World Ovarian Cancer Day is on 8 May

3 May 2022 

Republished with permission of New Zealand Doctor Rata Aotearoa

8 May is World World Ovarian Cancer Day. While ovarian cancer is an uncommon cancer (350 women a year1). Ovarian Cancer is also the leading cause of gynaecological cancer death (including Maori and Pacifica2). In fact, it kills as many women as all the other gynaecological cancers combined1.

The role of primary practice 
Time to diagnosis is a significant modifiable factor which may impact survival. The historical view that ovarian cancer is a "silent cancer" was disproven in 20003. Research shows that most women with ovarian cancer experience symptoms - many in the earlier stages of the disease4. This provides an opportunity for earlier diagnosis which could improve outcomes5.

Symptoms 
The symptoms women present with are variable but can include one or more of: bloating/distension, early satiety, urinary frequency/urgency, abdominal/pelvic/back pain,  bowel habit changes. But other symptoms including indigestion, nausea, fatigue, abnormal vaginal bleeding/discharge, unexplained weight changes and painful intercourse are also possible3, 5.

While it’s true these symptoms are very common in general practice - in women without ovarian cancer they are usually mild and occur 5 or less days a month6. In contrast, symptoms in ovarian cancer occur more frequently7. Consideration should be given to symptoms which occur often and are new, unusual or worsening. 

On average a General Practitioner (GP) with 2000 patients will see one patient with ovarian cancer every four and a half years8.The DOvE Pilot Project found a cancer incidence of 1 in 58 women aged 50 and over who had been experiencing any symptoms for >2 weeks and <1 year. Just under half were found to have ovarian cancer (1 in 138) with the majority of the remainder receiving a diagnosis of early-stage uterine cancer5.

Because of the non-specific nature of ovarian cancer symptoms, it is common for symptoms to initially be misattributed to irritable bowel syndrome (most common and associated with significantly delayed diagnosis), other gastrointestinal disorders, ovarian cysts, urinary tract infections, menopause, stress or depression3,8.

Risk factors

Ovarian cancer is much more common in the post-menopausal population. However, it is worth noting that one in eight cases occur in NZ women younger than 45 years2 - and in the 20-44 age group, ovarian cancer remains the fifth most common cause of female cancer death in New Zealand2. Younger age is a risk factor for delayed diagnosis3. 

Approximately one in ten ovarian cancers are hereditary9. Both BRCA1 and BRCA2 mutations, and HNPCC (Lynch Syndrome) can significantly increase the risk of ovarian cancer. Depending on the mutation the risk can range from 8%10. to a 44% lifetime risk11. These mutations can be inherited from either genetic parent. Because of this it is important to note if there is a family history of cancer - in particular breast, ovarian or colorectal cancer.

Because most serous ovarian cancers originate from the fallopian tube opportunistic salpingectomy significantly reduces an individual’s risk of ovarian cancer12.

Of less clinical significance a negative history of oral contraceptive use, nulliparity and endometriosis are associated with an increase in the risk of ovarian cancer (but the absolute lifetime risk change is small)9.

Investigations
Practitioners in countries with better survival are more willing to order an ultrasound at first visit for the following scenario “A 53-year-old woman whose last period was 6 months ago. She had experienced abdominal pain for the past 3 weeks. She has had no other symptoms and the same sexual partner for 20 years.”13.

Annual screening in low-risk women can identify ovarian cancer in some women before symptoms develop14 but it is not recommended as it has not been shown to significantly improve survival15. There is no consensus around its use in high-risk populations. In contrast, prompt investigation in symptomatic women is likely of benefit5.

Investigation for ovarian cancer usually includes a pelvic exam, CA-125 blood test and a trans-vaginal ultrasound (TVUS)16. Though pelvic exam has a low sensitivity when used as screening17 it remains an important part of assessment in symptomatic patients. District Health Boards in New Zealand report decreased wait times for ultrasound when positive.

A recent study in the United Kingdom (UK) found CA-125 to be more predictive of ovarian cancer than previously thought with 3.4% of women under and 15.2% of women over 50 years, with a CA-125 result of 35 U/mL or greater receiving a diagnosis of ovarian cancer18. The same study found that 12.3% of women with an elevated CA-125 result were diagnosed with another cancer. 

However, a normal result does not exclude ovarian cancer. In the same study 23% of women with ovarian cancer had a normal result18. A CA-125 <35 U/mL is more likely in younger women18 and early cancer19. In pre-menopausal patients measurements should be avoided immediately before or during menstruation as this can inflate the result20.  

It is possible for both TVUS and CA-125 results to be initially normal (particularly in low volume high-grade serous5) which is why patients should be encouraged to return if symptoms persist. Detection rates may be improved when TVUS is normal by repeating CA-125 measurements 4-6 weeks later if >25 U/mL, or 4 months later if <25 U/mL5. 

New Zealand context

The ovarian cancer situation in New Zealand is concerning. Compared to Australia,16% less women survive 5 years in New Zealand21. 

The International Cancer Benchmarking Partnership is an international collaboration, initiated by the UK, investigating survival differences among seven high-income countries with comparable health systems including New Zealand21. Recent research shows that New Zealand’s 5 year ovarian cancer survival rates of 36% have improved the least of all participating countries in the past 15 years21, while a Christchurch study found advanced ovarian cancer survival rates did not change at all over a ten year period22. UK’s survival has now overtaken NZ - though, along with Ireland, they also significantly lag behind the other participating countries21.

Countries that have shown a marked improvement in ovarian cancer survival have put significant investment into awareness and early diagnosis, sub-specialization of cancer services and have improved access to a number of anticancer drugs and clinical trials when compared to New Zealand.

Cure Our Ovarian Cancer (COOC) has conducted two surveys in the New Zealand Ovarian Cancer Support Group investigating factors (2020, 60+ respondents) and perceptions (2021, 40+ respondents) relating to diagnosis. The results suggest that symptomatic women in New Zealand may wait significantly longer to see a doctor than women in Australia, and longer to receive a diagnosis once they do.  

Most COOC survey respondents delayed presentation to their doctor with just 8% presenting in the first month compared to 55%23 reported in Australia. Over half reported feeling at times like a hypochondriac before their diagnosis. 

When they presented to a doctor, over half of women reported that they felt their doctor did not take their symptoms seriously. On average women had to visit their doctor 3-5 times before receiving the necessary testing to diagnose them. An audit by NZ gynaecological oncologist Dr Keating found that 34% of women in 2019 were diagnosed via the emergency department. Of note one in five survey respondents reported seeing a doctor for over a year before being diagnosed - which suggests overseas research indicating ovarian cancer is unlikely when symptoms are present for more than a year24 - may not apply to the New Zealand situation.

Difficulties accessing consistent evidence-based information is an issue. It is clear that national guidelines on the assessment of symptoms which could be ovarian cancer are required to improve the diagnostic pathway for prompt diagnosis. These should include the use of pelvic examination, a transvaginal ultrasound and CA-125 blood test. 

Respondents to a Cure Our Ovarian Cancer survey distributed through the Royal College of GPs newsletter overwhelmingly identified ultrasound access as a significant barrier to earlier diagnosis. Through Official Information Act (OIA) requests, Cure Our Ovarian Cancer has found that few District Health Boards include any reference to typical ovarian cancer presentations in their written criteria for assessing ultrasound eligibility, though most subscribe to Health Pathways.

While most District Health Boards try to see post-menopausal women with CA-125 ≥35 U/mL and pre-menopausal women with CA-125 ≥ 200 U/mL within 2 weeks (Mid Central DHB is an outlier) - there is significant discordance regarding symptomatic women with lower CA-125 results - with significant wait times in many regions, if indeed they are seen at all. CA-125 is more likely to be <35 U/mL in younger women with ovarian cancer18, and normal in half of all women with early ovarian cancer19. For pre-menopausal women with CA-125 <200 U/mL, and post menopausal women with CA-125 <35 U/mL private referral is the only option in some regions if the pelvic exam is normal. During the OIA process, one fifth of DHBs noted unprompted that referrals rarely included CA-125 test results, so Cure Our Ovarian Cancer initiated OIA requests for volume of CA-125 tests per DHB. Results are still pending but the first six responses show significant differences in regional testing rates from 0.7 to 9.6 per 1000 population. For comparison an English report in 2016 found a difference of 0.1 to 9.0 per 1000 by Primary Care Trust25. According to an ICBP study - primary care doctors in the UK have a significantly lower readiness to investigate on first visit than other countries (NZ not included in analysis) - and this correlates with lower survival13. Cure Our Ovarian Cancer’s survey indicated that just one in five women with ovarian cancer received investigation to diagnose their ovarian cancer on their first visit.

Additionally a lack of clinical trials and research may also have an impact on local survival. New Zealand women have significantly less access to clinical trials relative to Australia and disproportionately little research. A Te Aho O Te Kahu Cancer Agency Report stated that ovarian cancer received the least funding of 13 cancer funded by the Health Research Council between 2006 and 201926. In the time since just one “ovarian cancer” project has been funded. It focuses entirely on BRCA mutations in women with breast cancer27.

Inequity 

Where barriers exist to prompt and effective assessment and treatment they tend to have inequitable impacts in the NZ population. In New Zealand the following inequities have been documented:

Ethnicity: Corrected for age and stage incidence and mortality rates are higher in Pacific and Māori women28.

Socio-economic: Women from deprived areas of New Zealand and Māori and Pacific are more likely to not have tumour grade recorded28. Research from France suggests that women of low socioeconomic status have reduced survival because they are less likely to have surgical resection29.

Gender equity may also be an issue for ovarian cancer. Accident and Compensation Claims (ACC) recently raised the likelihood of gender bias in the NZ health system as a contributing factor to why females make less ACC claims and have more denials30. In the UK almost one in ten women with ovarian cancer are incorrectly told prior to diagnosis that their symptoms could be due to mental health condition31 while in the United States, relative to lethality - prostate cancer receives over 18 times more research funding than ovarian cancer32.

Conclusion

Ovarian cancer is a significant health issue in New Zealand. Women have a lower chance of survival at five years than many comparable countries. GPs have an essential role to rule out ovarian cancer in symptomatic women and diagnose those with cancer in a timely manner. 

Clear nationally applicable guidelines are required to ensure equitable and prompt access to investigations. In addition greater resources, improved treatment availability and further research are urgently required if this situation is to be addressed. 

References 

  1. Ministry of Health. Cancer: Historical Summary 1948–2017. September 2020
  2. Ministry of Health. Cancer: New registrations and deaths 2013. 2016
  3. Goff BA, Mandel L, Muntz HG et al. Ovarian Carcinoma Diagnosis. Cancer 2000; 89(10): 2068-75
  4. Hamilton W, Peters TJ et al. Risk of ovarian cancer in women with symptoms in primary care: population based case-control study. BMJ 2009; 339:b2998
  5. Gilbert L, Basso O, Sampaslis J et al. Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project. Lancet Oncol 2012; 13(3): 285-91
  6. Pitts MK, Heywood W et al. High prevalence of symptoms associated with ovarian cancer among Australian women. Aust N Z J Obstet Gynaecol 2011 Feb; 51(1):71-8.
  7. M. Robyn Andersen, Barbara A. Goff et al. Combining a Symptoms Index With CA 125 to Improve Detection of Ovarian Cancer. Cancer 2008; 113:484–9
  8. BMJ Learning: Recognising early symptoms of ovarian cancer (https://new-learning.bmj.com/course/10014285), accessed Dec 16 2021
  9. Sueblinvong T, Carney M. Current Understanding of Risk Factors for Ovarian Cancer. Curr Treat Options in Oncol 2009; 10(1-2): 67-81
  10. Nakamura K, Banno K et al. Features of ovarian cancer in Lynch syndrome (Review), Mol Clin Oncol 2014 Nov; 2(6): 909–916
  11. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017; 317(23): 2402–2416
  12. R Wendel Naumann, Brittany N Hughes et al. The impact of opportunistic salpingectomy on ovarian cancer mortality and healthcare costs: a call for universal insurance coverage. Am J Obstet Gynecol 2021 Oct; 225(4): 397 e1-397 26
  13. Rose PW, Rubin G, Perera-Salazar R, et al. Explaining variation in cancer survival between 11 jurisdictions in the International Cancer Benchmarking Partnership: a primary care vignette survey. BMJ Open 2015; 5:e007212
  14. Dilley J, Allen P et al. Symptoms reported by women with screen detected invasive epithelial ovarian cancer in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). 2015 (unpublished)
  15. Menon U, Gentry-Maharaj A. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 2021; 397: 2182-93
  16. Funston et al. Variation in the initial assessment and investigation for ovarian cancer in symptomatic women: a systematic review of international guidelines. BMC Cancer 2019; 19:1028 \
  17. Doroudi M, Kramer B et al. The bimanual ovarian palpation examination in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: Performance and complications. Med Screen 2017; 24(4) 220–222
  18. Funston G, Hamilton W et al. The diagnostic performance of CA125 for the detection of ovarian and non-ovarian cancer in primary care: A population-based cohort study. PLoS Med 2020; 17(10):e1003295
  19. Buys S, Partridge E et al. Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: Findings from the initial screen of a randomized trial. American Journal of Obstetrics and Gynecology 2005; 193(5): 1630-1639,
  20. Lehtovirta P, Apter D, Stenman UH. Serum CA 125 levels during the menstrual cycle. Br J Obstet Gynaecol 1990; Oct;97(10):930-3
  21. Arnold M, Rutherford MJ. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995-2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol 2019 Nov; 20(11):1493-1505
  22. Yeoh S, Simcock B et al. Trends in the overall survival rates in women with advanced ovarian cancer in a single tertiary centre in New Zealand. Aust N Z J Obstet Gynaecol 2019; 59: 861–866 
  23. Nagle CM, Francis JE et al. Reducing time to diagnosis does not improve outcomes for women with symptomatic ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2011 Jun; 29(16):2253-8.
  24. M. Robyn Andersen, Barbara A. Goff et al. Combining a Symptoms Index With CA 125 to Improve Detection of Ovarian Cancer. Cancer 2008; 113:484–9
  25. Target Ovarian Cancer. Regional Variation in the diagnosis of ovarian cancer in England, Target Ovarian Cancer 2017 (https://targetovariancancer.org.uk)
  26. Te Aho O Te Kahu Cancer Control Agency. He Pūrongo Mate Pukupuku o Aotearoa 2020 – The State of Cancer in New Zealand 2020 
  27. Health Research Council (https://www.hrc.govt.nz)
  28. Firestone RT, Wong KC et al. Characteristics of ovarian cancer in women residing in Aotearoa, New Zealand: 1993-2004. J Epidemiol Community Health. 2009 Oct;63(10):814-9
  29. Gardy J, Dejardin O, Thobie A, et al. Impact of socioeconomic status on survival in patients with ovarian cancer. International Journal of Gynecologic Cancer 2019; 29:792-801
  30. ACC. ACC’s Delivery to Priority Populations, Part 1 - Women. Published 22 April 21. Reference: GOV-010264 
  31. Target Ovarian Cancer Pathfinder 2016, Transforming futures for women with ovarian cancer (https://targetovariancancer.org.uk)
  32. Spencer RJ, Rice LW et al. Disparities in the allocation of research funding to gynecologic cancers by Funding to Lethality scores. Gynecol Oncol. 2019 Jan;152(1):106-111.