The Obesogenic Cancer War – Why Your Patients Need You!

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By Dr Diana Adams for oncologynews.com.au 

Cliff Hudis MD, President of the American Society of Oncology (ASCO), recently stated that obesity is quickly overtaking tobacco as the leading preventable cause of cancer.

We know that type 1 endometrial cancer leads tables in the incidence of obesity linked cancer with adenocarcinomas of the oesophagus, adenocarcinomas of the pancreas, high grade prostate cancers, kidney cancers, gallbladder cancer, some types of breast cancer (both post menopausal and recently established premenopausal) as well as colorectal cancers adding to the growing list of tumours.

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In addition, prognosis is worse with poorer survival if patients are obese in breast (post and premenopausal – the latter following a recent Early Breast Cancer Trials Group meta-analysis presented at ASCO this year), bowel or prostate cancer. As an example we know that 4 in 10 cases of endometrial cancer could be prevented by being a healthy weight and physically active. An info-graphic on ASCO’s website on Obesity’s Link to Cancer is a powerful visual tool in any doctor’s practice.

Obesity prevalence in Australia lies closely behind those in the USA with levels of obesity or overweight in Australia at a record 63% in 2011- 2012 (National Health Performance Agency NHPA data). We are now facing a tsunami of obesity driven cancers which may come in several waves. I use the tsunami example given possibly larger waves are to come beyond the current wave we are facing in our cancer clinics. This is due to the record level of childhood obesity with 1 in 4 children affected. This could lead to an even higher incidence of cancers, possibly occurring at a younger age for obesity driven cancers. And just as a tsunami can hit different shores, this obesity tsunami is affecting many tumour sites as described above – some with more devastating consequences and survivals than others.

Just why is obesity, and specifically central adiposity, a risk factor is for certain types of cancer?

Central adiposity is metabolically active. Adipocytes contribute to a protumerigenic microenvironment with increased systemic inflammation, insulin resistance and increased levels of adipokines with decreased levels of adiponectin.

Adiponectin is produced and secreted by adiopocytes and plays a role in energy metabolism, adipose tissue health and reduces insulin resistance and is inversely correlated with Body Mass Index (BMI) and the Homeostatic Model Assessment (HOMA) Index which is a measure of insulin resistance. In breast cancer, it can reduce aromatase activity and local oestrogen production. More than 10% weight loss can increase levels of adiponectin by 10%.  Its role as a risk biomarker and attractive target for chemoprevention was described in an editorial in the JCO a couple of years ago.

An excellent review on the difference between central adiposity and subcutaneous adioposity was described in Diabetology and the Metabolic Syndrome journal titled “Visceral Adiposity, Insulin resistance and Cancer risk”. It described the differences in preferential distribution of fat initially to subcutaneous then centrally in premenopausal women with this distribution moving to central adiposity upon reaching menopause. Men are described to store fat centrally.

The Obesogenic Cancer War – why your patients needs you

This article is based on a talk given at the COSA ACTNOW Workshop in May to oncologists titled “The Obesogenic Cancer War – why your patients needs you!”. The talk’s motivation comes from a brilliant article by Wendy Demark-Wahnefried in the JCO describing how “You the Oncologist may be optimally positioned to capitalize on the “teachable moment” to guide survivors towards behaviours that improve overall health and physical well being”. Oncologists could do much to help the health of their patients and the nation by transferring health knowledge to lead self empowerment to address the patient’s obesity.

Interventions as both primary (to prevent an obesity driven cancer developing in the first place) and secondary prevention measures to reduce risk of recurrence of future other obesity driven cancers developing are varied. They include exercise, diet and weight loss, metformin (for which there is a plethora of articles including research and observational studies demonstrating benefit) and bariatric surgery with behavioural and supportive therapy with all. ASCO has just brought out a patient and clinician information guide to assist patients in their journey to improve their metabolic health and weight in the hope to improve outcomes. An overweight and obesity model to consider and advocated in the Australian Family Practitioner (the RACGP monthly publication) is the 5 A’s model to Ask and Assess, Advise, Assist and Arrange. Recommendations are to establish a therapeutic relationship with the patient and to communicate and provide care in a way that is person centred, culturally sensitive, non directive and non judgemental.

Publications, including the Annual Report to the Nation on the Status of Cancer 1975-2008, featuring cancers associated with excess weight and lack of physical activity describe clearly the increased incidence of many cancers, adverse effects on quality of life of cancer survivors and worse prognosis for several cancers. Professor David Kerr, Professor of Cancer Medicine at the University of Oxford, in a recent response to a JCO article on link of sedentary behaviour to risk of bowel cancer has a delightful You Tube snippet telling us “today I would like to exhort all of you to get up off your bottoms and exercise”.

We know from the 2010 American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors that there are benefits to exercise in physical functioning, quality of life, and cancer-related fatigue in several cancer survivor groups. There are increasing studies showing improved survival in breast, bowel and ovarian cancer with increasing physical activity.

Exercise interventions have demonstrated both primary and secondary prevention in certain types of breast cancer which has led the field in Exercise Oncology. The Californian Teachers study of 110,599 women without breast cancer showed long term physical activity for more than 5 hours per week reduced the risk of developing oestrogen positive breast cancer by 20 % although an effect was not seen in Er –ve cancers. The Nurses Health Study in breast cancer survivors showed exercise could reduce relative risk of death.

I eagerly await the German SUCCESS-C study which is the First European Lifestyle Study in Breast Cancer with a lifestyle intervention programme as a secondary objective. The first randomisation related to chemotherapy regimen. A second randomisation compares disease-free survival in patients with a body mass index of 24–40 kg/m2 receiving either a telephone-based individualised lifestyle intervention program aiming at moderate weight loss or general recommendations for a healthy lifestyle alone. Weight loss goals, caloric deficits based on BMI and progressive physical activity with the assistance of pedometers, are being studied. In addition, the study will evaluate the predictive role of cancer-associated and obesity-related biomarkers for the prediction of disease recurrence and survival.

The SUCCESS-C trial results are awaited but less encouraging was the impact on a different study that had early closure due to loss of funding. This lifestyle intervention study called the Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) study by Dr Pamela Goodwin, originally planned to study the impact of weight loss on disease free survival in breast cancer patients. The call from Melissa Irwin in the accompanying JCO editorial for Drug Industries to consider a lifestyle intervention arm given the scarcity of funding from government agencies on a large scale, should be noted and hopefully embraced.

Exercise physiologist (E.P) Kerry Courneya and Australia’s own A/Prof Janette Vardy are driving the Challenge adjuvant colon cancer exercise intervention using a randomised clinical trial comparing 3 years of physical activity to health education on disease free survival in colon cancer survivors. It is the first exercise trial with a clinical outcome as its primary endpoint. Nine hundred and sixty two participants are planned and is funded by the NCIC-CTG and in Australis by the NHMRC. The Australian New Zealand Gynaecology Oncology Group (ANZGOG) is planning to run under the PI Professor Michael Friedlander and exercise physiologist Sandy Hayes, the ECHO trial examining exercise in patients undergoing chemotherapy with ovarian cancer as an intervention arm.

What is it about exercise that assists cancer survivors?

oncologynews.com.au ovarian cancer exerciseThis is an emerging field and one I personally need to understand more. Exercise is described quite rightly as the Real Polypill. Muscles make myokines and multiple other factors that may influence tumour behaviour including possibly tumour vasculature.  Exercise physiologist Lee Jones, previously from Duke University and now at the Memorial Sloan Kettering, has described up to 20% loss of cardiovascular capacity during chemotherapy that is never regained if not started during treatment itself. He presents elegant data to demonstrate the safety of even intense exercise during chemotherapy for breast cancer patients and has also demonstrated translational data suggesting reduced proliferation Ki 67 marker in the exercise arm in a neoadjuvant breast study. Lee has spoken at the Inaugural Flinders Biennial Cancer Survivorship conference in 2013 and I encourage you all to attend any sessions he speaks at or can listen to via virtual meetings.

But what about patients not on clinical trials? Where do we send them?

They can be referred by their GP’s via an Enhanced Primary Care (EPC) referral to an ESSA accredited exercise physiologist for 5 Medicare reimbursed sessions. We know this is not enough to modify behaviour but it is a start and I tell my patients to find an exercise with the EP they will likely want to continue. There’s no point in doing 5 sessions in a gym and discovering you will never set foot in there again! We have exercise physiologists now in record numbers here to help our patients yet the Medicare item codes are not wide enough to make use of their true potential. Exercise physiologist Bobby Cheema from the University of Western Sydney describes this well in a paper in the journal Sports Medicine published this year calling for exactly such measures.

So what is the story of metformin?

It is still having its “Lilac time” as mentioned in a JCO editorial and a pun on where it botanically comes from. We know that patients with breast cancer on metformin have better pathological responses to neoadjuvant chemotherapy than those diabetic patients on non metformin medications and better then the non diabetic group. Multiple studies have discussed the role of metformin in breast cancer which lead to the MA 32 study of Professor Patricia Ganz of adjuvant metformin in all subtypes of breast cancer which has accrued and results are awaited. We know the uro-oncologists are now calling for an adjuvant study in metformin in prostate cancer. A systematic review and meta- analysis at ASCO GU of observational studies of metformin in bowel cancer showed a reduced all-cause and Colorectal cancer-specific mortality and adjuvant prospective studies are ongoing.

Metformin’s mechanism of action is still being understood despite is longevity of use on the market. It inhibits mTOR and downstream pathways involved in cell proliferation and survival by inducing AMPK activation as well as acting through cyclic AMP. It is not listed on the PBS for the metabolic syndrome yet – I wonder whether this is where its use as a primary prevention is called for in treating the years of insulin resistance in the context of central adiposity that leads to the cancers I describe above.

Metformin is cheap. It does not cause hypoglycaemia and is the first medication used beyond diet to modify non insulin dependent diabetes. Intolerance can be a problem with nausea and diarrhoea that can herald the more yet incredibly rare lactic acidosis. Alternate formulations of metformin can be tried with mild / moderate intolerance. When used chronically it can lead to B12 deficiency that needs to be monitored. I myself refer my patients to an endocrinologist to discuss the metabolic syndrome and central adiposity. He has a standing desk and passionately advocates the role of dietary measures and exercise as well as metformin in their management.

We know BSA capping in the context of chemotherapy is not advised for the obese with ASCO guidelines just last year. Many queried before these were endorsed, whether outcomes for patients, particularly breast cancer, may have been worse due to under-dosing. However based on data presented by Dr Jennifer Ligibel at ASCO 2013, outcomes are worse for obese breast patients even when not capped inferring obesity is an independent risk factor for poor outcomes and negating arguments that perhaps patients’ survivals are worse by incorrect dosing as the cause. We also know of concerns of how effective aromatase inhibitors are in the context of morbid obesity and excess adipose tissue for the one size fits all dose of drug to inhibit conversion of fat into oestrogen but I await more data on this given the jury is still out.

A word of caution.

Not all obese patients sitting in your oncology practice developed their cancers from being obese and when dealing with the individual patient careful discussions around modifiable risk factors for development must be balanced with this knowledge although advice to modify behaviour after diagnosis can still be given.

Those who know me know I would not leave this article without addressing a societal question on obesity and cancer. Given Cliff Hudis’s acknowledgement that obesity will overtake tobacco, I would like to draw your attention to an editorial and accompanying articles in The Lancet Obesity series from 2011. Titles such as “Urgently needed: a framework convention for obesity control” and “The battle against obesity: lessons from tobacco” were called for.

Richard Nixon at a news conferenceWe know potential reasons for not addressing obesity inducing industries such as the soft drink/ sugar sweetened beverages and fast food are complex. Cycles of food security exist in chronic disease, very well laid out in a NEJM article titled “Hunger and Socioeconomic Disparities in Chronic disease”. Without assisting the economically-challenged to adopt healthier diets it is difficult to modify eating behaviours.

It is ironic that President Nixon who first described the “War on Cancer”, did not want food to be an election issue and corn farmers to struggle, resulting in high fructose corn syrup (HFCS) entering the diets of millions of Americans. It is argued now that HFCS has contributed massively to the obesity epidemic and according to Prof Lewis Cantley, the discoverer of PI3 kinase, who agrees now that fructose is metabolised differently in the liver to glucose and generates on oncolipid.  The FDA has now decided to overhaul food labelling in America in an attempt to curb obesity with clearer labelling of added sugars as well as what a healthy portion size should be.

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This goes back to calls from the Lancet Obesity Series. Should we consider Health Warnings on “energy rich, nutrient poor” foods akin to those labels we have come to know so well on cigarette packages. In Cancer Epidemiology, Biomarkers and Prevention in 2013 we know a higher intake of sugar sweetened beverages and sugar was associated with an increased risk of type I but not type II endometrial cancer, following nicely on an earlier article in JAMA advising the higher consumptions of sugar sweetened beverages is associated with a greater magnitude of weight gain and an increased risk for development of type 2 diabetes in women.

And I realise it is not one macronutrient in junk food that poses the obesity risk, but I marvel how the ACT (State) government Chief Health Minister has managed to ban the sale of fruit juice and soft drink in vending machines at Canberra public schools this year as part of tough measures to tackle the ACT’s alarming rate of childhood obesity.

Our current Federal Government declined a Food Star Rating that could have been the first step to educate the Nation on healthier eating. This is despite calls on the Federal Government from the Obesity Policy Coalition (which includes Cancer Council Victoria) to commit to a National Action Plan to prevent obesity following the figures released by the NHPA I mentioned above. Hopefully the rating will be up and running given its planned reinstatement after much pressure from primary health prevention advocates. I met the Hon. Peter Dutton, our current Federal Health Minister, at an Obesity Forum which specifically showed how interventions in the morbidly obese can lower BMI and improve health outcomes in a multidisciplinary way. I raised the concerns of Childhood obesity to him and its impact of them developing obesity driven future cancers.

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Some do not believe in the “Nanny” state and call to stop “the Food Police”.

I realise an adult individual’s decision-making is autonomous in what he or she does in their health lifestyle choices. However health education for children and for parents including, I believe, better food labelling to assist food and health choices for their children is urgently needed.

I agree with Obesity Policy Coalition’s call on advertising of junk food to children, however masked, be more carefully regulated. It is because we are involved in mankind we have to advocate for our patients and future patients.

I call for my colleagues in the oncology community to work with their patients – will you educate your patients and advocate to address obesity knowing its potential survival and quality of life impact?

 

A tsunami starts as a ripple. A positive wave of awareness and transfer of education to a patient can help our patients ride this crest of the wave of the teachable moment so well promoted in Wendy Demark-Wahnefried’s Review Article. Don’t let us have ignored the warning bells that sounded out when we are so uniquely positioned to help.

The position statements and sentiments in this article are of own personal belief and do not necessarily represent opinions of any of the organisations I am affiliated with.

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Diana Adams

Dr Diana Adams is a Consultant Medical Oncologist at Macarthur Cancer Therapy Centre, Sydney South West Area Health Service.

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