Disappointing survival data

PARP Inhibitor Maintenance After First-Line Chemotherapy in Advanced-Stage Epithelial Ovarian Cancer A Systematic Review and Meta-Analysis

https://tinyurl.com/ymznp6pu

For women with ovarian cancer personalised care has been game-changing with expectation of longer and better life. PARP inhibitors help to restore DNA repair pathways and have been shown to significantly lengthen progress free survival (PFS). However, like many medical interventions there is a cost, with increased adverse drug reactions some of which, such as leukaemia, can be fatal.

When assessing randomised clinical trials (RCT) for cancer patients the usual endpoint is the PFS. This is because the duration of such a trial is shorter than a trial which looks at overall survival (OS) which requires a greater time span of 5 years or more. This bias towards shorter trials has resulted in a false confidence that PARP inhibitors may also prolong OS.

This multi-centre study looks at data from 7 RCTs of more than 4000 patients, with advanced ovarian cancer treated with PARP inhibitors as maintenance therapy after initial standard care. No improvement in OS was shown in any of the trials and the risk of significant adverse effects was increased, in one instance being almost 5 times more likely.

The authors suggest that there are differences between outcomes for some of the PARP inhibitor drugs with individual response meaning careful therapy choice is required. Also, use of PARP inhibitors for those 50% of ovarian cancer patients without defective DNA repair is of dubious benefit.

Sugar doesn’t feed cancer

Revisiting the Warburg-Based “Sugar Feeds Cancer” Hypothesis: A Critical Appraisal of Epidemiological, Experimental and Mechanistic Evidence

https://tinyurl.com/3v2tysdt

Many clinical care professionals receive queries from cancer patients about whether they should modify their diet to reduce consumed sugar. This concern is based on a misunderstanding of some basic medical research known as the Warburg effect. Research from 1956 showed that cancer cells alter their metabolism to enable increased glucose uptake and increase energy production.

A misunderstanding of this effect has led to incorrect dietary advice to cancer patients suggesting sugar restriction may be beneficial. As a result, malnutrition, which is already a significant cause of morbidity for cancer patients, can be exacerbated. No hard evidence that low sugar diets alter survival exists. Some anecdotal reports suggest a slight correlation with risk. This study is an appraisal of all credible reports which link cancer risk and sugar restriction.

Data was collected for multiple different cancer types. No evidence of any increased cancer risk was found when high sugar consumers are compared to those whose diet fits within the WHO guidelines with sugar, being 10% or less of energy intake. Similarly, no evidence of any survival benefit was shown for cancer patients who restrict sugar intake. It is however important to recognise that obesity does increase cancer risk, possibly due to inflammation.

A complex Genetic profile

Multiple ETS family transcription factors bind mutant p53 via distinct interaction regions

https://tinyurl.com/3znkudu5

The genetic profile of ovarian cancer is complex with more information being acquired all the time. Mutation of the P53 gene is found in almost all cases of High Grade Serous Ovarian Cancer, which is the commonest type.

Normally the P53 gene has a protective action which inhibits abnormal cell division, promotes DNA repair and may cause death of abnormal cancer cells. P53 mutation is common in many cancers and has been the subject of much research. It is unclear whether the mutation has a cancer promoting effect due to loss or gain of function.

This study performed on ovarian cancer cells under laboratory conditions looks at gain of function with increased activity of Erythrocyte Transformation Specific factors (ETS). The ETS promotes cancer spread by multiple means such as new vessel formation, immune suppression and cellular invasion.

Findings from the study show that multiple different ETS proteins have increased activity after binding with mutant P53 genes. With this understanding, the authors suggest that reversal of this TP53 mutation effect may be an important target for new treatments of ovarian cancer.

False assumptions about BMI

Body Mass Index and Chemotherapy Completion among Patients Newly Diagnosed with Ovarian Cancer

https://tinyurl.com/y9jdtek8

It has been common knowledge that obese ovarian cancer patients did not have the same therapeutic benefit from chemo, with lower blood levels of drug activity called relative drug intensity, RDI.

Often women during their course of chemo have variations of the dose, this may be due to adverse side effects prompting dose reduction. Obese women require higher doses of chemo because of their high body surface area. This sometimes meant that the adverse effects were more intense, as a result drug capping of chemo was introduced, especially of the drug Paclitaxel which is part of the commonest initial chemo drug course for oavrian cancer.

The result was that maximum RDI at 100% in the obese is rarely achieved, with consequently less likelihood of cure. As a result, this drug capping was discontinued in 2012. This study looked at RDI achieved in 622 patients from the Yale Tumour Registry who started Paclitaxel treatment during the period 2012-2022.

The results showed that about 1/3rd of the group stopped treatment early with nearly all patients having some interruption of their chemo. Most patients did not achieve an RDI of 100%. The obese patients showed no worse RDI compared to the non-obese and were no more likely to not complete the treatment course.

Is Breastscreen up for change?

Risk-Based vs Annual Breast Cancer Screening: The WISDOM Randomized Clinical Trial

https://tinyurl.com/mpe28amd

Screening women for breast cancer has been a great success. The death rate for women aged 40-70 from breast cancer has been reduced by 45% following the introduction of mammographic screening every two years.

However, this has not been without criticism. The high cost and use of otherwise necessary resources, together with the great number of biopsies and psychological trauma due to cancer anxiety are stated as flaws in the scheme.

The WISDOM clinical trial compared personalized care to standard annual screening. In the randomized trial of over 28,000 women, half were assigned to a risk-based arm. In this arm, women were screened based on genetic and individual risk; for example, those at low risk were not assigned to start regular mammography until age 50. This group’s outcomes were compared to a similar-sized cohort assigned to annual screening.

The initial report shows no disadvantage in terms of advanced (stage IIIB) tumours. The number of biopsies was surprisingly similar in both groups. The authors suggest that risk-based screening is a viable alternative to the current regime.

Some sites of metastases are worse than others

Impact of single-site distant metastases on prognosis in advanced ovarian cancer: a Surveillance, Epidemiology, and End Results population-based study

https://tinyurl.com/4neetm9k

In general, the presence of a distant metastasis is a bad prognostic indicator for women with ovarian cancer. The 5-year survival rate for these women is about 30%.

Distant metastases may occur in the liver, lungs, bones or brain. This study looks at the different survival outcomes for each site. Using the SEER database, which collects cancer information from the US population, the overall survival for 639 patients was determined.

From the information collected the most likely site of distant metastasis is in the liver which was seen in about half of the group. Next the lungs (40%), bones (5%) and brain (1%).

Survival for all these patients is affected. The least impact is seen for those women with liver disease, which has significantly better survival than other distant metastasis sites. This knowledge may help to determine appropriate management of this grave complication of ovarian cancer.

Cancelled RCTs

Characteristics and potential predictors of prematurely terminated interventional clinical trials for ovarian cancer in the ClinicalTrials.gov database

https://tinyurl.com/55efrnfz

Many randomised clinical trials (RCT) do not reach their endpoint with about 25% being terminated for various reasons. This study used data from the Clinical Trials.gov website to discover whether this is true for ovarian cancer also.

The website records all clinical trials recruiting in the US and World-wide, a listing on this site does not require FDA or NIH approval. During the period 2003-2022 1420 RCTs for ovarian cancer were included.

Of these, 21% were terminated early. Mostly this was a result of logistic issues such as recruitment or funding. About 1/5th of the terminations was due to the intervention being non-effective.

The RCTs most likely to be terminated tended to be larger trials requiring big numbers of participants and were more likely when the trial was phase 2. A trial involving multiple large centres of care was most likely to be successfully completed.