Sometimes being early is bad news

Diagnostic Timing and Ovarian Cancer Survival

https://tinyurl.com/3aekcbad

Common wisdom has it that the shorter the time before diagnosis of ovarian cancer, the better the outcome. This retrospective survey using data from the UNC cancer registry looked at the interval before diagnosis and compared the outcome of overall survival.

2309 women were included in the survey, the median delay in diagnosis was 33 days after investigation of a relevant presenting symptom. The group was divided into three according to the delay in diagnosis, early with intervals of less than 10 days, a standard group with a median delay of 80 days, and a delayed group whose diagnosis was delayed by more than 120 days.

Results from the survey showed that the early diagnosis and the late diagnosis groups had significantly worse survival outcomes. This finding appears counterintuitive in that the expectation is that a shorter diagnosis delay would result in smaller more confined disease. However, the authors suggest that many of those women diagnosed early may have more aggressive cancer and be sicker.

As in many aspects of ovarian cancer this study demonstrates the complexity of the management dilemma. It has been thought that applying scarce resources to enable early diagnosis would always improve cancer survival. Unfortunately, the study shows this to be debatable. However, it is still important to avoid a long delay before diagnosis which does shorten survival.

Why ovarian cancer incidence is up

Reproductive Shifts and Ovarian Cancer Risk in Women Aged 40 Years or Older

https://tinyurl.com/58neb6xd

For many years the incidence of ovarian cancer was seen to be decreasing, this was thought mostly to be due to hormonal contraception, which results in fewer lifetime menstrual cycles. Now in some populations, especially South-East Asia the incidence is rising.

This population survey of women in South Korea looks at why this is occurring. The study group includes all women aged 40 or more who underwent health screening in 2009 and were followed until diagnosis of ovarian cancer. Those women who had delivered two or more children and breast-fed had a lower risk of ovarian cancer as did women with a history of more than one year’s use of hormonal contraception.

In the last 50 years there has been a dramatic decline in fertility for women in South Korea from a rate of more than four to less than one lifetime births. Also, the menarche is happening earlier. These two factors have the potential to markedly increase the number of lifetime menstrual cycles and warrant close attention to prevent yet more increase in the number of women who develop ovarian cancer.

Cancer after IVF

Cancer Incidence in Women After Medically Assisted Reproduction

https://tinyurl.com/y5pjhxy9

A feature of medical care in the 21st Century has been the rise of Medically Assisted Reproduction (MAR). About one in six couples seek such intervention. This population study of more than 400,000 women in Australia looks at the incidence of cancer following MAR.

The data included MAR treatments, pregnancies, subsequent cancers, and deaths. All the information was obtained from the Medicare Benefits Schedule and the Pharmaceutical Benefits Schedule during the period 1991-2018.

Results from the study showed small increases in the incidence of ovarian, uterine and breast cancer, with a slight increase in the incidence of melanoma. Some cancers were less likely after MAR, these include pancreatic, renal, lung, and myeloid leukaemia. The authors note than the increases are small with overall increase of about 16/100,000 pa. There are some limiting factors in the conclusions in that there is little data about the nature of any malignant change and that the follow-up period is short. Some of the increase in cancers may be due to pre-existing conditions such as endometriosis or PCOS.

Why is chemo so nauseous?

Novel therapies for nausea and vomiting in advanced illness and supportive cancer care

https://tinyurl.com/52nu5m5z

For cancer patients on chemo one of the most distressing adverse effects is nausea and vomiting. About 50% of them experience severe nausea. Some chemo, notably the platinum drugs are even more likely to result in severe nausea, with all patients being affected to some degree. Up to 20% of them will either cease or have their treatment modified because of it. Despite this being so common the cause is little understood.

It is thought that the emetic effect of chemo is due to altered gastric and bowel transit, increased mucosal sensitivity, altered gut-brain communication or psychiatric anxiety, Support for the latter cause comes from the effectiveness of antipsychotic medication such as haloperidol in managing nausea for some patients, these drugs act to block neurotransmitter receptors.

To counter this it is now standard therapy to treat patients prophylactically with Ondansetron being the most used drug, increasingly quadruple therapy, which adds receptor blockers with steroids and anti-psychotic treatment, is employed.

Other forms of treatment are in development. These include Blonanserin an antipsychotic used trans dermally for nausea and Mirtazapine an anti-depressant. In acute presentations inhaling fumes from alcohol infused prep wipes has been shown in controlled trials to be effective and reduce drug costs, this mostly reduces nausea, less so vomiting.

Class actions, who wins?

Australian women file writ against Johnson & Johnson over link between talcum powder causing mesothelioma and cancer

https://tinyurl.com/vzvvj9yh

Class actions or contingent litigation are increasingly common and have become important sources of income for lawyers and third-party funders. This no win, no fee legal process groups together individuals who believe they have been adversely affected by the actions of big corporate business. One of the latest in Australia involves an attempt to obtain financial compensation for cancer caused allegedly by talcum powder. 1300 women have registered an interest in a case to be heard in the Victorian Supreme Court.

Defendants in the writ are the multinational Johnson and Johnson who have been subject to many similar suits in the US. They dispute the link betewen talc and cancer and deny that their product might be contaminated with asbestos, which is a well proven cause  of mesothelioma. In a recent statement the World Health Organisation has classified talc as probably carcinogenic.

The legal process in the US has been lengthy and remains incomplete. No doubt any case in Australia would be similar. Many of the women will not understand the legal delay and judging by previous similar cases, could well be disappointed with the result.

Liquid biopsy trial fail

Implosion of Grail’s Galleri Cancer Screening Test?

https://tinyurl.com/3extfeuh

One of the major goals in cancer research is to develop means of early diagnosis for cancers which typically present at an advanced stage, such as ovarian cancer. The Grail cancer screening test is one such attempt. Using circulating tumour DNA as a marker of disease, the test seeks to identify cancer early to improve survival.

This test has been applied over the last three years in the Galleri Clinical Trial in the UK. The prospective trial has 142000 participants aged between 50 and 77, with possible expansion to one million and is administered by the NHS. The key endpoint is reduction in numbers of cancers presenting on diagnosis as stage 3 or 4, with a later stated goal of fewer than 20% of cancers presenting at stage 4. The trial was controversial with complaints of poor use of limited resources and possible bias. However, political pressure in the form of honouring an electoral promise, ensured it’s commencement.

Now the test manufacturer; Grail has announced the preliminary results which show that the primary endpoint has not been achieved. This has caused a collapse in the stock price of the company and led to no further increase in participants for the NHS-sponsored test. The manufacturer claims it is too soon to evaluate the test; numbers of end stage 4 tumour diagnoses are reduced, and survival benefits will take more time to be seen. Of course they would say that wouldn’t they?

New hope for the platinum resistant

FDA approves pembrolizumab with paclitaxel for platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma

https://tinyurl.com/dndxk5ea

Paclitaxel, a combination therapy of a taxane and a platinum drug for chemotherapy of ovarian cancer has been used for more than 30 years. This combination of a cytotoxic and a growth suppressant radically changed the survival for women with this disease.

Unfortunately, drug resistance to this combination especially to the platinum drug is inevitable and for some women this occurs early in the first 6 months after initial treatment, this is known as “platinum resistance”.

Platinum resistance is a grave finding and difficult to treat. Recent results from a clinical trial called KEYNOTE-B96 have shown promising response to a new combination of immunotherapy and chemo using a checkpoint inhibitor (Keytruda) together with paclitaxel with median improved overall survival of 18 months.

Previously immunotherapy with checkpoint inhibitors has not been shown to be effective for high grade serous ovarian cancer. In the context of platinum resistance there is evidence of change in the immune profile with loss of tumour suppression genetic activity and increased circulating programmed cell death protein (PD-1). It is PD-1 which is the marker of checkpoint protection of cancer cells.

Of the 643 patients in the KEYNOTE trial about 70%  were shown to be PD-1 expressers. Severe side effects meant that treatment was terminated early for 16% of those patients who received Keytruda. However, the significantly improved survival for those women in the treatment arm of the trial has prompted FDA approval of the use of Keytruda in combination with Paclitaxel for treatment of platinum resistant ovarian cancer when PD-1 expression is present.

resistant ovarian cancer when PD-1 expression is shown.