Jane McLennan, MD; Beth Karlan, MD; Jeffrey Weitzel, MD; Ping Sun, PhD; Steven A. Narod, MD; for the Hereditary Ovarian Cancer Clinical Study Group. JAMA. 2006;296(2):185-192. doi:10.1001/jama.296.2.185.

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7. Susan M. Domchek, MD; Tara M. Friebel, MPH; Christian F. Singer, MD, MPH; D. Gareth Evans, MD; Henry T. Lynch, MD; Claudine Isaacs, MD; Judy E. Garber, MD, MPH; Susan L. Neuhausen, PhD; Ellen Matloff, MS; Rosalind Eeles, PhD; Gabriella Pichert, MD; Laura Van t’veer, PhD; Nadine Tung, MD; Jeffrey N. Weitzel, MD; Fergus J. Couch, PhD; Wendy S. Rubinstein, MD, PhD; Patricia A. Ganz, MD; Mary B. Daly, MD, PhD; Olufunmilayo I. Olopade, MD; Gail Tomlinson, MD, PhD; Joellen Schildkraut, PhD; Joanne L. Blum, MD, PhD; Timothy R. Rebbeck, PhD. Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality. JAMA. 2010;304(9):967-975. doi:10.1001/jama.2010.1237.

8. Opportunistic salpingectomy for ovarian cancer prevention. Gillian E. Hanley, Jessica N. McAlpine, Janice S. Kwon and Gillian Mitchell. Gynecologic Oncology Research and Practice20152:5. DOI: 10.1186/s40661-015-0014-1

9. Andriole GL1, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, Fouad MN, Isaacs C, Kvale PA, Reding DJ, Weissfeld JL, Yokochi LA, O'Brien B, Ragard LR, Clapp JD, Rathmell JM, Riley TL, Hsing AW, Izmirlian G, Pinsky PF, Kramer BS, Miller AB, Gohagan JK, Prorok PC; PLCO Project Team. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012 Jan 18;104(2):125-32. doi: 10.1093/jnci/djr500. Epub 2012 Jan 6.

10. Menon U, Ryan A, Kalsi J, Gentry-Maharaj A, Dawnay A, Habib M, Apostolidou S, Singh N, Benjamin E, Burnell M, Davies S, Sharma A, Gunu R, Godfrey K, Lopes A, Oram D, Herod J, Williamson K, Seif MW, Jenkins H, Mould T, Woolas R, Murdoch JB, Dobbs S, Amso NN, Leeson S, Cruickshank D, Scott I, Fallowfield L, Widschwendter M, Reynolds K, McGuire A, Campbell S, Parmar M, Skates SJ, Jacobs I. Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening. J Clin Oncol. 2015 Jun 20;33(18):2062-71. doi: 10.1200/JCO.2014.59.4945. Epub 2015 May 11.

3. Secondary care and initial pre- treatment assessment

In young women below 40 years of age with suspected ovarian cancer, consider measuring α-fetoprotein, β human chorionic gonadotropin, hormonal levels, and inhinin additionally to CA125, to identify possible non epithelial ovarian cancer. (Level III)

3.1. Secondary careAfter referral of a patient to a cancer centre with the urgent suspicion of ovarian cancer an expansion of the tumour marker profile could potentially narrow the possibility of non ovarian malignancy. A preoperative CA 125/CEA ratio < 25 (if CA-125 is elevated), especially in combination with an elevated CA19-9 might possibly indicate peritoneal carcinomatosis due to a gastrointetsinal tumour, so a gastrointestinal endoscopy should be considered prior to cytoreductive surgery to possibly exclude upper GI or colo-rectal cancer. [Grade B]A novel biomarker, the HE4 (Human epididymis protein 4) has shown promising diagnostic and prognostic value in various retrospective and prospective studies, but is not part of the

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NICE guidelines. Its significance lies especially in younger women with pelvic inflammatory disease and endometriosis, where CA125 is often elevated but HE4 not.60-62 Large prospective studies from the International Ovarian Tumour Analysis consortium (IOTA) suggest that utilising “m”(malignant) and “b” (benign) rules to identify masses as suspicious may be highly accurate. Using these rules, the reported sensitivity was 95%, specificity 91%, positive likelihood ratio 10.37, and negative likelihood ratio 0.06. The accuracy of these rules has been demonstrated in secondary care, predominantly with specialists in ultrasonography. These models are not currently in common use in the NHS. Results from an ongoing study to evaluate the best serum diagnostic tests and ultrasound models to detect Ovarian cancer are awaited. 63

Additional tumour markers such as alpha fetoprotein (AFP), beta human chorionic gonadotrophin (β-hCG), LDH, inhibin, and hormonal levels (such as oestrogen, testosterone, prolactin, sex hormone-binding globulin, and thyroid hormones depending on clinical picture) should be considered in women, especially those <40y old who have radiological suspicion of a germ cell tumour. [Grade B]

3.2. Advised examinations prior to defining treatment

In patients with presumed ovarian cancer further imaging per CT will provide further information about dissemination of disease and potential distant metastases or secondary cancers. (Level III, GPP)

CT prediction of suboptimal cytoreduction is not highly reliable and may not be reproducible. In the absence of favourable data from larger, prospective trials, it should not be used as single modality to guide management. (Level III)

MRI should not be routinely used for assessing women with suspected ovarian cancer outside of clinical trials but MRI scans can be useful in providing extra detail in situations in the pelvis where the results of the USS are not helpful in confirming a diagnosis, especially in young women with a solitary pelvic mass who want a fertility sparing approach. (Level III)

PET CT is not recommended for routine preoperative staging in the NHS outside a clinical trial. (Level III)

CT scans of chest/abdomen and pelvis are increasingly routinely used to determine the extent of disease and to aid in surgical planning. Retrospective results have shown that CT cannot accurately predict the full extent of tumour dissemination, especially in the case of fine nodule peritoneal carcinomatosis, and hence prediction of suboptimal cytoreduction is not always reliable and may not be reproducible.46 Current prospective imaging trials are underway to prospectively assess the value of novel imaging techniques in theatre planning and operability. CT has a significant value in excluding distant disease spread such as

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intraparenchymal liver or lung metastases and nodal involvement (LoE IIa) or even to exclude secondary cancers. NICE guidance for diagnosis and management of ovarian masses are as follows: 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 but MRI scans can be useful in providing extra detail in situations in the pelvis where the results of the USS are not helpful in confirming a diagnosis, especially in young women with a solitary pelvic mass who want a fertility sparing approach. MRI does not form currently part of routine investigations and a cost- effectiveness balance should be considered prior to every additional imaging study with high cost but questionable benefit. There is also no evidence based value in the routine use of specialized imaging techniques such as PET CT, apart from situations with a highly specialized question such as the evaluation of thoracic/mediastinal lymph nodes involvement, especially with relapse disease, where intraabdominal debulking surgery is considered.59 An increasing role of the newly emerging diffusion weighted MRI is playing a role in description of tumour dissemination patterns and assessment of operability, but prospective evidence data for that are warranted.

3.3. Cytological/Histological Diagnosis

• If offering cytotoxic chemotherapy to women with suspected advanced ovarian cancer first obtain a confirmed tissue diagnosis by histology in all but exceptional cases. (Level III, GPP)

• Offer cytotoxic chemotherapy for suspected advanced ovarian cancer without a tissue diagnosis but just a cytology only in exceptional cases (ie. Patients with low performance status, advanced age etc.) after discussion within the multidisciplinary team, and careful consideration of risks and benefits (Level III Grade C)

Histological diagnosis is not mandatory prior to upfront debulking surgery if the clinical picture, imaging and tumour marker profile are highly suggestive of epithelial ovarian cancer (CA125:CEA ratio >25:1). If ascites is sent for cytological analysis, the absence of malignant cells does not exclude ovarian malignancy, especially in the presence of inflammation (Grade B).57,58 The use of immunohistochemistry on a cell block can be of help in such cases if sufficient atypical cells are present to allow for separation from background cells and interpretation of patterns of staining. This is of high value to aid tissue diagnosis in mixed or undifferentiated tumours.

All patients with non-emergency clinical presentation/ histology / cytology showing suspected / actual carcinoma of the ovary should be reviewed at the gynae multidiscipliary tumour board (MDT).

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If offering neoadjuvant or primary cytotoxic chemotherapy to women with suspected advanced ovarian cancer, a confirmed histological tissue diagnosis by laparoscopy or image guided biopsy is mandatory in all but exceptional cases, where cytology, together with a CA125/CEA ration of >25:1 would be sufficient in patients with very poor performance status and where a laparoscopic or image guided biopsy is not feasible (GPP).Histological confirmation can in the majority of the cases be performed per ultrasound or CT guided biopsy. The value of laparoscopy in the assessment of operability and impact on overall surgical and clinical outcome of advanced ovarian cancer has not been established in prospective randomized trials yet. Emerging research protocols utilize laparoscopically obtained multiple intraabdominal biopsies to define molecular biological profile of each individual patient. However the survival benefit of this approach has not been yet proven in any prospective randomized trials. [LoE III]. A multidisciplinary discussion within an MDT, which should be defined by the expertise of its members across all important fields who are personally involved in the care of the patient (gyn oncology, medical and clinical oncology, gynaecopathology, clinical nurse specialists and imaging) and not just by the multidisciplinary nature as such, is crucial for the appropriate management of each individual patient prior to a decision to operate, offering chemotherapy or palliative treatment.

3.4. Significance and caveats of cytology

In about two thirds of patients with known ovarian carcinoma, malignant cells are seen in the ascitic fluid. There are strong reservations in using peritoneal or ascitic cytology without histological confirmation in the primary diagnosis of ovarian cancer. Cytology preparations lack architectural patterns. When used in trial settings, they do not lend themselves to archiving, tissue microarrays and some molecular testing. False positive tests can be obtained from serous borderline tumours, especially in cases with exophytic tumours. The exfoliation of other cells such as epithelial cells from Mullerian rests and reactive mesothelial cells maybe mistaken for carcinoma. This problem can be resolved by making cytoblocks and performing suitable immunohistochemistry. The use of cytology in the diagnosis of ovarian carcinoma has a high false negative rate and is operator dependent. It may, however, be used in some patients in whom obtaining material for histology may not be possible. It is also important to consider examining any pleural fluid in women with effusions for malignant cells and cytology (preferably with immunohistochemistry on any cell pellet). (57,58).

References

31. Jacobs I1, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990 Oct;97(10):922-9.

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45. Zheng H, Gao Y. Serum HE4 as a useful biomarker in discriminating ovarian cancer from benign pelvic disease. Int J Gynecol Cancer. 2012 Jul;22(6):1000-5. doi: 10.1097/IGC.0b013e318249bee7.

46. MacKintosh ML, Rahim R, Rajashanker B, Swindell R, Kirmani BH, Hunt J, Brockbank E, Barton DP, Clayton RD. CT scan does not predict optimal debulking in stage III-IV epithelial ovarian cancer: a multicentre validation study. J Obstet Gynaecol. 2014 Jul;34(5):424-8. doi: 10.3109/01443615.2014.899330. Epub 2014 Apr 11.

57. Shen-Gunther J, Mannel RS. Ascites as a predictor of ovarian malignancy. Gynecol Oncol. 2002 Oct;87(1):77-83

58. Allen VA, Takashima Y, Nayak S, Manahan KJ, Geisler JP. Assessment of False-negative Ascites Cytology in Epithelial Ovarian Carcinoma: A Study of 313 Patients. Am J Clin Oncol. 2014 Sep 5.

Recognition and Initial management of Ovarian Cancer: summary of NICE guidance Redman C, Duffy S, Bromham N and Francis S on behalf of the Guidelines Group BMJ 2011;342:d2073 doi: 10.1136/bmj.d2073

59. Mapelli P, Incerti E, Fallanca F, Gianolli L, Picchio M. Imaging biomarkers in ovarian cancer: the role of 18F-FDG PET/CT. Q J Nucl Med Mol Imaging. 2016 Feb 9.

60. Int J Gynecol Cancer. 2012 Sep;22(7):1106-12. doi: 10.1097/IGC.0b013e318263efa2. Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. Wu L1, Dai ZY, Qian YH, Shi Y, Liu FJ, Yang C.

61. Braicu EI, Fotopoulou C, Van Gorp T, Richter R, Chekerov R, Hall C, Butz H, Castillo-Tong DC, Mahner S, Zeillinger R, Concin N, Vergote I, Sehouli J. Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: Results from the OVCAD study. Gynecol Oncol. 2013 Feb;128(2):245-51. doi: 10.1016/j.ygyno.2012.11.023. Epub 2012 Nov 21.

62. Braicu EI, Chekerov R, Richter R, Pop C, Nassir M, Loefgren H, Stamatian F, Muallem MZ, Hall C, Fotopoulou C, Sehouli J, Pietzner K. HE4 Expression in Plasma Correlates with Surgical Outcome and Overall Survival in Patients with First Ovarian Cancer Relapse. Ann Surg Oncol. 2013 Nov 12. [Epub ahead of print]

63. Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group. Dirk Timmerman, Lieveke Ameye, Daniela Fischerova, Elisabeth Epstein, Gian Benedetto Melis, Stefano Guerriero, Caroline Van Holsbeke, Luca Savelli, Robert Fruscio, Andrea Alberto Lissoni, Antonia Carla Testa, Joan Veldman, Ignace Vergote, Sabine Van Huffel, Tom Bourne, consultant gynaecologist, Lil Valentin, BMJ 2010;341:c6839)

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4. Pathology and Genetics

The diagnosis and management of ovarian carcinoma is based on robust pathological input. Therefore basic clinical information and history on the histopathology request sign is crucial to ensure a high quality histopathology report. (Level IV, GPP).

Frozen sections may be performed if their results may affect clinical management during surgery, while the clinicians should be cautioned about the limitations of the technique. (Level III)

4.1. Clinical information required on the specimen request form

These guidelines are based on the Royal College of Pathology guidelines for reporting ovarian carcinomas. Provision of accurate clinical details assists diagnosis of pathology in biopsy and surgical specimens. Clinical details should include patient demographic details, clinical presentation, results of previous biopsies and radiological investigations for tumour staging, and details of the surgical procedures performed. It is desirable to include details of any family history of cancer and relevant hormonal therapy. The nature of surgical specimens from multiple sites should be carefully recorded and the specimen pots should be labelled to correspond to the specimen details on the request form and appropriately labelled as to site of origin.

4.2. Reporting of frozen sections

In most institutions in the UK, intra-operative frozen sections are rarely performed in patients with ovarian carcinoma. Frozen sections may be performed if their results may affect clinical management during surgery, for example to determine extent of resection and radicality. It is important that clinicians who request frozen sections are cautioned about the potential limitations of the technique.

4.3. High-grade serous ovarian carcinoma and relation to STIC

The origin of high-grade serous ovarian carcinoma (HGSC) has been the subject of intense study. The distal fallopian tube has emerged as the likely site of origin for most pelvic HGSC. This observation is, in great part, attributable to the use of sampling protocols that thoroughly examine the distal fallopian tube and also due to the greater number of specialist pathologists with a sub specialty interest in gynaecological-pathology. The discovery of high grade serous tubal intraepithelial carcinoma (STIC) in women with BRCA1 or BRCA2 mutations, in women with risk-reducing salpingo-oophorectomies and in women with advanced ovarian carcinoma lead to the concept that many pelvic high grade serous carcinomas arise from the fallopian tube. Identification of STIC supports a tubal origin in 18% to 60% of cases of advanced or symptomatic HGSCs. STICs have been shown to be characterized by DNA damage, TP53 mutation, and progressive molecular abnormalities that are also seen in high-grade serous carcinoma. An origin from epithelial inclusion cysts in the ovary is being offered as a potential explanation as site of origin in the cases where complete examination of the fallopian tube does not reveal any abnormalities (52-56).

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4.4. Immunohistochemical features of HGSC

HGSC of tubo-ovarian and peritoneal origin have similar morphological and immunohistochemical features. HGSC can be arranged in papillary, glandular or solid architecture. HGSC exhibits moderate to marked nuclear atypia and greater than 12 mitoses per 10 high power fields. Necrosis and multinucleate cells are often present. The distinction between low-grade and high-grade serous carcinoma is based on cytological and not architectural features. On immunohistochemistry, HGSC of tubo-ovarian and peritoneal origin are typically positive for CK7, WT1, oestrogen receptors and CA125. They do not stain for CK20, CEA and CDX2. P53 shows aberrant expression characterized by either diffuse strong positive staining in greater than 75% of cells or by complete lack of staining.

4.5. Genetics

Recently it has been shown that ~18% (much higher in certain groups such as Ashkenazi Jews) of the population of women presenting with high grade serous or G3 endometrioid ovarian carcinoma will carry a germline BRCA mutation, 44% of whom have no positive family history (52, Cancer genome Atlas ref) This now fulfils the NICE (www. Familial breast cancer ref) criteria for testing of every patient with this histological diagnosis for BRCA counselling and testing if they wish. Advantages of this approach are several:

Prognostic information -this group is likely to have longer remissions Predictive genetic testing and advice for other family members who are at risk of

inheriting BRCA, about screening and risk reductive surgery to minimise their chance of developing cancers

Potential interventions PARP inhibitor treatment which may offer a chance of longer term remission and response for some of the BRCA population.

Olaparib is recommended within its marketing authorisation as an option for treating adults with relapsed, platinum sensitive ovarian, fallopian tube or peritoneal cancer who have BRCA1 or BRCA2 mutations and whose disease has responded to platinum based chemotherapy only if:• they have had 3 or more courses of platinum based chemotherapy and

the drug cost of olaparib for people who remain on treatment after 15 months will be met by the company. (NICE olaparib)

Mutation analysis of other relevant known cancer predisposition genes can be undertaken in consenting affected individuals from families assessed to be at “high” risk (>20% lifetime risk of carcinoma of the ovary).

4.6. Special histological features of different subtypes

- Endometrioid Carcinoma of ovaryThese represent the second most common form of ovarian malignancy and account for 10 – 15% of ovarian carcinomas. A significant number are associated with endometriosis in the ovary or elsewhere in the pelvis and about 15% of them show synchronous endometrial

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carcinomas. (Van Gorp 2004, Zaino 1984). Endometrioid carcinomas of the ovary can show a variety of patterns of which an adenofibromatous pattern and squamous metaplasia are amongst confirmatory endometrioid features (Lim 2016). The clinical managment of high-grade endometrioid ovarian cancers is identical to that described for high-grade serous ovarian cancer.

-Clear cell carcinomaClear cell carcinoma is the ovarian carcinoma that is most frequently associated with pelvic endometriosis, paraneoplastic hypercalcaemia and venous thromboembolism. The tumour is composed of clear or hobnail cells arranged in papillary, glandular or solid patterns in a hyaline stroma. The cells are typically WT1-/p53 wild type and show staining with napsin A. They mostly lack expression of oestrogen and progesterone receptors. (Iwamoto 2015). Clear cell carcinomas of the ovary can be managed in an identical manner to high-grade serous ovarian cancer but is often less responsive to chemotherapy than serous or endometrioid histological subtypes.

-CarcinosarcomaCarcinosarcoma is a rarer gynecological neoplasm that accounts for 1% to 3% of ovarian tumours; they can also arise from any other area of the gynaecological tract. It belongs to the category of mixed Mullerian tumours, with both components (epithelial and mesenchymal) being malignant, thus also called malignant mixed Mullerian tumour. Recent immunohistochemical and molecular findings support the hypothesis that gynecological carcinosarcomas represent metaplastic carcinomas. Cell lines established from carcinosarcomas are able to differentiate into either epithelial, mesenchymal components, or both (Sreenan 1995). Immunohistochemistry demonstrates the expression of epithelial markers in the sarcomatous component of carcinosarcoma. Moreover, clonality studies patterns, genomic analysis, and loss of heterozygosity studies have shown that carcinomatous and sarcomatous components of these tumours share common genetic alterations including aberrant p53 expression and occasionally germline mutation of BRCA2 (Jin 2003, Fuji 2000). The transformation of a carcinoma to a sarcoma in these tumours may represent a transdifferentiation as seen in epithelial-to-mesenchymal transition phenomena (Amant 2003).

Overall, the prognosis for carcinomosarcomas is worse than for high-grade ovarian carcinomas of a similar FIGO stage (Ruah-Hain 2011). Most (90%) present as advanced disease. At present they should be managed in the same way as HGSOC.

References:

www.nice.org.uk/guidance/cg164/resources/familial-breast-cancer-classification-care-and-managing-breast-cancer-and-related-risks-in-people-with-a-family-history-of-breast-cancer-35109691767493)

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52. Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, Mitchell G. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012 Jul 20;30(21):2654-63. doi: 10.1200/JCO.2011.39.8545. Epub 2012 Jun 18. Erratum in: J Clin Oncol. 2012 Nov 20;30(33):4180.

Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma.Nature 474:609-615, 2011

53. Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001;195:451–456.

54. Crum CP, Herfs M, Ning G, et al. Through the glass darkly: intraepithelial neoplasia, top-down differentiation, and the road to ovarian cancer. J Pathol. 2013;231:402–412.

55. Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol. 2007;31:161–169.

56. Howitt BE, Hanamornroongruang S, Lin DI, Conner JE, Schulte S, Horowitz N, Crum CP, Meserve EE. Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma. Am J Surg Pathol. 2015 Mar;39(3):287-93

Van Gorp T, Amant F, Neven P, Vergote I, Moerman P. Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol. 2004 Apr;18(2):349-71

Zaino RJ, Unger ER, Whitney C. Synchronous carcinomas of the uterine corpus and ovary. Gynecol Oncol. 1984 Nov;19(3):329-35

Lim D, Murali R, Murray MP, Veras E, Park KJ, Soslow RA. Morphological and Immunohistochemical Reevaluation of Tumours Initially Diagnosed as Ovarian Endometrioid Carcinoma With Emphasis on High-grade Tumours. Am J Surg Pathol. 2016; 40(3):302-12

Iwamoto M, Nakatani Y, Fugo K, Kishimoto T, Kiyokawa T. Napsin A is frequently expressed in clear cell carcinoma of the ovary and endometrium. Hum Pathol. 2015;46(7):957-62

Sreenan JJ, Hart WR. Carcinosarcomas of the female tract. A pathological study of 29 metastatic tumours: further evidence for the dominant role of the epithelial component and the

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conversion theory of histogenesis. Am J Surg Pathol. 1995;19:666Y674.

Fujii H, Yoshida M, Gong ZX, et al. Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity.Cancer Res. 2000;60:114Y120.

Amant F, Vloeberghs V, Woestenborghs H, et al. Transition of epithelial toward mesenchymal differentiation during ovarian carcinosarcoma tumourigenesis. Gynecol Oncol. 2003;90:372Y377.

Rauh-Hain JA, Growdon WB, Rodriguez N, et al. Carcinosarcoma of the ovary: a case-control study. Gynecol Oncol. 2011;121:477Y481

Olaparib for maintenance treatment of relapsed, platinum-sensitive, BRCA mutation-positive ovarian, fallopian tube and peritoneal cancer after response to second-line or subsequent platinum-based chemotherapy NICE technology appraisal guidance [TA381] Published date: 27 January 2016

Jin Z, Ogata S, Tamura G, Katayama Y, Fukase M, Yajima M, Motoyama T.Carcinosarcomas (malignant mullerian mixed tumours) of the uterus and ovary: a genetic study with special reference to histogenesis. Int J Gyna Pathol. 2003 Oct;22(4):368-73.

5. Surgical treatment

5.1. Suspected or Confirmed Early Stage Disease

Women with suspected epithelial ovarian cancer should undergo surgery at a Cancer Centre by specialised surgeons who are core members of an MDT. Women requiring chemotherapy should be treated by a medical/clinical oncologist who is a core member of an MDT. (Level III, Grade B)

Affected women should ideally have an identified key worker and responsible clinician. (GPP)

Treatment summaries, including symptoms of recurrence, should be provided to all women on completion of each episode of treatment and on discharge to primary care (GPP)

The aim of surgery for early ovarian cancer is complete tumour resection and adequate surgical staging. Staging of patients with early ovarian cancer would help defining the indication for adjuvant treatment and also to provide valuable prognostic information. [LoE Ia].

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Very early disease may often be an incidental finding at surgery for a suspected ‘benign’ condition, so a second surgical procedure may be required although the availability of frozen section may allow the necessary surgical staging to be done at the time of initial surgery in some cases. Adequate, non fertility sparing surgery would consist of peritoneal washings or cytology, ideally taken prior to manipulation of the tumour, bilateral salpingo-oophorectomy, hysterectomy, multiple peritoneal biopsies from the paracolic spaces, and the subdiaphragmatic spaces bilaterally – even in the absence of macroscopic peritoneal disease-, infragastric omentectomy, appendicectomy should be considered in case of mucinous histology and pelvic and bilateral para-aortic lymph node assessment up to the level of the insertion of the ovarian vessels in the absence of peritoneal dissemination [LoE Ia]. (47).

In the EORTC ACTION randomised trial, 448 patients with early ovarian carcinoma were randomized between observation and adjuvant platinum-based chemotherapy. Here patients benefited overall from platinum based adjuvant treatment in terms of a significantly better OS and PFS. Subanalysis of the patients allocated to observation only performed in a subgroup of optimally staged patients (group A), versus patients in whom all staging steps were performed except para-aortic or pelvic lymph node sampling (group B), versus patients who fulfilled all staging criteria but in whom no blind peritoneal biopsies were taken (group C), showed a significantly improved 5-year DFS (p = 0.03) and 5-year OS (p = 0.01) in group A (optimally staged) versus group B (no lymph node sampling). A significant difference was also shown in 5-year DFS (P = 0.02) and 5-year OS (P = 0.003) between group A and group C (no blind biopsies). Recurrences occurred in 14.6% of patients in group A, vs 34.8% of patients in group B, and 35.7% in group C. The 5-year DFS in group A was 79% versus 61% and 64% in groups B and C, respectively. The 5-year OS decreased from 89% in group A to 71% in group B and 65% in group C. (47)

Ten-year follow-up results of ICON1 and updated results from the ACTION trial are now available and provide further evidence. The updated median follow-up in ICON1 is 10- years with a further 32 women who relapsed (seven after five years), giving a total of 165 (35%) women who have developed disease recurrence or died (71 immediate adjuvant chemotherapy, 94 no immediate adjuvant chemotherapy) [63]. Comparison of Kaplan-Meier curves for recurrence-free survival gives an estimated hazard ratio (HR) = of 0.69 (95%CI=0.51-0.94, p=0.02) This translates into a 10% RFS improvement from immediate adjuvant chemotherapy at 10 years, from 60% to 70%.

Depending on the histological grade and subtype, up to 30% of the patients with apparently early epithelial ovarian cancer will be upstaged after comprehensive surgical staging (3). Cass and colleagues showed in 96 patients with grade 3 tumours and gross disease confined to one ovary, that 15% had microscopically positive lymph nodes (4). Among these patients, 50% had positive pelvic nodes, 36% had positive para-aortic node and both were positive in 14% of the cases. Maggioni and colleagues reported on a prospective randomized trial of systematic lymphadenectomy in patients with ovarian cancer macroscopically confined to the pelvis. Positive nodes were detected in 22% of patients undergoing systematic

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lymphadenectomy compared to only 9% of patients who underwent merely a sampling (p=0.007). Although a trend for improved progression-free and overall survival was observed for the lymphadenectomy group compared to control, the study lacked the statistical power (5). Increasing evidence shows, that the rate of positive lymph nodes in stage IA mucinous cancer is extremely low (near 0%), and there is no value in performing this given the potential morbidity of such the procedure. (6-8).

When young women are affected, fertility sparing surgery could be considered in early stage disease, but always after thorough discussion with the patient about the potential risk of recurrent epithelial ovarian cancer. Patients with stage IA or stage IC with unilateral ovarian involvement and favourable histology, that is, grade 1 or 2 mucinous, serous, endometrioid, or mixed histology, would be amenable to organ preserving surgery but only in combination with complete surgical staging. In large retrospective analyses women with G3 disease or stage IC3 with clear cell histology had a higher risk of recurrence, but mainly related to the higher incidence of extraovarian spread observed in grade 3 tumours, rather than to a higher relapse rate in the preserved ovary (9). Therefore, these patients should be carefully informed about their prognosis to enable them to make a personalized and informed choice. Retrospective evidence reveals that 3.5%-11% of the women with unilateral disease will have contralateral pelvic lymph node metastases despite negative ipsilateral nodes (10,11).

5.2. Surgical management of primary advanced ovarian cancer

Surgery versus no surgery after three cycles of chemotherapy after initial suboptimal or diagnostic surgery significantly lengthens progression-free and overall survival in patients with advanced disease. (Level I, Grade A)

The aim of curative cytoreductive surgery in the management of advanced stage ovarian cancer would be complete surgical resection of all visible disease in patients fit enough to undergo this procedure, as this has been shown to be significantly associated with an improved progression free- and overall survival. (Level IIb Grade B)

Primary debulking surgery is the standard of care where complete or optimal cytoreduction seems achievable in patients with good performance status. Where this is not achievable 2 randomized trials have showed non inferiority of the neoadjuvant approach followed by interval debulking surgery. Both trials demonstrated reduction in morbidity, but equal quality of life in both arms. (Level I Grade A)

“Second look” operation with cytoreductive attempt after neoadjuvant chemotherapy and after upfront debulking surgery with residual disease despite maximal effort has no survival benefit (Level I, Grade A).

A full pelvic and paraaortic LND in patients with advanced ovarian cancer has been shown to significantly influence progression free survival, but not overall survival over

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just removal of bulky lymph nodes in a prospective randomized trial. (Level I, Grade A). The value of LND in patients without residual disease and without bulky LN has been addressed in a recent multicentre, prospectively randomised trial; results are awaited.

In advanced epithelial ovarian cancer the aim is complete cytoreduction of all macroscopically visible disease, since this has been shown to be associated with a significantly increased overall and progression free survival in numerous prospective and retrospective trials (LoE IIb) (12-14). It is not yet fully identified whether this association is causal or whether resectable tumours are intrinsically biologically more chemosensitive and less likely to recur quickly (4). The only multicentre trial comparing maximal effort debulking surgery versus no surgery was the EORTC trial by van der Burg et al (13) which randomised 319 patients to surgery versus no surgery after three cycles of cyclophosphamide and cisplatin after initial suboptimal or diagnostic surgery. The study showed that debulking surgery significantly lengthened progression-free and overall survival. The risk of deathwas reduced by one third, after adjustment for a variety of prognostic factors (Level I, Grade A).In order to achieve total macroscopic tumour clearance in peritoneally disseminated disease, a maximal surgical effort is required, potentially including multivisceral resection techniques such as peritoneal stripping, diaphragmatic resection, removal of bulky pelvic/ para-aortic lymph nodes, splenectomy and bowel resection. Retrospective data suggest that additional surgical procedures do result in improved rates of cytoreduction. This requires specialist training and surgical expertise as well as coordinated institutional effort to safely deliver this. [LoE IIa] (15). Thus, women with advanced disease should ideally undergo such surgery in specialized centres with adequate infrastructure, staff and training (NICE interventional procedure guidance https://www.nice.org.uk/guidance/IPG470/chapter/1-Recommendations). These centres should consider keeping prospective records of the surgical procedures performed, the amount and location of any residual disease and associated morbidity and mortality. Surgery should be ideally performed within 2-4 weeks of decision to operate, depending also however on patients wishes, comorbidities and prior history.The Chief Medical officer has emphasised the need for specialist surgical training and the need for a national audit in Ovarian cancer to improve outcomes. (Department of Health. Annual Report of the Chief Medical Officer, 2014The Health of the 51%: Women)

Optimal cytoreduction is defined as total macroscopic tumour clearance with no residual visible disease as documented by a comprehensive visual assessment of all the areas of the abdomen (Grade A). When complete cytoreduction is not achievable at the time of laparotomy attempts should be made to achieve near-optimal cytoreduction (<1cm residual disease) (Grade B) as meta-analysis suggests that patients in whom <1cm residual disease remains have a greater overall survival than those with >1cm residual disease (12). The value of systematic pelvic and para-aortic lymphadenectomy in advanced disease in the absence of bulky lymph nodes has not been prospectively proven to influence overall survival. A large prospectively randomised trial which randomized patients with residual disease <1cm to removal of bulky lymph nodes only versus systematic pelvic and paraaortic LND showed that

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5years- PFS could be significantly improved in the systematic LND arm from 21.6% to 31.2% by a median of additional 7 months (16). The study failed however to show any significant survival benefit. Caveat of the study was however, that 63% of the patients had residual disease, for whom we know that systematic LND has no prognostic value.An exploratory analysis of three prospective randomized trials 1st line studies (65) evaluating 1924 patients showed that lymphadenectomy was associated with superior survival of LND in patients without gross residual disease. In patients with and without lymphadenectomy, the median survival time was 103 and 84 months, respectively, and 5-year survival rates were 67.4% and 59.2%, respectively (P .0166); multivariate analysis confirmed a significant impact of lymphadenectomy on overall survival (OS; hazard ratio [HR] 0.74; 95% CI,0.59 to 0.94; P .0123). In patients with small residual tumors up to 1 cm, the effect oflymphadenectomy on OS barely reached significance (HR 0.85; 95% CI, 0.72 to 1.00; P .0497).In patients without residual diseased and clinically /radiologically normal lymph nodes multivariate analysis did not show any significant impact on overall survival (65). A large multicentre prospectively randomized trial of systematic pelvic and paraaortic (lymphadenectomy (up to the renal vessels) in this group of patients has just completed accrual (LION Trial, AGO-OVAR OP.3 [NCT00712218]) and results are awaited.

There is no proven value or survival benefit in interval/secondary cytoreductive surgery after 3 cycles of chemotherapy to clear any disease remaining after primary surgery despite maximal surgical effort (LoE I, Grade A) (17) unless a maximal attempt at cytoreduction was not performed upfront (LoE Ib). Similarly, a “second look” diagnostic laparoscopy or laparotomy after completion of treatment to assess intraperitoneal status should not be routinely performed, except in the context of pertinent clinical trials, as its impact on survival has not been demonstrated.

References:

47. Timmers PJ, Zwinderman K, Coens C, Vergote I, Trimbos JB. Lymph node sampling and taking of blind biopsies are important elements of the surgical staging of early ovarian cancer. Int J Gynecol Cancer. 2010 Oct;20(7):1142-7.

3. Garcia-Soto AE, Boren T, et.al. Is comprehensive surgical staging needed for thorough evaluation of early-stage ovarian carcinoma? YMOB 2012;206: 242.e1-242.e5. and Timmers PJ, Zwinderman AH, Coens C, Vergote I, Trimbos JB. Understanding the problem of inadequately staging early ovarian cancer. In: Eur J Cancer; 2010. p. 880-884.

4. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014 Apr 17. pii: S0140-6736(13)62146-7. doi: 10.1016/S0140-6736(13)62146-7. [Epub ahead of print] Review.

5. Maggioni A, Benedetti Panici P, Dell'Anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E, Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C. Randomised study of systematic

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lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer. 2006 Sep 18;95(6):699-704. Epub 2006 Aug 29.

6. Schmeler KM, Tao X, Frumovitz M, Deavers MT, Sun CC, Sood AK, Brown J, Gershenson DM, Ramirez PT. Prevalence of lymph node metastasis in primary mucinous carcinoma of the ovary. Obstet Gynecol. 2010; 116:269-73

7. Kleppe M, Wang T, Van Gorp T, Slangen BF, Kruse AJ, Kruitwagen RF. Lymph node metastasis in stages I and II ovarian cancer: a review. Gynecol Oncol. 2011;123(3):610-4. Epub 2011 Oct 6.

8. Powless CA, Aletti GD, Bakkum-Gamez JN, Cliby WA. Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging. And Gynecol Oncol. 2011;122(3):536-40.

9. Fruscio R, Corso S, Ceppi L, Garavaglia D, Garbi A, Floriani I, Franchi D, Cantù MG, Bonazzi CM, Milani R, Mangioni C, Colombo N. Conservative management of early-stage epithelial ovarian cancer: results of a large retrospective series. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2013;24: 138-144.

10. Suzuki M, Ohwada M, Yamada T, Kohno T, Sekiguchi I, Sato I. Lymph node metastasis in stage I epithelial ovarian cancer. Gynecol Oncol. 2000;79(2):305-8.

11. Nomura H, Tsuda H, Susumu N, Fujii T, Banno K, Kataoka F, Tominaga E, Suzuki A, Chiyoda T, Aoki D. Lymph node metastasis in grossly apparent stages I and II epithelial ovarian cancer. Int J Gynecol Cancer. 2010;20(3):341-5.

12. du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d&apos;Investigateurs Nationaux Pour les Etudes des Cancers de l&apos;Ovaire (GINECO). Cancer 2009;115: 1234-1244.

13. van der Burg ME, van Lent M, Buyse M, Kobierska A, Colombo N, Favalli G, Lacave AJ, Nardi M, Renard J, Pecorelli S. The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 1995; 332: 629-34.

14. Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RHM, van der Burg MEL, Lacave AJ, Panici PB, Kenter GG, Casado A, Mendiola C, Coens C, Verleye L, Stuart GCE, Pecorelli S, Reed NS, Group EOfRaToC-GC, Group NCT. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. The New England journal of medicine 2010;363: 943-53.

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15. Aletti GD, Gostout BS, Podratz KC, Cliby WA. Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon. Gynecol Oncol. 2006 Jan;100(1):33-7. Epub 2005 Sep 8. Erratum in: Gynecol Oncol. 2006 Jun;101(3):553.

16. Panici PB, Maggioni A, Hacker N, Landoni F, Ackermann S, Campagnutta E, Tamussino K, Winter R, Pellegrino A, Greggi S, Angioli R, Manci N, Scambia G, Dell&apos;anna T, Fossati R, Floriani I, Rossi RS, Grassi R, Favalli G, Raspagliesi F, Giannarelli D, Martella L, Mangioni C. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. Journal of the National Cancer Institute 2005;97: 560-566.

17. Rose PG, Nerenstone S, Brady MF, Clarke-Pearson D, Olt G, Rubin SC, Moore DH, Small JM. Secondary surgical cytoreduction for advanced ovarian carcinoma. N Engl J Med 2004;351: 2489-97.

59. Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol. 2003;27:985–93

60. Yemelyanova AV, Vang R, Judson K, et al. Distinction of primary and metastatic mucinous tumours involving the ovary: analysis of size and laterality data by primary site with reevaluation of an algorithm for tumour classification. Am J Surg Path 2008;32:128–38.

61. Lee KR, Scully RE. Mucinous tumours of the ovary: a clinicopathologic study of 196 borderline tumours (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'. Am J Surg Pathol. 2000 Nov;24(11):1447-64

62. Rodriguez IM, Prat J. Mucinous tumours of the ovary: a clinicopathologic analysis of 75 borderline tumours (of intestinal type) and carcinomas. Am J Surg Pathol. 2002;26:139–52.

63. Frumovitz M, Schmeler KM, Malpica A, Sood AK, Gershenson DM. Unmasking the complexities of mucinous ovarian carcinoma. Gynecol Oncol. 2010 Jun;117(3):491-6

64. Rouzbahman M, Chetty R. Mucinous tumours of appendix and ovary: an overview and evaluation of current practice. J Clin Pathol. 2014 Mar;67(3):193-7

65. Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials.du Bois A, Reuss A, Harter P, Pujade-Lauraine E, Ray-Coquard I, Pfisterer J; Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom; Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens.J Clin Oncol. 2010 Apr 1;28(10):1733-9. doi: 10.1200/JCO.2009.25.3617. Epub 2010 Mar 1.

Collinson F, Qian W, Fossati R, Lissoni A, Williams C, Parmar M, Ledermann J, Colombo N, Swart A; ICON1 collaborators. Optimal treatment of early-stage ovarian cancer. Ann Oncol. 2014 Jun;25(6):1165-71. doi: 10.1093/annonc/mdu116. Epub 2014 Mar 14.

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6. Systemic treatment of early stage ovarian cancer

Adjuvant platinum-based chemotherapy should be discussed and offered in all cases of early ovarian cancer apart from Ia/Ib G1. (Level I, Grade A)

Adjuvant platinum-based chemotherapy should be discussed and offered in all cases of early ovarian cancer apart from Ia/Ib G1 not only in case of incomplete staging but also to optimally staged higher risk early disease, such as higher grade or serous subtype [LoE 1A].Two prospectively randomized trials examined the value of chemotherapy after surgery in early stage ovarian cancer. ACTION and ICON1 included a broad range of early stage patients with Grade 2 and 3 Stages IA/B - and all grades of stages IC/IIA, in order to recruit sufficient patients. The primary analysis of ICON1 on its own, with a median follow-up of four-years demonstrated a significant improvement in both RFS (Hazard Ratio (HR)=0.65, 95%CI=0.46-0.91, p=0.01) and OS (HR=0.66,95%CI=0.45-0.97,p=0.03) in favour of immediate adjuvant chemotherapy with six cycles of single agent carboplatin (AUC 5/6) (18). Very similar findings were reported in the ACTION trial in which the majority of patients received a platinum-based combination chemotherapy (19).

A recent Cochrane meta-analysis of 5 large prospective clinical trials (4 of 10 with platinum-based chemotherapy) shows that chemotherapy is more beneficial than observation in patients with early stage ovarian cancer (20). Patients who received platinum-based adjuvant chemotherapy had better OS [hazard ratio (HR) 0.71; 95% confidence interval (CI) 0.53–0.93] and PFS (HR 0.67; 95% CI 0.53–0.84) than patients who did not receive adjuvant treatment (20). Nevertheless, in all above mentioned trials only approximately one third of the patients were optimally staged, the remainder having a 30% chance of being understaged and harboring occult disease. Despite this, benefit for chemotherapy in optimally staged patients cannot be excluded and adjuvant chemotherapy should be discussed and offered to all patients with high risk early stage ovary cancer. [1A].

In the planned joined analysis of these two large multicentre prospective randomized trials ICON 1 and ACTION platinum-based adjuvant chemotherapy improved overall survival and recurrence-free survival at 10 years in patients with early-stage ovarian cancer as defined by the inclusion criteria of the two trials (48) (Level I). Overall survival at 10 years was 73% in the chemotherapy arm versus 64% in the observation arm. Recurrence-free survival at 10 years was also better in the adjuvant chemotherapy arm than it was in the observation arm (70% versus 60%) (Collinson 2014). Chemotherapy regimens included single agent carboplatin (87%) and combinations with cisplatin or carboplatin.

The addition of targeted therapies such as bevacizumab and other VEGF inhibitors such as nintedanib and cediranib, tyrosine kinase inhibitors or PARP inhibitors is not of any established evidence, so far and should not be offered outside clinical trials for early stage ovarian cancer. The response rates in non-serous histologies like clear cell, low grade or mucinous tumours is even less, but currently there are no valid studies to offer alternative treatment regimens.

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References

18. Colombo N, Guthrie D, Chiari S, Parmar M, Qian W, Swart AM, Torri V, Williams C, Lissoni A, Bonazzi C; International Collaborative Ovarian Neoplasm (ICON) collaborators. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in patients with early-stage ovarian cancer. J Natl Cancer Inst. 2003;95(2):125-32.

19. Trimbos JB, Vergote I, Bolis G, Vermorken JB, Mangioni C, Madronal C, Franchi M, Tateo S, Zanetta G, Scarfone G, Giurgea L, Timmers P, Coens C, Pecorelli S; EORTC-ACTION collaborators. European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst. 2003;95(2):113-25.

20. Winter-Roach BA, Kitchener HC, Dickinson HO. Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer. Cochrane Database Syst Rev 2009: CD004706.

48. Trimbos JB1, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, Vermorken JB, Torri V, Mangioni C, Pecorelli S, Lissoni A, Swart AM; International Collaborative Ovarian Neoplasm 1; European Organisation for Research and Treatment of Cancer Collaborators-Adjuvant ChemoTherapy un Ovarian Neoplasm. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst. 2003 Jan 15;95(2):105-12.

Collinson F, Qian W , Fossati R, Lissoni R, Williams C, Parmar M , Ledermann J, Colombo N & Swart A on behalf of the ICON1 collaborators. Optimal treatment of early-stage ovarian cancer Annals of Oncology 25: 1165–1171, 2014

7. FIRST-LINE CHEMOTHERAPY FOR ADVANCED DISEASE (FIGO II – IV)

7.1. Neo-adjuvant chemotherapy

Primary debulking surgery is the standard of care where complete or optimal cytoreduction seems achievable in patients with good performance status. Where this is not achievable 2 randomized trials have showed non inferiority of the neoadjuvant approach followed by interval debulking surgery. Both trials demonstrated reduction in morbidity, but equal quality of life in both arms.

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Several prospectively randomized trials have been undertaken to show that treating patients with advanced ovarian cancer with neaoadjuvant chemotherapy followed by interval surgery (after 3 cycles) is no worse than first-line surgery (44,36,37). Overall, some of these trials describe sicker patients who respond to chemotherapy although fewer patients achieved optimal surgical resection rates, perhaps due to the rather limited scope of procedures performed at cytoreduction and less theatre time. (44,36). None of these studies were designed to challenge the accepted understanding that for fit patients, whose disease can be optimally debulked (i.e no residual disease), primary surgery would appear to be the best option. They have however shown that neoadjuvant chemotherapy is an alternative therapy option, associated with lower surgical morbidity and mortality, for those who are unwell with significant comorbidities and / or poor nutrition and / or disease that is unable to be fully resected by a specialized team. Until a definitive trial is conducted both options –upfront vs neoadjuvant- should be discussed with patients with advanced disease and treatment decisions made based on patients’ performance status, symptoms, comorbidities and preference/choice but also on institutional and surgical expertise and resources.

A chemotherapy response score, based on pathologist evaluation of surgically obtained material in comparison with primary omental diagnostic biopsies –the “chemotherapy response score (CRS)” has been developed in a single centre. The three-tier CRS system applied to omental samples from this initial study showed high reproducibility (kappa, 0.67) and predicted progression free survival. The score also predicted sensitivity to first-line platinum therapy. Validation studies are under way and expected to be published soon. (Böhm 2015).

7.2. Intraperitoneal chemotherapy

Intraperitoneal (ip) chemotherapy could be offered within clinical trials and from centres who have the appropriate expertise and resources.

Four randomised clinical trials have shown improved survival with IP chemotherapy, an impact that has been shown to extend even beyond 10 years (49) but because of concerns over potential toxicity, it has not been widely adopted in Europe and is currently the subject of ongoing trials the results of which are eagerly awaited. Meta-analysis of the current trial data suggests that research is still needed to determine the optimal agent, dose and scheduling (Elit 2007). The answer to whether the survival benefit is due to dose dense application of iv / ip paclitaxel or to the IP application per se (50), may be derived from the recently presented trial at SGO in 2016; the GOG 252, a phase III trial of bevacizumab with IV vs. IP chemotherapy for ovarian, fallopian tube, and peritoneal carcinoma. The study showed that the progression free survival was not improved with IP chemotherapy. IV and IP carboplatin arms using weekly dose-dense paclitaxel were better tolerated than the IP cisplatin arm. Neurotoxicity was a major problem on all arms. The investigators concluded that reduced dose IP cisplatin regimen does not appear to be as effective as previously reported high dose

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cisplatin regimens and also that possibly crossover, may have compromised the efficacy. Differences in the cisplatin arm from the GOG 172 study include a dose reduction of cisplatin from 100 mg to 75 mg and a shorter infusion time from 24 hours to 3 hours. Survival data is not yet mature. Fact remains that the study failed to demonstrate an advantage for patients with advanced ovarian cancer or build on results of the GOG172, a landmark trial reported more than a decade ago. An analysis of patient-reported outcomes (PROs)—quality of life, neuropathy, nausea, fatigue, and abdominal discomfort—showed consistently lower scores among patients in the cisplatin arm,. PRO scores did not differ appreciably between the two carboplatin arms, with the exception of slower improvement in abdominal discomfort in patients treated with IP carboplatin. (Walker JL, Brady MF, DiSilvestro PA, et al. A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube and primary peritoneal carcinoma NCI-supplied agent(s): bevacizumab (NSC #704865, IND #7921) NCT01167712 a GOG/NRG trial (gog 252). Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Late-breaking abstract.)

7.3. Adjuvant cytotoxic chemotherapy

The current standard of care in advanced disease is carboplatin (AUC5/6) and paclitaxel (175mg/m2) three weekly for 6 cycles. (Level I, Grade A)

The efficacy and survival benefit of dose dense 1st line regimes is currently being addressed in a large multicentre UK study (ICON 8).

Following surgery, all patients with FIGO stage II-IV ovarian cancer should be offered platinum based chemotherapy +/- paclitaxel [Grade A]. The addition of paclitaxel during the 1990s generated some controversy as to how to interpret the data but the meta-analysis still showed superiority of combination (Covens 2002). The standard of care is thus carboplatin (AUC5/6) and paclitaxel (175mg/m2) given three weekly for 6 cycles. Dose dense scheduling of the paclitaxel (80mg/m2 days 1, 8, 15 every 21 days with carboplatin AUC 5/6 on day 1) has been shown to improve overall survival in a Japanese population. The European equivalent MITO7 phase III trial randomized patients to three weekly carboplatin /paclitaxel as per standard doses (given above) or weekly carboplatin (AUC 2) and paclitaxel (60mg/m2) showed no difference in PFS / OS but the weekly treatment was better tolerated (Pignata 2014). These results may have been related to the lower dose of paclitaxel used in this study. The ICON 8 trial, currently in follow up, has randomized over 1000 patients to receive either three weekly carboplatin / paclitaxel or three weekly carboplatin and weekly paclittaxel (80mg/m2) or weekly carboplatin (AUC 2) and weekly paclitaxel (80mg/m2). [when available = Level 1A]. (22-24).

The addition of a third cytotoxic agent or more cycles has failed to show any survival benefit in various prospectively randomized trials (Bookman 2009, Lambert 1997) [LoE 1A] For those patients who develop allergy to or do not tolerate paclitaxel, the combination of protein-bound paclitaxel (Abraxane)-carboplatin or pegylated liposomal doxorubicin-carboplatin can be considered as alternatives based on two randomized clinical trials that

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showed similar efficacy [LoE 1A] (25,26). Hypersenstivity to carboplatin may occur in which case a desensitisation regimens can be useful (Li 2014) or the carboplatin can be substituted by cisplatin. Although both agents are equally effective treatment related toxicity with cisplatin appears higher.

7.4. Anti-angiogenics in adjuvant first-line treatment of ovarian cancer

Targeted therapies in addition to the conventional 1st line cytotoxic chemotherapy have been shown to significantly increase PFS, but not OS, when given in maintenance. Treatment related toxicity is also significantly increased under targeted therapy. (Level A, Grade I)

Addition of bevacizumab concurrently to chemotherapy and as maintenance for up to 12 months afterwards in the ICON 7 (Perren et al) and for 15 months in the GOG 218 (Burger 2011) has been shown to significantly prolong PFS in patients with advanced disease regardless of their residual disease [LoE 1A]. The prospectively randomized phase III GOG 262 study, showed no survival benefit of the combination of bevacizumab and weekly paclitaxel 80mg/m2 (Level 1, Grade A) (Chan, NEJM 2016). In a not preplanned analysis of 112 patients who did not receive bevacizumab due to patients or physiscians choice, weekly paclitaxel significantly improved their PFS by ~4 months compared to threeweekly regime (Chan, NEJM 2016). The ICON 8B trial opened in 2015 to randomise patients between three weekly carboplatin / paclitaxel with bevacizumab and carboplatin / weekly paclitaxel with and without bevacizumab in order to explore this question further.

The addition of other anti-angiogenic agents eg. the oral tyrosine kinase inhibitors nintedanib and pazopanib have also been shown to have significant efficacy on PFS but not on OS. Pazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy in a large multicentre phase III study but with significantly increased treatment related Grade 3 or 4 adverse events such as hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%). (Level I, Grade A) (du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Harter P. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol. 2014 Oct 20;32(30):3374-82. doi: 10.1200/JCO.2014.55.7348. Epub 2014 Sep 15).

Nintedanib in combination with carboplatin and paclitaxel has also been demonstrated to be an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer in a recent large multicentre phase III trial, but is associated with more gastrointestinal adverse events. (du Bois A1, Kristensen G2, Ray-Coquard I3, Reuss A4, Pignata S5, Colombo N6, Denison U7, Vergote I8, Del Campo JM9, Ottevanger P10, Heubner

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M11, Minarik T12, Sevin E13, de Gregorio N14, Bidziński M15, Pfisterer J16, Malander S17, Hilpert F18, Mirza MR19, Scambia G20, Meier W21, Nicoletto MO22, Bjørge L23, Lortholary A24, Sailer MO25, Merger M25, Harter P26; AGO Study Group led Gynecologic Cancer Intergroup (GCIG)/European Network of Gynaecologic Oncology Trials Groups (ENGOT) Intergroup Consortium. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2016 Jan;17(1):78-89. doi: 10.1016/S1470-2045(15)00366-6. Epub 2015 Nov 16).

Future studies should focus on improving patient selection and optimisation of tolerability.

7.5. Adjuvant / first line chemotherapy in non-serous histological subtypes

The efficacy of conventional chemotherapy in more rare histologies, such as low-grade endometrioid and mucinous subtypes has been shown to be less effective (Mackay 2010). Nevertheless, all large phase III randomized chemotherapy trials so far have included all histologies (not excluding low grade ovarian cancer), and trials focused on rarer histological subtypes has been shown to be challenging mostly due to recruitment issues. For example, a GCIG Intergroup multicentre trial of open label carboplatin and paclitaxel +/- bevacizumab compared with oxaliplatin and capecitabine +/- bevacizumab as first line chemotherapy in patients with mucinous Epithelial Ovarian Cancer (mEOC) had to stop early due to poor recruitment. Furthermore the oncologic safety of omitting adjuvant conventional chemotherapy in these tumourtypes has never been shown in any randomised trials and therefore chemotherapy should be still offered and discussed with the affected patients.

It is hope that the imminent establishment of a national prospective observational study of rare neoplasias of gynaecological origin (RANGO) will allow the collection of information about such rare ovarian tumours in the future. In time, this project will link in with an international Gynaecological Cancer Inter-Group mega-database initiative.

References:Bohm S, Faruqi A, Said I, Lockley M, Brockbank E, Jeyarajah A, Fitzpatrick A, Ennis D, Dowe T, Santos JL, Cook LS, Tinker AV, Le ND, Gilks CB, Singh N. Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma. J Clin Oncol. 2015 Aug 1;33(22):2457-6)

44. Bristow RE, Chi DS. Platinum- based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta- analysis. Gynecol Oncol 2006; 103(3): 1070-6.

14. Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, Verheijen RHM, van der Burg MEL, Lacave AJ, Panici PB, Kenter GG, Casado A, Mendiola C, Coens C, Verleye L, Stuart GCE, Pecorelli S, Reed NS, Group EOfRaToC-GC, Group NCT.

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Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. The New England journal of medicine 2010;363: 943-53

36. Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, Luesley D, Perren T, Bannoo S, Mascarenhas M, Dobbs S, Essapen S, Twigg J, Herod J, McCluggage G, Parmar M, Swart AM. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 2015 May 19. pii: S0140-6736(14)62223-6.

37. Onda T, Yoshikawa H, Shibata T, et al: Comparison of treatment invasiveness between upfront debulking surgery versus interval debulking surgery following neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and peritoneal cancers in phase III randomized trial: JCOG0602. ASCO Annual Meeting. Abstract 5508. Presented May 31, 2014.

Elit L, Oliver TK, Covens A, et al: Intraperitoneal chemotherapy in the first-line treatment of women with stage III epithelial ovarian cancer: A systematic review with meta-analyses. Cancer 109: 692-702, 2007

22. Katsumata N, M Y, Isonishi S, al. e. Long-term follow-up of a randomized trial comparing conventional paclitaxel and carboplatin with dose-dense weekly paclitaxel and carboplatin in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: JGOG 3016 trial. J Clin Oncol 2012;30: (suppl; abstr 5003)

23. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009.

24. Pignata S, Scambia G, Dionyssios Katsaros, Ciro Gallo, Eric Pujade-Lauraine, Sabino De Placido, Alessandra Bologna, Beatrice Weber, Francesco Raspagliesi, Pierluigi Benedetti Panici, Gennaro Cormio, Roberto Sorio, Maria Giovanna Cavazzini, Gabriella Ferrandina, Enrico Breda, Viviana Murgia, Cosimo Sacco, Saverio Cinieri, Vanda Salutari, Caterina Ricci, Carmela Pisano, Stefano Greggi, Rossella Lauria, Domenica Lorusso, Claudia Marchetti, Luigi Selvaggi, Simona Signoriello, Maria Carmela Piccirillo, Massimo Di Maio, Francesco Perrone, on behalf of the Multicentre Italian Trials in Ovarian cancer (MITO-7), Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens et du sein (GINECO), Mario Negri Gynecologic Oncology (MaNGO), European Network of Gynaecological Oncological Trial Groups (ENGOT-OV-10), and Gynecologic Cancer InterGroup (GCIG) Investigators Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7):a randomised, multicentre, open-label, phase 3 trial Lancet Oncol 2014; 15: 396–405

Bookman M, Brady M, McGuire W, Harper P, Alberts D, Friedlander M, Colombo N, Fowler J, Argenta P, De Geest K, Mutch D, Burger R, Swart A, Trimble E, Accario-Winslow

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C, and Roth L. Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup J Clin Oncol 2009 27:1419-1425

Lambert HE, Rustin GJ, Gregory WM, Nelstrop AE. A randomized trial of five versus eight courses of cisplatin or carboplatin in advanced epithelial ovarian carcinoma. A North Thames Ovary Group Study. Annals Onc. 1997; 8(4):327-33.

25. Pignata S, Scambia G, Ferrandina G, Savarese A, Sorio R, Breda E, Gebbia V, Musso P, Frigerio L, Del Medico P, Lombardi AV, Febbraro A, Scollo P, Ferro A, Tamberi S, Brandes A, Ravaioli A, Valerio MR, Aitini E, Natale D, Scaltriti L, Greggi S, Pisano C, Lorusso D, Salutari V, Legge F, Di Maio M, Morabito A, Gallo C, Perrone F. Carboplatin plus paclitaxel versus carboplatin plus pegylated liposomal doxorubicin as first-line treatment for patients with ovarian cancer: the MITO-2 randomized phase III trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011;29: 3628-3635.

26. Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, Parkin D, Paul J, Hay A, Kaye SB. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004;96: 1682-91.

Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 2011; 365:2484-2496

Burger RA, et al. New Engl J Med. 2011;365:2473-2483

Chan JK, Brady MF, Penson RT, Huang H, Birrer MJ, Walker JL, DiSilvestro PA, Rubin SC, Martin LP, Davidson SA, Huh WK, O'Malley DM, Boente MP, Michael H1, Monk BJWeekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer. NEJM 2016 ;374(8):738-48. doi: 10.1056/NEJMoa1505067

49. Tewari D, Java JJ, Salani R, Armstrong DK, Markman M, Herzog T, Monk BJ, Chan JK. Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2015 May 1;33(13):1460-6. doi: 10.1200/JCO.2014.55.9898. Epub 2015 Mar 23.

50. Gore M, du Bois A, Vergote I. Intraperitoneal chemotherapy in ovarian cancer remains experimental. J Clin Oncol. 2006 Oct 1;24(28):4528-30.

21. Andreas Du Bois, Anne Floquet, Jae Weon Kim, Jörn Rau, Jose Maria Del Campo, Michael Friedlander, Sandro Pignata, Keiichi Fujiwara, Ignace Vergote, Nicoletta Colombo, Mansoor Raza Mirza, Bradley J. Monk, Pauline Wimberger, Isabelle Ray-Coquard, Rongyu Zang, Ivan Diaz-Padilla, Klaus H. Baumann, Jae Hoon Kim, Philipp Harter. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed

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after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): Results of an international Intergroup trial (AGO-OVAR16). J Clin Oncol 31, 2013 (suppl; abstr LBA5503)

Covens A, Carey M, Bryson P, Verma S, Fung Kee Fung M, Johnston M. Systematic review of first - line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer . Gynecol Oncol. 2002 Apr;85(1):71-80. Review

Li Q, Cohn D, Waller A, Backes F, Copeland L, Fowler J, Salani R, O'Malley DOutpatient rapid 4-step desensitization for gynecologic oncology patients with mild to low-risk, moderate hypersensitivity reactions to carboplatin/cisplatin. Gyn Oncol 2014 Oct;135(1):90-4. doi: 10.1016/j.ygyno.2014.07.104. Epub 2014 Aug 7

Mackay HJ, Brady MF, Oza AM, Reuss A, Pujade-Lauraine E, Swart AM, Siddiqui N, Colombo N, Bookman MA, Pfisterer J, du Bois A; Gynecologic Cancer InterGroup. Prognostic relevance of uncommon ovarian histology in women with stage III/IV epithelial ovarian cancer. Int J Gyn Oncol 2010 Aug;20(6):945-52. doi:10.1111/IGC.0b013e3181dd0110.

Walker JL, Brady MF, DiSilvestro PA, et al. A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube and primary peritoneal carcinoma NCI-supplied agent(s): bevacizumab (NSC #704865, IND #7921) NCT01167712 a GOG/NRG trial (gog 252). Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Late-breaking abstract.

8. FOLLOW UP

A careful history, assessment of new and potentially tumour related symptoms and clinical examination is essential at follow up visits. (Grade III, Level GPP)CA125 measurement is not mandatory and has not been proven to be of survival benefit. (Level I, Grade A)Patients should ideally have the contact details of their key worker so that they can have early local review for unexpected symptoms. (Grade III, Level GPP)

Follow-up is not only performed to assess risk and/or presence of recurrence but also to deal with ongoing toxicity related to previous therapy and to educate and help patients plan their lives, outlining different treatment and timing options in a holistic manner.

Duration of follow up and intervals between follow up visits varies according to local practices but generally is every 3 months for the first 2 years and then every 6 months, even though there is no randomised trial to prove survival benefit of strict follow up protocols vs

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an individualized patient and symptom led approach.

Rises in CA125 can be used to document progressive disease in patients who achieve a normal CA125 after primary treatment but tend to precede symptomatic relapse by a median of 4.5 months (range 0.5–29.5 months). A prospectively randomized MRC/EORTC trial demonstrated no difference in overall survival (HR 1.00) between patients who received chemotherapy based on a rising CA125 and those who did not receive chemotherapy until they were symptomatic (29). This finding led to many questioning the utility of routine CA125 measurements. However some patients prefer to know as accurately as possible what might lie ahead; for a few a rise in CA125 might indicate surgically resectable recurrence and for others it might trigger imaging which will determine timing and value of further treatment. (Hall 2011) Participation in first-line trials also generally requires regular CA125 measurements in order to accurately determine trial end points. However it has been of high clinical value knowing that rising CA125 alone without clinical or radiographic evidence of recurrence – is not sufficient enough to commence systemic chemotherapy [Grade A].

The results of the prospectively randomized DESKTOP III (NCT01166737) and GOG 0213 (NCT00565851) trials should further define and potentially change practice if they show that secondary debulking is associated with improved survival. Emerging maintenance therapies such as immunotherapy may also alter the aims and characteristics of follow up in the future.

References:

29. Rustin GJ, van der Burg ME, Griffin CL, et al. Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/ EORTC 55955): a randomised trial. Lancet. 2010;376:1155–63.Ann Oncol. 2014 Jul;25(7):1320-7. doi: 10.1093/annonc/mdu119. Epub 2014 Mar 11.

Stuart G, Kitchener H, Bacon M, duBois A, Friedlander M, Ledermann J, Marth C, Thigpen T, Trimble E; participants of 4th Ovarian Cancer Consensus Conference (OCCC); Gynecologic Cancer Intergroup. 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynae Cancer 2011 May;21(4):750-5. doi: 10.1097/IGC.0b013e31821b2568.

Hall M and Rustin G. ‘Relapsed Ovarian Cancer: When to treat and how’Curr Oncol Rep. 2011 Dec;13(6):459-71. Review.

9. MANAGEMENT OF RECURRENT DISEASE

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9.1. Surgery

Cytoreductive surgery could be offered to patients with ovarian cancer relapse, seemingly operable disease (total macroscopic tumour clearance achievable), long treatment free interval and a good performance status, as this has shown to be associated with improved OS and PFS in retrospective studies and metaanalyses (Level IIB, Grade B). Nevertheless patients should be aware that the disease will remain chronic, and that no prospective trials have yet proven a survival benefit.

Palliative surgery e.g. for bowel obstruction should be discussed after failure of all conservative treatments such as placement of endoscopic stents, and after careful consideration of overall patients prognosis, quality of life, previous treatments, future therapeutic options and overall comorbidities. Iatrogenic induced short bowel syndrome with the necessity of long life total parenteral nutrition should be avoided. (Level III, Grade C).

The value of surgery for relapsed ovarian cancer on overall survival of EOC patients has never been established in prospectively randomized trials but where recurrent cancer can be completely removed in appropriate patients, various retrospective series have shown significantly longer OS and PFS compared to women with residual disease following surgery for relapse (27, 28, 32) [LoE IIb], even in multifocal and peritoneal disseminated relapse, as long as total macroscopic tumour clearance could be obtained. Therefore surgery should not be offered to every patient at relapse, but to try to carefully identify surgical candidates who would benefit from a surgical approach. In a large retrospective systematic evaluation (DESKTOP I), patients with 2 out of 3 of the following criteria: complete resection at first surgery, good performance status and absence of ascites, had the best survival (27). Four prospective multicentre randomized trials evaluating the value of surgery at relapse are now underway: DESKTOP III [NCT01166737] which using selection criteria detailed above and just completed recruitment, GOG 213 [NCT00565851] which also incorporates the addition of bevacizumab to chemotherapy, the SOC1 - NCT01611766 from the Shanghai Gynecologic Oncology Group and the SOCceR : (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3337) from the Netherlands. The results of these prospective trials will define the value of cytoreductive surgery at relapse.

Palliative surgery in patients with intestinal and other complications from ovarian cancer requires multidisciplinary input (32). Benefits should be very carefully balanced with risks for each individual patient. Factors such as comorbidities, baseline quality of life, previous response to chemotherapy, treatment intervals and patient wishes all need to be taken into account. Specialized surgical input from gynaecological oncologists rather than general surgeons alone is preferable since they understand the meaningful responses that ovarian cancer patients can have after such ‘palliative’ surgical input and the overall tumorbiology. These complex cases should be managed by dedicated multidisciplinary teams comprising surgical and non surgical gynaeoncologists.

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Attributed to the diffuse tumour dissemination pattern along the peritoneal layers, EOC-patients often present with the clinical picture of impaired intestinal passage or even bowel obstruction in the relapsed setting. The newly emerging novel implementation of targeted therapies with antiangiogenetic potential may additionally favor fistula formation or intestinal perforation (Burger RA, Brady MF, Bookman MA, Monk BJ, Walker JL, Homesley HD, Fowler J, Greer BE, Boente M, Fleming GF, Lim PC, Rubin SC, Katsumata N, Liang SX. Risk factors for GI adverse events in a phase III randomized trial of bevacizumab in first-line therapy of advanced ovarian cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2014 Apr 20;32(12):1210-7. doi: 10.1200/JCO.2013.53.6524. Epub 2014 Mar 17.). EOC complicated by such severe and acute events constitutes a therapeutic dilemma. Progress in endoscopic techniques such as placement of intestinal stents and gastrostomies have improved care of patients with reduced morbidity. However in case of multiple level obstructions a single stent or stoma formation are not helpful and further options such as Percutaneous Endoscopic Gastrostomy to be used for output could be considered for highly selected cases. Surgical interventions should be ideally considered only in case of distal stenosis /blockage otherwise they may end up in high output jejunostomies which significantly impair patients quality of life and would require long life total parenteral nutrition. Preoperative imaging eg CT, gastropgraphin swallow showing the most proximal obstruction should identify patients with a level critical for iatrogenic induced short bowel syndrome. Often a simple palliative stoma formation alone is not feasible due to the severe peritoneal carcinosis and inflammation, that make plane dissections and repair techniques very challenging. (Fotopoulou et.al. Salvage Surgery Due To Bowel Obstruction in Advanced or Relapsed Ovarian Cancer Resulting in Short Bowel Syndrome and Long-Life Total Parenteral Nutrition: Surgical and Clinical Outcome. Int J Gynecol Cancer 2013;23: 1495-1500)

9.2. Systemic treatment of recurrent disease

Recommendations: In patients with longer treatment free intervals (TFI) (eg > 6 months), combination relapse therapy should be consideredIn patients with shorter TFI (eg <3months) single agent relapse therapy is equally effective and less toxicExtending the platinum free interval (PFI) may improve response to subsequent platinum therapy, this can be achieved by utilising maintenance therapies such as bevacizumab

Other than the individual patient’s wishes and co-morbidities, the most important objective factors in decisions about the choice of chemotherapy for relapsed ovarian cancer are interval from the end of the previous treatment to recurrence, duration of response to previous platinum-based therapy, treatment free interval (TFI), and platinum-free interval (PFI). The last three factors are interrelated, and it is likely that they will all influence choice of subsequent chemotherapy regimen as well as neuropathy or other residual toxicity and prior hypersensitivity reactions. The previously defined conventional definitions of platinum

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sensitivity intervals with a six month discriminator were rather arbitrarily chosen based on likelihood to respond to platinum re-treatment and were rooted in older trials from Blackledge (Blackledge 1989, Stuart 2010). In an era of novel and more accurate imaging techniques and with maintenance regimens, these intervals are nowadays more fluent and the traditional definition of platinum sensitive disease is rather outdated (5 th OCCC Consensus Conference, Tokyo, Japan, 2015).

Not only is the duration of response to platinum important but retrospective data suggests that extending the PFI may help improve the patient’s subsequent response to platinum retreatment; there are now several studies supporting this concept (34,35).

In patients with platinum sensitive or partially platinum sensitive ovarian cancer recurrence, published clinical evidence reports response rates to second-line therapy ranging between 27% and 33%, regardless of whether a platinum based re-challenge or non-platinum drugs are used. Combination therapy (such as carboplatin / paclitaxel, carboplatin / liposomal doxorubicin or carboplatin / gemcitabine) improves PFS and OS in this group of patients (33, Raja 2013). The addition of bevacizumab to relapse chemotherapy in the platinum sensitive setting and as maintenance afterwards also increases PFS compared with combination carboplatin / gemcitabine alone and possibly OS although results of the GOG213 study are awaited to confirm / refute this (40, Coleman 2015).

In the platinum refractory / resistant setting, there does not appear to be any advantage in using combination therapies which is associated with higher rates of adverse events. In the platinum-resistant setting, second-line single-agent chemotherapy with non-platinum drugs (such as liposomal doxorubicin, weekly paclitaxel, etoposide or topotecan) results in short-lived response rates of approximately 10% to 25%, regardless of type of drugs used (33). However, the addition of bevacizumab to conventional chemotherapy has been shown to increase PFS compared to monotherapy alone (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan) in a careful selected population (41). If the patient cannot tolerate chemotherapy and/or symptoms are not requiring a rapid response to chemotherapy, then hormonal treatment could be an alternative [Grade B]. Patients with platinum resistant and refractory EOC should be considered for trials with new agents where outcomes should prioritize improvement in symptoms and extending PFS rather than gains in OS. Patient Reported Outcome Measures (PROMs) are thus increasingly used in the clinical trials emerging in this setting.

Palliative radiation has a role in some situations eg. lymph node ulceration. References:

27. Harter P, Hahmann M, Lueck HJ, Poelcher M, Wimberger P, Ortmann O, Canzler U, Richter B, Wagner U, Hasenburg A, Burges A, Loibl S, Meier W, Huober J, Fink D, Schroeder W, Muenstedt K, Schmalfeldt B, Emons G, du Bois A. Surgery for recurrent ovarian cancer: role of peritoneal carcinomatosis: exploratory analysis of the DESKTOP I

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Trial about risk factors, surgical implications, and prognostic value of peritoneal carcinomatosis. Annals of Surgical Oncology 2009;16: 1324-1330.

28. Zang RY, Harter P, Chi DS, Sehouli J, Jiang R, Tropé CG, Ayhan A, Cormio G, Xing Y, Wollschlaeger KM, Braicu EI, Rabbitt CA, Oksefjell H, Tian WJ, Fotopoulou C, Pfisterer J, du Bois A, Berek JS. Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. British journal of cancer 2011;105: 890-896.

32. Christina Fotopoulou, Rongyu Zang, Murat Gultekin, David Cibula, Ali Ayhan, Dongli Liu, Rolf Richter, Ioana Braicu, Sven Mahner, Philipp Harter, Fabian Trillsch, Sanjeev Kumar, Michele Peiretti, Sean C. Dowdy, Angelo Maggioni, Claes Trope, Jalid Sehouli. Value of tertiary cytoreductive surgery in epithelial ovarian cancer: an international multicentre evaluation. Ann Surg Oncol. 2013 Apr;20(4):1348-54. Epub 2012 Oct 2.

Blackledge G, Lawton F, Redman C. et al: Response of patients in phase II studies of chemotherapy in ovarian cancer: Implications for patient treatment and the design of phase II trials. Br J Cancer 59:650-653, 1989

Stuart G, Kitchener H, Bacon M, duBois A, Friedlander M, Ledermann J, Marth C, Thigpen T, Trimble E; participants of 4th Ovarian Cancer Consensus Conference (OCCC); Gynecologic Cancer Intergroup. 2010 Gynecologic Cancer InterGroup (GCIG) consensus statement on clinical trials in ovarian cancer: report from the Fourth Ovarian Cancer Consensus Conference. Int J Gynae Cancer 2011 May;21(4):750-5. doi: 10.1097/IGC.0b013e31821b2568.

33. Hall M and Rustin G. ‘Relapsed Ovarian Cancer: When to treat and how’Curr Oncol Rep. 2011 Dec;13(6):459-71. Review.

34. Tanguay JS, Ansari J, Buckley L, Fernando I. Epithelial ovarian cancer: role of pegylated liposomal doxorubicin in prolonging the platinum-free interval and cancer antigen 125 trends during treatment. Int J Gynecol Oncol. 2009;19:361–6.

35. Colombo N. Efficacy of trabectidin in platinum-sensitive relapsed ovarian cancer: new data from the randomised OVA- 301 study. Int J Gynecol Oncol. 2011;21:S12–6.Raja F, N. Counsell N, Colombo N, Pfisterer J, du Bois A, Parmar M, Vergote I, Gonzalez-

Martin A, Alberts D, Plante M, Torri V & Ledermann J. Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis using individual patient data Annals of Oncology 24: 3028–3034, 2013 doi:10.1093/annonc/mdt406 40. Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent

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epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012 Jun 10;30(17):2039-45. doi: 10.1200/JCO.2012.42.0505. Epub 2012 Apr 23.

Coleman RL, Brady RF, Herzog TJ, et al. A phase III randomized controlled clinical trial of carboplatin and paclitaxel alone or in combination with bevacizumab followed by bevacizumab and secondary cytoreductive surgery in platinum-sensitive, recurrent ovarian, peritoneal primary and fallopian tube cancer. Presented at: Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer 2015; March 28-31, 2015; Chicago, IL. Abstract 3 (late breaking - See more at: http://global.onclive.com/conference-coverage/sgo-2015/Bevacizumab-Regimen-Extends-Survival-in-Phase-III-Ovarian-Cancer-Trial#sthash.C3YwG0Ut.dpuf

41. Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, Pereira D, Wimberger P, Oaknin A, Mirza MR, Follana P, Bollag D, Ray-Coquard I. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014 May 1;32 (13):1302-8. doi: 10.1200/JCO.2013.51.4489. Epub 2014 Mar 17.

Fotopoulou et.al. Salvage Surgery Due To Bowel Obstruction in Advanced or Relapsed Ovarian Cancer Resulting in Short Bowel Syndrome and Long-Life Total Parenteral Nutrition: Surgical and Clinical Outcome. Int J Gynecol Cancer 2013;23: 1495-1500)

10. RARER EPITHELIAL OVARIAN CANCERS

10.1. Low Grade Serous Ovarian Cancer (LGSOC)

Surgery is the most effective management for LGSOC by lower rates of chemotherapy response compared to high grade serous ovarian cancer. (Level IIb, Grade B)

Despite the limitations of the platinum-taxane regimen and no superior alternative at the moment, a proven response rate of almost 25% of platinum-based chemotherapy of LGSOC patients do not justify to withhold chemotherapy in advanced disease (Level IIb, Grade B)

Patients should be registered on rare tumour databases and offered participation into specific LGSOC trials

These constitute about 5% of all serous carcinomas (Köbel 2010), occur in younger women and are characterised by a uniform population of cells arranged typically in papillary clusters and showing sparse mitotic activity. Neither necrosis nor mutation of p53 are features of low grade serous ovary cancer (Altman 2013). Also see serous borderline tumours with invasive implants

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Management of patients with LGSOC is predominantly surgical. Good primary surgery aiming to remove all visible disease is imperative and may be considered again at relapse. Even though response to chemotherapy is lower than in high grade serous counterparts, there are no randomised trials to prove oncologic safety of omitting adjuvant chemotherapy especially in advanced, peritoneally disseminated disease. A large metaanalysis showed a response to platinum based chemotherapy of approximately 24% in patients with advanced primary low grade advanced ovarian cancer after upfront surgery. (Grabowski JP, Harter P, Heitz F, Pujade-Lauraine E, Reuss A, Kristensen G, Ray-Coquard I, Heitz J, Traut A, Pfisterer J, du Bois A. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. Gynecol Oncol. 2016 Mar;140(3):457-62.) The authors conclude that HGSOC and LGSOC differ mainly with respect to its chemosensitivity, but also to its growth pattern and outcome despite complete surgery. The primary cytoreduction with complete tumor resection could be identified as an effective therapy in LGSOC. In contrast, the currently recommended platinum-taxane-chemotherapy showed limited activity in approximately 1 in 4 LGSOC patients. Despite the limitations of the platinum-taxane regimen and no superior alternative at the moment, the available data do not justify to withhold chemotherapy. International multicenter studies on alternative therapies (e.g. MEK inhibitors, hormonal therapy) are urgently needed. Registration on rare tumour databases is also important (Gourley 2014).

10.2. Mucinous carcinoma of the ovary

True advanced mucinous primary ovarian tumours are very rare and systemic management / treatment strategies are very limited. Rare tumour data collection is essential.Exclude mucinous tumours from other organs such as GI tract.

These account for 3 – 5% of all ovarian carcinomas. They are typically confined to the ovary at presentation. The tumours are large and show a continuum of architectural features including benign, borderline and malignant areas. Confluent and expansile patterns of invasion are often seen. However when an infiltrative pattern is present, the pathologist must be alert to the possibility of a metastatic carcinoma. Invasive mucinous carcinoma with an infiltrative pattern has a more aggressive course than mucinous carcinoma with an expansile pattern. Mucinous carcinomas of the ovary exhibit a CK7+/CK20-/CDX2- immunoprofile.

Advanced mucinous tumours, with intra-peritoneal involvement are unlikely to be of ovarian origin as these are very rare (Zaino 2011). Many of these are Krukenberg tumours (see below) or arise from other organs such as the appendix. Ovarian tumours metastatic from appendiceal primaries may have morphological features of mucinous borderline tumours.The presence of dissecting mucin in the peritoneal cavity (psuedomyxoma peritonei) favours this diagnosis. Rarely however advanced mucinous tumours can arise from an ovarian teratoma.Surgery with adequate peritoneal staging is the standard treatment for the majority of primary mucinous ovarian tumours. Fertility sparing surgery should be considered in young women with unilateral disease. Management of advanced true primary ovarian mucinous tumours is challenging as these are not particularly chemo-responsive. The importance of data collection about these rare patients is imperative to allow progress to be made in determining

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appropriate therapeutic strategies. (Ledermann 2014)

Colonoscopy and gastroscopy should be performed to exclude metastasis from the GI tract.

10.3. Other subtypesRarer carcinoma histotypes include malignant Brenner tumour, seromucinous carcinoma and undifferentiated carcinoma. Transitional cell carcinomas are no longer included in the WHO classification. (Kurman RJ 2014). Mesenchymal tumours that are seen in the ovaries include endometrial stromal sarcomas and a variety of other sarcomas. Multiple different histotypes of cancer can also arise from mature teratomas such as squamous cell carcinoma (Glasspool 2014) and carcinoid tumours (Reed 2014)

Mixed epithelial and mesenchymal tumours: Adenosarcoma is a rare biphasic tumour in the ovary composed of malignant mesenchymal and benign epithelial elements. Carcinosarcoma is a commoner neoplasm composed of malignant epithelial and mesenchymal elements. Molecular studies indicate that the sarcomatous components of the neoplasms arise from carcinomatous components. (Jin 2003, Fujii 2000) High-grade serous carcinomas and carcinosarcomas share several molecular abnormalities including aberrant p53 expression and occasional germline mutation of BRCA2. (see above Section..)

Wolffian tumour: Previously termed FATWO (female adnexal tumour of Wolffian origin), this is an uncommon tumour that is presumed to arise from the Wolffian remnants in the adnexal region. The tumour is usually benign and composed of cysts of varying size with sieve like areas admixed with solid and spindled areas.

Ovarian small cell carcinoma of the hypercalcaemic type: This is a rare and highly malignant tumour that typically occurs in young women and is often associated with paraneoplastic hypercalcaemia. The tumours are usually unilateral with extra-ovarian spread in nearly 50% of cases at the time of presentation (Young 1994). A diffuse growth pattern with foci of follicle like spaces is typical. The lining cells are monotonous, showing high grade atypia, brisk mitotic activity and necrosis. On immunohistochemistry (IHC), the cells are positive for WT1 with focal staining for epithelial markers. It has been shown that the cella are characterised by inactivation of the SMARCA4 gene (encoding the BRG1 protein) resulting in a loss of BRG1 protein expression on IHC. (Foulkes 2014). This means that the so-called “ovarian” small cell carcinoma is in fact a malignant rhabdoid tumour. (Reed 2014)

Metastatic carcinoma (incl. Krukenberg tumours): Metastasis to the ovary is not an uncommon phenomenon and sometimes may be the sentinel indication of a cancer. Gross features that favour metastases are small size, bilaterality, nodular appearance and involvement of the ovarian surface. Microscopic features favouring metastases are an infiltrative growth pattern, stromal desmoplasia, necrosis, hilar and vascular involvement. Immunohistochemistry may assist in determining the primary site of a mucinous carcinoma The commonest metastases other than the endometrium or cervix are colorectal, gastric,

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pancreaticobiliary and appendicular carcinomas. The latter may also be the primary site for a borderline mucinous tumour which can progress to the well recognised but rare condition pseudomyxoma peritoneii. Krukenberg tumours are eponymous tumours characterised by bilateral solid ovarian masses that show replacement of the ovarian stroma by signet ring, mucinous cells. The primary site is most often gastric or breast, where similar signet ring mucinous cells are seen.

10.4. BORDERLINE OVARIAN TUMOURS (BOT)

Surgical resection and adequate peritoneal surgical staging has been shown to be associated with a longer PFS in patients with Borderline tumors. (Level III, Grade B)

Borderline ovarian tumors with “invasive” implants as per old FIGO classification are according to the new FIGO classification classified as low grade ovarian cancers.

There is no role in staging pelvic and paraaortic lymph node dissection in patients with BOT. (Level III, Grade B).

It is safe for young patients with BOT to receive fertility sparing surgery, being aware of the higher risk of local relapse (in ipsi- or contralateral ovary), and would therefore need regular sonographic follow up. (Level III, Grade B)

Ovarian epithelial tumours are characterised by a unique category of borderline tumours which implies that although the morphology of these tumours have no invasive characteristics, clinically the behaviour, specifically of the serous and sero-mucinous borderline tumours is not always entirely benign. Borderline endometrioid, clear cell and Brenner tumours behave in a benign fashion as do correctly diagnosed mucinous borderline tumours although these are maintained in the classification. But serous and seromucinous borderline tumours may exhibit a distinct clinical behaviour

Serous borderline tumours (SBTs): These tumours show a typical hierarchical branching pattern lined by cells that show low grade nuclear atypia. When clusters of cells less than 5mm in greatest dimension, typically with a surrounding clear space, are seen in the stroma, the term microinvasion is applied. Microinvasion is seen more commonly in pregnant patients (Mooney 1997) but the presence of microinvasion does not alter the outcome. Women with stage I disease have the same outcome as the general population irrespective of microinvasion (Hannibal 2014)

SBTs can also be associated with peritoneal lesions that are termed implants. When the implants are confined to peritoneal/ mesothelial lined surfaces and lack invasion of underlying tissue they are termed non- invasive implants. Where there is invasion of the underlying fat or muscle, the term invasive implants is used. In some instances, unequivocal

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invasion is not demonstrable, but the lesion displays the cytological features of invasive implants (Bell 2001) WHO 2014 classification recommends that because these lesions with invasive implants may behave like low grade serous carcinomas, they should be designated as such. Finally serous borderline tumours with micropapillary and microacinar architecture have a greater association with extraovarian disease and a higher incidence of recurrence and death from disease than typical SBTs (Seidman 2000) Morphologically, micropapillae typically lack stromal cores and hierarchical branching. They are composed of cells that are cuboidal, have a high nuclear cytoplasmic ratio and form finger like protrusions that are at least five times longer than broad.

Mucinous borderline tumours (MBTs): These typically present as large unilateral masses that are confined to the ovary. There are no well-documented cases of mucinous borderline tumours with implants. Adequate sampling of these tumours is crucial (McCluggage 2010) since they are typically heterogenous and can harbour occult foci of carcinoma. Mucinous borderline tumours are lined by mucinous epithelium with varying degrees of stratification, tufting and papillary formation. When the lining cells are markedly atypical it is termed MBT with intraepithelial carcinoma. MBT with microinvasion is defined as small foci of microinvasion less than 5mm in greatest linear dimension. (Khunamornpong 2011). These features do not appear to affect prognosis adversely in stage 1 tumours. (Lee 2000). Non-ovarian mucinous tumours, including metastatic ovarian mucinous tumours associated with pseudomyxoma peritonei and metastatic mucinous carcinomas (Krunkenberg tumours) with a deceptive pattern of invasion, are recognized as tumours that can simulate primary MBTs. (Ronnett 2004)

Clinical Management of Borderline Tumours Complete tumour resection should be aimed for in all surgery for BOT [Grade B], while adequate surgical staging: peritoneal biopsies, cytology, omentectomy and appendicectomy in case of mucinous histology. A fertility sparing approach in young patients does not preclude adequate peritoneal staging since even in the presence of peritoneal implants, peritonectomies under preservation of at least one ovary and tube and uterus can be performed. Adequate surgical staging at initial presentation of the BOT is a defining factor predicting progression free and overall survival. The largest retrospective evaluation on 950 patients with BOT showed that, in multivariate analysis, higher stage, incomplete staging, residual tumour, and fertility sparing surgery are independent prognostic factors for recurrence. (30). Thus patients should be informed about the risks and benefits of completion staging after simple cystectomy or salpingo-oopherectomy with an incidental finding of BOT. Simple cystectomy in an ovary with BOT carries a risk of relapse. Thus it should be considered mainly for fertility sparing reasons and after thorough informed consent (42). However relapse in these patients is mostly local, and not in terms of peritoneal disease, so that overall prognosis is not impaired and just a completion salpingo-oophorectomy is required. In early stages with small volume masses and in the absence of extensive peritoneal implants this can be performed by laparoscopy [Grade B], since it has been shown that laparoscopy is

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as safe as laparotomy for early stage BOT, from an oncologic point of view. Hysterectomy has no value in complete staging of a patient with BOT, and hysterectomy should be considered if the patient wishes so or for cytoreduction if the uterus is involved with invasive disease (30).

There is no value in lymph node sampling or lymph node dissection in BOT and should therefore not be routinely performed, unless bulky lymph nodes are present in which case they should be removed. [Grade B].BOT can relapse decades after the initial diagnosis, the follow up should therefore be carried out on a long term, especially in patients after fertility sparing surgery. In case of non fertility sparing surgery BOT relapse will be usually localized on the peritoneal layers. There is no value in the routine CA125 based follow up for BOT patients [Grade B].

There is no proven value of cytotoxic chemotherapy in patients with Borderline tumour (30). Relapse of Borderline disease should be mainly treated surgically, if disease seems operable, since response to chemotherapy is small [Grade B].

References

Kobel M, Kalloger SE, Huntsman DG, Santos JL, Swenerton KD, Seidman JD, Gilks CB; Cheryl Brown Ovarian Cancer Outcomes Unit of the British Columbia Cancer Agency, Vancouver BC. Differences in tumour type in low-stage versus high-stage ovarian carcinomas. Int J Gynecol Pathol. 2010 May;29(3):203-11

Altman AD, Nelson GS, Ghatage P, McIntyre JB, Capper D, Chu P, Nation JG, Karnezis AN, Han G, Kalloger SE, Köbel M. The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumours. Mod Pathol. 2013 Sep;26(9):1255-63

Zaino RJ, Brady MF, Lele SM, Michael H, Greer B, Bookman MA. Advanced stage mucinous adenocarcinoma of the ovary is both rare and highly lethal: a Gynecologic Oncology Group study. Cancer. 2011 Feb 1;117(3):554-62

Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumours of the Female Reproductive Organs. 4th Edition IARC Lyon 2014

Jin Z, Ogata S, Tamura G, Katayama Y, Fukase M, Yajima M, Motoyama T.Carcinosarcomas (malignant mullerian mixed tumours) of the uterus and ovary: a genetic study with special reference to histogenesis. Int J Gynecol Pathol. 2003;22(4):368-73.)

Fujii H, Yoshida M, Gong ZX, Matsumoto T, Hamano Y, Fukunaga M, Hruban RH, Gabrielson E, Shirai T. Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity. Cancer Res. 2000

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Jan 1;60(1):114-20).

Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Pathol. 1994;18(11):1102-16)

Mooney J, Silva E, Tornos C, Gershenson D. Unusual features of serous neoplasms of low malignant potential during pregnancy. Gynecol Oncol. 1997;65(1):30-5

Hannibal CG, Vang R, Junge J, Frederiksen K, Kjaerbye-Thygesen A, Andersen KK,Tabor A, Kurman RJ, Kjaer SK. A nationwide study of serous "borderline" ovarian tumours in Denmark 1978-2002: centralized pathology review and overall survival compared with the general population. Gynecol Oncol. 2014;134(2):267-73

Bell KA, Smith Sehdev AE, Kurman RJ. Refined diagnostic criteria for implants associated with ovarian atypical proliferative serous tumours (borderline) and micropapillary serous carcinomas. Am J Surg Pathol. 2001 Apr;25(4):419-32.

Seidman JD, Kurman RJ. Ovarian serous borderline tumours: a critical review of the literature with emphasis on prognostic indicators. Hum Pathol. 2000;31(5):539-57

McGluggage GW, Wilkinson N. Datasets for the histopathological reporting of neoplasms of the ovaries and fallopian tubes and primary carcinomas of the peritoneum (3rd edition). RCPath United Kingdom. November 2010

Khunamornpong S, Settakorn J, Sukpan K, Suprasert P, Siriaunkgul S. Mucinous tumour of low malignant potential ("borderline" or "atypical proliferative" tumour) of the ovary: a study of 171 cases with the assessment of intraepithelial carcinoma and microinvasion. Int J Gynecol Pathol. 2011;30(3):218-30

Lee KR, Scully RE. Mucinous tumours of the ovary: a clinicopathologic study of 196 borderline tumours (of intestinal type) and carcinomas, including an evaluation of 11 cases with 'pseudomyxoma peritonei'. Am J Surg Pathol. 2000;24(11):1447-64)

Ronnet BM, Kajdacsy-Balla A, Gilks CB, Merino MJ, Silva E, Werness BA, Young RH. Mucinous borderline ovarian tumours: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior. Hum Pathol. 2004;35(8):949-60)

Gynecologic Cancer InterGroup (GCIG) Consensus Review for Mucinous Ovarian Carcinoma Jonathan A. Ledermann, MD, FRCP,* Daniela Luvero, MD,* Aaron Shafer, MD,fi Dennis O’Connor, MD,fl Giorgia Mangili, MD,§ Michael Friedlander, MBChB, FRACP, PhD,|| Jacobus Pfisterer, MD,¶ Mansoor R. Mirza, MD,# Jae-Weon Kim, MD,** Jerome Alexandre, MD,fifi Amit Oza, MD, FRPCPC, MBBs,flfl and Jubilee Brown, MD§§ Int J Gynecol Cancer 2014;24: S14YS19

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Gourley, Farley J, Provencher D, Pignata S, Mileshkin L, Harter P, Maenpaa J, Kim J, Pujaide-Lauraine E, MD, Glasspool R, Ray-Coquard I, Gershenson D, Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian and Primary Peritoneal Low-GradeSerous Carcinomas Int J Gynecol Cancer 2014;24: S9YS13

Reed N, Gomez-Garcia E, Gallardo-Rincon D, Barrette B, Baumann K, Friedlander M, Kichenadasse G, Kim J, Lorusso D, Mirza M, Ray-Coquard I Gynecologic Cancer InterGroup (GCIG) Consensus Review for Carcinoid Tumours of the OvaryInt J Gynecol Cancer 2014;24: S35YS41

Reed N, Pautier P, vall-Lundqvist E, Choi C, du Bois A, Friedlander M, MBChB, Fyles A, Kichenadasse G, Provencher D, Ray-Coquard I, Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian Small Cell Cancers. Int J Gynecol Cancer 2014;24: S30Y S33

Glasspool R, Gonzalez Martın A, Millan D, Lorusso D, vall-Lundqvist E, Hurteau J, Davis A, Hilpert F, Kim J, Alexandre J, Ledermann J, Gynecologic Cancer InterGroup (GCIG) Consensus Review for Squamous Cell Carcinoma of the Ovary Int J Gynecol Cancer 2014;24: S26Y S29

30. Borderline tumours of the ovary: A cohort study of the Arbeitsgmeinschaft Gynäkologische Onkologie (AGO) Study Group. du Bois A, Ewald-Riegler N, de Gregorio N, Reuss A, Mahner S, Fotopoulou C, Kommoss F, Schmalfeldt B, Hilpert F, Fehm T, Burges A, Meier W, Hillemanns P, Hanker L, Hasenburg A, Strauss HG, Hellriegel M, Wimberger P, Keyver-Paik MD, Baumann K, Canzler U, Wollschlaeger K, Forner D, Pfisterer J, Schröder W, Münstedt K, Richter B, Kommoss S, Hauptmann S; Arbeitsgmeinschaft Gynäkologische Onkologie (AGO) Study Group. Eur J Cancer. 2013 May;49(8):1905-14.

42. Trillsch F, Mahner S, Woelber L, Vettorazzi E, Reuss A, Ewald-Riegler N, de Gregorio N, Fotopoulou C, Schmalfeldt B, Burges A, Hilpert F, Fehm T, Meier W, Hillemanns P, Hanker L, Hasenburg A, Strauss HG, Hellriegel M, Wimberger P, Baumann K, Keyver-Paik MD, Canzler U, Wollschlaeger K, Forner D, Pfisterer J, Schroeder W25, Muenstedt K26, Richter B27, Kommoss F28, Hauptmann S29, du Bois. Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study11. Supportive needs for patients with ovarian cancerWomen with epithelial ovarian cancer who require elective surgery in the NHS should have access to a holistic assessment with a nurse specialist

Supportive care for women with ovarian cancer 

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Women with ovarian cancer should have the information and support they require be able to make decisions about their care from the time of suspected cancer and diagnosis. The decisions made during this time will impact on their immediate treatment, quality of life and post-treatment consequences. 

According to NICE guidelines1, women with ovarian cancer should be offered information about their disease (including the stage of the disease, treatment options and prognosis, management of side effects, sexuality, fertility, menopause management, signs and symptoms of recurrence, genetic information, self-help strategies, and dealing with emotions) that: 

* is available at the time they want it;

* includes the amount of detail that they want and are able to deal with; and

* is in a suitable format, including written.

For many women, having ovarian cancer and treatment can result in continuing physical, emotional, psychological, financial and spiritual distress, which can give rise to an extensive range of issues and challenges with the potential to affect every aspect of life and ultimately shorten life2. Support and information to women at the time of diagnosis should involve provision of an individual and personalised holistic assessment with a care plan tailored to individual need3,4. This Holistic Needs Assessment (HNA) should be part of every cancer patient’s care5. Effectively assessing individual needs and concerns can lead to early interventions and open up communication based on partnership, empowering the patient towards self-management and the confidence to access available help and support. 

The HNA should be a formal process best led by a framework or tool to ensure that physical, psychological, spiritual emotional and social domains are considered and documented to develop an individualised care plan that can be shared with other healthcare professionals as appropriate2. The HNA, together with a treatment summary, a cancer care review and a health and wellbeing event are key elements of the Recovery Package which, when delivered together, can improve outcomes for people living with and beyond cancer4. 

Supporting women and their families effectively should be co-ordinated through the MDT, where at least one core member with direct clinical contact has training and supervision to enable them to practice at level 2 for the psychological support of cancer patients and carers6.

References

1 National Institute for Health and Clinical Excellence (NICE)(2011). Recognition and initial management of ovarian cancer. (Clinical guideline 122.) www.nice.org.uk/CG122. 2 Hughes C, Henry R, Richards S, Doyle N (2014) Supporting delivery of the recovery package for people living with and beyond cancer. Cancer Nursing Practice 13: 10 , 30 -35. 3 Department of Health, Macmillan Cancer Support, NHS Improvement (2010) The National Cancer Survivorship Initiative Vision. Department of Health, London. 4 Department of Health, Macmillan Cancer Support, NHS Improvement (2013). Living with and beyond cancer: taking action to improve outcomes. Department of Health, London. 5 National Cancer Action Team (2007) Holistic Needs Assessment for people with cancer: a practical guide for healthcare professionals. National Cancer Action Team, London. 6 National Peer Review

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Programme, NHS Improving Quality (2014) Manual for Cancer Services Gynaecology Measures Version 1.0. Crown Copyright (2013), London.

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APPENDICES

Flow charts

NICE GDG

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2014 FIGO ovarian, fallopian tube, and peritoneal cancer staging system and corresponding TNM

Stage I. Tumour confined to ovaries or fallopian tube(s)

TNM staging FIGO staging 2009 Description

T1a-N0-M0 Stage IA Tumour limited to one ovary (capsule intact) or fallopian tube; no tumour on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings

T1b-N0-M0 Stage IB Tumour limited to both ovaries (capsules intact) or fallopian tubes; no tumour on ovarian or fallopian tube surface; no malignant cells in the ascites or peritoneal washings

T1c N0-M0 Stage IC1 Tumour limited to one or both ovaries or fallopian tubes, with surgical spill

T1c-N0-M0 Stage IC2 Tumour limited to one or both ovaries or fallopian tubes, with capsule ruptured before surgery or tumour on ovarian or fallopian tube surface

T1c-N0-M0 Stage IC3 Tumour limited to one or both ovaries or fallopian tubes, with malignant cells in the ascites or peritoneal washings

Stage II. Tumour involves one or both ovaries or fallopian tubes with pelvic extension (below pelvic brim) or primary peritoneal cancer

T2a-N0-M0 Stage IIA Extension and/or implants on uterus and/or fallopian tubes and/or ovaries

T2b-N0-M0 Stage IIB Extension to other pelvic intraperitoneal tissues

Stage III. Tumour involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes.

T1/T2-N1-M0 Stage IIIA1

Stage IIIA1(i)

Stage IIIA1(ii)

Positive retroperitoneal lymph nodes only (cytologically or histologically proven)

Metastasis up to 10 mm

Metastasis more than 10 mm

T3a2-N0/N1-M0 Stage IIIA2 Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes

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T3b-N0/N1-M0 Stage IIIB Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes

T3c-N0/N1-M0 Stage IIIC Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumour to capsule of liver and spleen without parenchymal involvement of either organ)

Stage IV. Distant metastasis excluding peritoneal metastases

Any T, any N, M1

Stage IVA Pleural effusion with positive cytology

Any T, any N, M1

Stage IVB Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397237/table/T1/

Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014 Jan;124(1):1-5. Epub 2013 Oct 22

II. RMI Calculation (31)

Risk of malignancy index (RMI I)

RMI I combines three pre-surgical features: serum CA125 (CA125), menopausal status (M) and ultrasound score (U). The RMI is a product of the ultrasound scan score, the menopausal status and the serum CA125 level (IU/ml).

RMI = U x M x CA125 The ultrasound result is scored 1 point for each of the following characteristics: multilocular cysts, solid areas, metastases, ascites and bilateral lesions. U = 0 (for an ultrasound score of 0), U = 1 (for an ultrasound score of 1), U = 3 (for an ultrasound score of 2–5). The menopausal status is scored as 1 = pre-menopausal and 3 = post-menopausal The classification of ‘post-menopausal’ is a woman who has had no period for more than 1 year or a woman over 50 who has had a hysterectomy. Serum CA125 is measured in IU/ml and can vary between 0 and hundreds or even thousands of units.

U 1 point for each of the followingMultilocular lesionSolid areas

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Bilateral lesionsAscitesIntra abdominal mets

U=1 If ultrasound score is 1U=3 If ultrasound score is 2-5M=1 premenopausalM=3 Postmenopausal (more than 1 year of amenorrhea or women over 50 who have

had a previous hysterectomy)

RMI = U x M x CA 125

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