̽��ֱ�� of Cambridge - Tobias Janowitz

New way of predicting kidney function could improve chemotherapy dosing for many cancer patients

cjb250 — Fri, 07 Jul 2017 20:29:03 +0000

Kidneys perform a number of vital functions, including filtering waste and toxins out of the blood, producing vitamin D, and regulating blood pressure. ̽��ֱ��filtration function of the kidneys is measured by the glomerular filtration rate (GFR), the rate at which blood is passed through the glomeruli, the small blood vessel filters in the kidneys.

Determination of the GFR is important because the assessment of kidney function can indicate how a disease is progressing, whether a drug treatment is having adverse side-effects on key bodily functions, and if it is safe to prescribe a drug at a certain dose, a question of particular importance to cancer doctors when prescribing chemotherapy drugs. However, measuring GFR is technically difficult. Doctors therefore often rely on ways to estimate GFR, which can be relatively inaccurate.

“Almost every patient with cancer gets a measurement of their kidney function, reported as estimated GFR, and this value influences many treatment decisions, but until now, we did not know the best way to provide this value for patients with cancer,” says Dr Tobias Janowitz from the Cancer Research UK (CRUK) Cambridge Institute at the ̽��ֱ�� of Cambridge, joint first author. “Given how important this measure is in day-to-day clinical practice, we felt that we should provide an evidence-based model for its calculation in this context.”

Now, in a study published today in the Journal of Clinical Oncology, the authors describe a new and better way to estimate the GFR, which has been developed using data from a large dataset of over 2,500 patients. They used accurate measurements of GFR to provide a gold standard and then statistical modelling methods to find the best mathematical model to estimate GFR. ̽��ֱ��new model also provides a measure of the uncertainty for this estimate.

To test the use of this revised method of estimating GFR, the researchers focused on the precision of chemotherapy dosing, specifically dosing of carboplatin, which is used to treat multiple cancers, such as lung cancer, germ cell tumours, ovarian cancer, and breast cancer. ̽��ֱ��new model reduced the probability of incorrect dosing for carboplatin substantially compared to the current models used in clinical practice, from more than 20% for the currently published models to 11.7% with the new model.

“Accuracy in chemotherapy dosing is very important,” says Edward Williams, joint first author, also from the CRUK Cambridge Institute. “Too much chemotherapy can be toxic and can even be life threatening, but too little chemotherapy may be ineffective against the cancer. Our model should help doctors calculate chemotherapy doses more accurately and thereby reduce the risk of toxicity or treatment failure.”

̽��ֱ��model has been made available for clinicians to access online free of charge.

“We believe this tool, which is based on stringent methodology, could have a positive impact on the care for a great many patients with cancer,” says senior author Professor Helena Earl from the Department of Oncology at Cambridge. “This is why we have made it free and easily accessible.”

“ ̽��ֱ��limitation of our work that we are most aware of is that due to the patient demographics in our data set, our model does not provide guidance on the impact of race on the estimated GFR, though it is well known that race can be a key variable,” explains Dr Janowitz. “This will be addressed in future work. We are also keen to explore how well the new model performs for patients with diseases other than cancers.

“ ̽��ֱ��work is a very good example of scientists from different specialties coming together to provide an advance for the care that we offer to patients with cancer.”

̽��ֱ��study was supported by Cancer Research UK, the Wellcome Trust, and the National Institute of Health Research Cambridge Biomedical Research Centre.

Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “Chemotherapy drugs are very powerful, so having the correct dose makes an enormous difference to how effective they are and how we can avoid unnecessary side effects. This way of measuring how well a patient’s kidneys are working and how quickly chemotherapy drugs like carboplatin leave the body helps to make our treatments more accurate and better suited to each individual.”

Reference
Janowitz, J et al. A new model for estimating glomerular filtration rate in patients with cancer. Journal of Clinical Oncology; 7 July 2017; DOI: 10.1200/JCO.2017.72.7578

Scientists at the ̽��ֱ�� of Cambridge have developed a new statistical model which estimates kidney function in patients with cancer. This is the most accurate model for estimating kidney function yet developed and should help cancer specialists treat their patients more safely and improve the accuracy of chemotherapy dosing. ̽��ֱ��model is now available free online.

Accuracy in chemotherapy dosing is very important. Too much chemotherapy can be toxic and can even be life threatening, but too little chemotherapy may be ineffective against the cancer

Edward Williams

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CRUK Cambridge Institute

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Weight loss condition provides insight into failure of cancer immunotherapies

cjb250 — Tue, 08 Nov 2016 17:00:36 +0000

Cancer immunotherapies involve activating a patient’s immune cells to recognise and destroy cancer cells. They have shown great promise in some cancers, but so far have only been effective in a minority of patients with cancer. ̽��ֱ��reasons behind these limitations are not clear.

Now, researchers at the Cancer Research UK Cambridge Institute at the ̽��ֱ�� of Cambridge have found evidence that the mechanism behind a weight loss condition that affects patients with cancer could also be making immunotherapies ineffective. ̽��ֱ��condition, known as cancer cachexia, causes loss of appetite, weight loss and wasting in most patients with cancer towards the end of their lives. However, cachexia often starts to affect patients with certain cancers, such as pancreatic cancer, much earlier in the course of their disease.

In research published today in the journal Cell Metabolism, the scientists have shown in mice that even at the early stages of cancer development, before cachexia is apparent, a protein released by the cancer changes the way the body, in particular the liver, processes its own nutrient stores.

“ ̽��ֱ��consequences of this alteration are revealed at times of reduced food intake, where this messaging protein renders the liver incapable of generating sources of energy that the rest of the body can use,” explains Thomas Flint, an MB/PhD student from the ̽��ֱ�� of Cambridge School of Clinical Medicine and co-first author of the study. “This inability to generate energy sources triggers a second messaging process in the body – a hormonal response – that suppresses the immune cell reaction to cancers, and causes failure of anti-cancer immunotherapies.”

“Cancer immunotherapy might completely transform how we treat cancer in the future – if we can make it work for more patients,” says Dr Tobias Janowitz, Medical Oncologist and Academic Lecturer at the Department of Oncology at the ̽��ֱ�� of Cambridge and co-first author. “Our work suggests that a combination therapy that either involves correction of the metabolic abnormalities, or that targets the resulting hormonal response, may protect the patient’s immune system and help make effective immunotherapy a reality for more patients.”

̽��ֱ��next step for the team is to see how this discovery might be translated for the benefit of patients with cancer.

“If the phenomenon that we’ve described helps us to divide patients into likely responders and non-responders to immunotherapy, then we can use those findings in early stage clinical trials to get better information on the use of new immunotherapies,” says Professor Duncan Jodrell, director of the Early Phase Trials Team at the Cambridge Cancer Centre and co-author of the study.

“We need to do much more work in order to transform these results into safe, effective therapies for patients, however,” adds Professor Douglas Fearon, Emeritus Sheila Joan Smith Professor of Immunology at the ̽��ֱ�� of Cambridge and the senior author, who is now also working at Cold Spring Harbor Laboratory and Weill Cornell Medical College. “Even so, the results raise the distinct possibility of future cancer therapies that are designed to target how the patient’s own body responds to cancer, with simultaneous benefit for reducing weight loss and boosting immunotherapy.”

̽��ֱ��research was largely funded by Cancer Research UK, the Lustgarten Foundation, the Wellcome Trust and the Rosetrees Trust.

Nell Barrie, senior science information manager at Cancer Research UK, said: "Understanding the complicated biological processes at the heart of cancer is crucial for tackling the disease - and this study sheds light on why many cancer patients suffer from both loss of weight and appetite, and how their immune systems are affected by this process. Although this research is in its early stages, it has the potential to help make a difference on both fronts - helping treat weight loss and also improving treatments that boost the power of the immune system to destroy cancer cells."

Reference
Flint, TR et al. Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. Cell Metabolism; 8 Nov 2016; DOI: 10.1016/j.cmet.2016.10.010

A weight loss condition that affects patients with cancer has provided clues as to why cancer immunotherapy – a new approach to treating cancer by boosting a patient’s immune system – may fail in a substantial number of patients.

Cancer immunotherapy might completely transform how we treat cancer in the future – if we can make it work for more patients

Tobias Janowitz

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