Why does alcohol cause OC?

Alcohol Consumption and Breast and Ovarian Cancer Development: Molecular Pathways and Mechanisms

https://tinyurl.com/39h72xhz

A link between alcohol consumption and increased risk of breast cancer is well known. It now is becoming clear that a similar association with ovarian cancer exists albeit less clear cut.

Alcohol abuse is common, it is estimated that alcohol is the cause of 5% of all deaths. The exact mechanism of increased cancer risk remains uncertain. Recent understanding suggests that in the case of ovarian cancer three important mechanisms are responsible. These are; hormonal modulation, DNA damage, and cellular oxidation.

Alcohol is metabolised in the liver, with acetaldehyde as an intermediate product. Both these substances can damage DNA and disrupt repair. The presence of alcohol in the body causes oxidative stress, with an imbalance of free radicals and antioxidants. In good health free radicals, which are oxygen containing molecules with an uneven electron charge, have an important function to control disease. If the balance is disrupted as with alcohol consumption cellular damage may occur.

Hormonal effects of alcohol are due to disruption of  the normal metabolism via aromatase, sometimes causing breast cancer and Low-Grade Ovarian Cancer.  More extensive damaging effect with increased ovarian cancer risk is suspected,

Further understanding will help to determine whether a safe level of alcohol consumption is possible and enable individuals to make their own risk assessment.

Which is best?

The prognostic influence of hospital type, method of first histological confirmation and time to chemotherapy in patients with advanced primary ovarian cancer

https://tinyurl.com/cburpu7d

There is a constant effort to improve the management of ovarian cancer. It is clear that the best chance of complete cure is at the time of the initial surgery. If the cancer can be completely cleared, survival is more likely.

Towards this end a proposed change in management has been developed, with a two-stage process, whereby an initial limited procedure is performed, to obtain a tissue biopsy, prior to complete clearance.

This review of 115 women with ovarian cancer, looks at whether there is any difference in outcome when the two-stage process is used. Also, the hospital type where the first procedure occurred may be significant, in that complete surgery at a centre of excellence has been shown to be advantageous for survival.

Results from the review showed no difference in overall survival, there was a delay in starting chemo for those having two-stage management. A surprising number of women, (10 out of 55 who had two-stage procedures), developed a metastasis at the entry port for the biopsy. Meaning that progression free survival was worse for them.

Is pollution causing OC?

Outdoor Air Pollution Exposure and Ovarian Cancer Incidence in a United States–Wide Prospective Cohort Study

https://tinyurl.com/yjzydbdz

Ever increasing rates of cancer in young patients has raised the concern that this is a consequence of pollution. For the first time evidence supporting this theory in relation to ovarian cancer is available.

Pollution presents mainly in two forms: particulate material such as micro plastics and sulphur, or gaseous such as nitrous dioxide and ozone. Using information from the” Sisters”study, which enrolled more than 50,000 women who had at least one sister with a history of breast cancer, it was possible to show how rates of ovarian cancer varied in relation to different geographic areas, with different pollution levels.

Results from this prospective analysis showed a positive association with increased nitrous dioxide levels but no association with particulate pollution or increased ozone. Nitrous dioxide is found in the atmosphere as the result of combustion mostly from fossil-fuelled transport or internal heating. Elimination of this pollutant would be a good side effect of more use of electric vehicles.

Is it cost-effective?

Cost and Clinical Implications of Utilizing Homologous Recombination Deficiency Status to Guide First-Line Maintenance Therapy Selection in Advanced Ovarian Cancer

https://tinyurl.com/yrydv7t8

With success comes overuse. A typical example of this is the widespread use of enzyme inhibitors, such as PARPi in ovarian cancer, for women who because of their genotype are unlikely to have any benefit.

The current cost in the US to treat 100 women with PARPi for ovarian cancer is just over  $US 62 million for the 5-year treatment course. This imposes a strain on personal and community finances. If these patients are screened using a biomarker guide (BMG), the cost overall is reduced, (by 17.5%), despite the significant cost  of performing BMG on 100 women.

Savings from treatment also include reduced clinical costs due to prolonged survival and better health. For costly treatment such as targeted enzyme inhibition, it is important to ensure it is only used when most cost-effective. This study shows that for each dollar spent on HRD testing, another twenty-six dollars of savings will result.

Earlier is better

Timing of Palliative Care, End-of-Life Quality Indicators, and Health Resource Utilization

https://tinyurl.com/yc2bf5p3

For most ovarian cancer patients and their carers there comes a time for acceptance and a need for support and compassion. This is best provided through Palliative Care (PC). This study looks at the benefits to the individual and community which result from earlier referral to PC.

Retrospective analysis of the outcomes of more than 8000 women with ovarian cancer showed survival of about 3 years with death around the age of Seventy. 98% of these women received PC. One third of the women did not start PC before the last 3 months of life

There was a significant difference in the amount of aggressive end-of-life care, with fewer admissions to ICU, consultations with specialists, and less late stage chemotherapy for those women who began PC early. Also significant was the lower rate of death in Hospital which was about two-thirds less likely.

Avoiding aggressive end-of-life care has previously been shown to greatly improve the individual’s quality of life. The authors also stress the savings to the community which results from decreased use of high-cost clinical services. Education of care providers and cancer patients towards early PC will benefit all.

Why the FDA withdrew support for PARPi

Regulatory histories of recently withdrawn ovarian cancer treatment indications of 3 PARP inhibitors in the US and Europe: lessons for the accelerated approval pathway

https://tinyurl.com/3mrm6z4r

The recent decision by the FDA to withdraw access to PARP inhibitors for patients with recurrent ovarian cancer has raised issues about the approval process and questions about the efficacy of these drugs

Personalised therapy with enzyme inhibitors such as PARPi has revolutionised the treatment of ovarian cancer. The success, in terms of increased survival, led to pressure for the use of such drugs to be expanded beyond the initial target group to more women.

Real-world experience often causes reappraisal of the benefits and it is now clear that use of PARPi for treatment of recurrent ovarian cancer increases the likelihood of major adverse effects such as marrow suppression. A decrease in survival compared to standard therapy was also seen and long-term use of PARPi reduces the effectiveness of standard platinum-based chemo.

All of these drugs benefited from accelerated approval processes. Recent decisions by the FDA to approve some expensive drugs with contentious experimental evidence, such as aducanumab for dementia, have caused criticism of the accelerated process. The withdrawal of these PARPi drugs will increase the scrutiny and may result in unavoidable delays to important changes in cancer treatment.

Most times it’s not cancer

Ovarian cancer risk among older patients with stable adnexal masses

https://tinyurl.com/5fytnf57

Benign ovarian masses are common. About 30% of women with a normal menstrual cycle will develop an ovarian mass. For women with irregular menstruation this figure increases to 50%.

It is important to recognise this and avoid invasive surgery. This study looks at older women of over 50 years in age and demonstrates that, for stable tumours smaller than 10 cm in size, there is a low likelihood of cancer.

Almost 5000 women in this age group, presented to one community health organisation with ovarian masses, during the period 2016-2020. Of whom, more than 4000 had a stable appearance at repeat ultrasound examination 6 weeks later. Those women, with stable appearances, did not have surgery. 

During the almost 4 years of follow up, the incidence of ovarian cancer was very low, with only 11 cancers being detected (0.27%). The authors suggest that, with a stable appearance at the 6 weeks ultrasound, older women with a small ovarian mass do not need active follow up.

An impossible dream?

Reducing ovarian cancer mortality through screening: an impossible dream?

https://tinyurl.com/4524jh8f

The history of screening tests for ovarian cancer is not good. Two huge trials; the UKCTOCS with more than 200,000 recruits over 20 years and the PLCO trial with more than 3 million pathology samples showed no benefit in terms of survival from ovarian cancer.

This article addresses the stages of ovarian cancer using an alternative approach called the clinical continuum, which divides cancer into 3 phases, no disease, pre-clinical (detectable disease), and clinical (overt cancer).

Obviously for a screening test to be effective, cancer needs to be detected before the clinical phase. However, ovarian cancer is unlike other cancer in that the precursor occurs in the fallopian tube and there is an argument to say that, by the time ovarian cancer has occurred, it is always advanced and metastatic. This time interval between initial and advanced disease has been called, “the sojourn”. A short sojourn implies that screening tests are unlikely to be helpful.

Any ovarian screening test would have to demonstrate cost-effectiveness. Because of the short sojourn, screening would need to be at less than yearly intervals. Also, the authors note the continual decline in the incidence of ovarian cancer, over the last 100 years. These factors make the allocation of scarce resources to ovarian cancer screening unlikely.

Why Old?

The Gut Microbiome in Ageing and Ovarian Cancer

https://tinyurl.com/yk8nt6w6

Ovarian cancer is mostly a disease of the seventh decade. The reasons for this are unclear. One suggestion is that changes in the Gut bacterial flora or microbiome may be associated.

This review looks at which bacteria become more common with age and which decrease. Using data from previously published material, it is clear that bacteria which increase inflammatory change become more common, and that bacteria which assist oestrogen metabolism decrease.

The overall complexity of the microbiome changes with age, with some loss of diversity. However, no correlation of ovarian risk to bacterial diversity has been shown.

Most women with ovarian cancer receive antibiotic therapy during chemo, this has been shown in mice to change the microbiome and decrease survival from ovarian cancer.

No definite association between ovarian cancer and the aged microbiome is known but the inflammatory changes and altered oestrogen metabolism may prove to be important factors in the late presentation.

Prevention better than cure

FIGO position statement on opportunistic salpingectomy as an ovarian cancer prevention strategy

https://tinyurl.com/4db8sj3y

The importance of pre-cancerous change in the fallopian tubes as a precursor to ovarian cancer has led to suggest that removal of the fallopian tubes at the time of other abdominal surgery is a significant protective measure.

Now FIGO, (The International Federation of Obstetrics and Gynaecology) have issued a position statement saying they firmly support this.

Evidence for this position is linked to pilot studies in Canada which showed significant reduction in subsequent ovarian cancer rates when the tubes were removed at the time of hysterectomy, (this is not usual practice). 

In addition, an Austrian study showed good acceptance of additional surgery. When women facing gallbladder removal were offered tube resection, 60% accepted. The average increase in operating time was 13 minutes and there was no extra post-operative complication.

One less cause to worry

The impact of inter-cycle treatment delays on overall survival in patients with advanced-stage ovarian cancer

https://tinyurl.com/mrxpksk9

Many patients with ovarian cancer have interruption of their chemo. This may occur because of adverse side effects of treatment, or external factors such as other priorities and logistic issues.

This interruption may cause anxiety which can be expressed as concern that the chemo is less effective.

This retrospective study looked at more than 1500 women with advanced ovarian cancer first diagnosed during the period 2015-2019. The two-year survival for women who had an uninterrupted chemo course was compared to those whose chemo was unavoidably disrupted. Disruption is common with 37% having breaks of at least 7 days. No difference in survival was seen in the two groups.

Knowledge that chemo is just as effective despite interruption means that factors which affect the patient's quality of life can be addressed without fear of harm.

The real financial cost

Study Finds Nearly $70 Billion in Socioeconomic Losses Across 11 Countries Attributable to Ovarian Cancer

https://tinyurl.com/4spw37yz

Ovarian cancer is extremely costly to the individual, the state and the family of each patient. This study uses a true cost of illness approach to assess the annual economic burden of each case of ovarian cancer in high-, middle-, and low-income countries.

Factors included in this determination include cost of treatment, the opportunity cost of loss of productivity for the individual and the carers and the often-forgotten cost of unpaid carer time.

The sums are mind-boggling with an estimate of almost $70 Billion total annual expenditure and individual costs of up to 120 times the usual health expenditure per capita for low-income countries.

Obviously, there is concern about whether this is sustainable and shows the urgent need to reduce the incidence of ovarian cancer.

Alternative therapy ineffectual

Impact of metformin, statins, and beta blockers on survival in patients with primary ovarian cancer: combined analysis of four prospective trials of AGO-OVAR and ENGOT/GCIG collaborators

https://tinyurl.com/597m54hb

Anecdotal experience has previously suggested that off-label use of some commonplace drugs may improve survival for patients with ovarian cancer. This meta-analysis of 4 prospective randomised trials looks at the effect of some of these.

Data was obtained from the trials which recorded use of the additional drug treatment. The prime purpose of the trials having been assessment of efficacy of the enzyme inhibitor, Pazopanib. From the data, patients could be subdivided into two groups; those who had received additional drug therapy and those who had not.

Finding from the results show that use of off-label drugs was associated with greater co-morbidity. Neither metformin or statin therapy had any effect on survival. Use of betablockers had a negative effect, those patients had worse survival outcomes.

Serendipity

Incidental Findings of Borderline Ovarian Tumour or Ovarian Cancer -Real-World Data on Surgical and Oncological Outcome

https://tinyurl.com/5n8284dj

Sometimes ovarian cancer is found by chance during surgical procedures performed for other reasons. The standard of care for such cases is to undergo a repeat surgical procedure at a specialised surgical oncology centre. This study looks at real-world cases and seeks to determine whether this course of action results in worse outcomes. 

This retrospective survey of 390 patients at Bern Hospital during a 10-year period from 2010 showed 228 cases of either borderline ovarian tumour or ovarian cancer. The outcomes for these women were compared to those for women who were known to have ovarian cancer prior to single stage surgery at the same centre.

Apart from a small delay in starting chemo for those women who has a second operation, no difference in outcomes which include morbidity, mortality, and recurrence intervals was noted. 

Comorbidity, poisoned soil

Charlson’s comorbidity and remission outcomes in women diagnosed with epithelial ovarian cancer.

https://tinyurl.com/2hmnmvp9

Any surgery carries risk. Complex surgery such as that required for total clearance of ovarian cancer has a mortality of 4%. For some women this risk is increased by pre-existing medical conditions known as comorbidity.

This retrospective cohort study seeks to measure the risk increase in the presence of comorbidity. Using the Charlson comorbidity index, which shows associated significant pre-existing disease as a risk factor, even the lowest measure at more than 1 significantly decreased the prospect of complete remission and survival from ovarian cancer.

This means that patients who have one or more other major health issues are less likely to benefit from intensive primary treatment and that maybe alternative therapy, such as maintenance with personalised care should be considered?