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.

Fatal blood clot

Cancer-associated thrombosis in the era of precision oncology: Mechanisms, challenges and future directions

https://tinyurl.com/52e2xt9p

For people with cancer the risk of dying from other causes is increased. The most likely non-cancer cause of death is from thrombosis. Either arterial clot with possible stroke or infarct or venous clot with subsequent pulmonary embolus. Death from thrombosis is up to 12 times more likely for patients with cancer compared to the general population especially early, during chemo.

This review describes why cancer patients are at high risk of thrombosis; it appears there are two groups of cancers those which are at high risk of thrombosis which includes ovarian cancer patients who have a 20% risk, and those which are relatively low risk, breast cancer is in this group.

Thrombosis is a result of slow blood flow, vascular damage or increased clotting factors. Cancer increases all these hazards with some specific issues such as, platelet adhesion and increase in extracellular DNA fibres which act as a focus for blood clot, these are known as neutrophil extracellular traps (NET). As the cancer progresses and spreads the risk of thrombosis is greater.

The presence of venous clot greater decreases the survival of cancer patients. The authors suggest that thrombosis should be anticipated and prophylactic prevention should be routine for cancer patients.

Time toxicity

Health Care Contact Days in Older Adults with Metastatic Cancer

https://tinyurl.com/yjwcbcpn

Sometimes health care professionals forget or fail to recognise the impact a cancer diagnosis can have on the lifestyle of the individual affected. This retrospective study looked at the Medicare reference data for more than 50000 patients with metastatic cancer of varying types, with a comparison of the number of healthcare contact days in 2008 to the same period in 2019.

Findings from the study showed a significant change with the mean number of contact days increasing by about 50% to around 62 days each year. For some cancers, notably breast cancer, the contact days increased even more sharply.

This represents 16% or more of an individual’s already limited life expectancy; this burden on cancer patients has been labelled “time toxicity”. The authors suggest this information should be included in informed consent communication and that attempts to reduce the number of contact days, by arranging same-day appointments would improve the quality of life for cancer patients.

How ovarian cancer changes the abdomen

 

Ovarian cancer metastasis to the human omentum disrupts organ homeostasis and induces fundamental tissue reprogramming

https://tinyurl.com/ydth346z

One of the most important factors which determine whether women are cured of ovarian cancer is the completeness of the initial surgery. A multi-specialist intervention is now common with surgical oncologists co-operating with gastro -intestinal and renal surgeons to ensure clearance of the cancer. Despite this many women with ovarian cancer who are deemed to have had complete clearance will have tumour recurrence and die.

This research suggests that a reason for this is a change in the tumour microenvironment caused by metastasis to the omentum. Commonly known as the abdominal policeman, the omentum is formed in two parts early in embryological development, the greater omentum is a fold of peritoneum attached to the stomach and colon, the lesser omentum lies between the stomach and liver covering the kidneys and pancreas. Its function is complex partly acting to contain infection and promote immune defence against cancer.

In this small study, samples of the greater and lesser omentum were taken from patients, with and without ovarian cancer and examined to determine any difference. Findings from the study suggest that the omentum loses protective capacity with damage to the normal immune response to cancer. This finding suggests that more extensive surgery particularly involving the lesser omentum may be required for complete clearance. This would increase peri-operative mortality and morbidity.

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.