Opiates, Surgery and Prostate Cancer

My son, George, showed no fear when it came to the surgical treatment of his osteosarcoma. He had multiple major operations, some lasting more than 12  hours, in which his bones were moved from one place to the next, tissues cut out from one place and refashioned and repurposed elsewhere. With a tumour in his jaw, the surgeons at St George's Hospital in London worked absolute miracles. And, in the end, it wasn't the tumour in the jaw that killed him, but the metastatic spread to the pelvis and elsewhere. To this day I am astounded at the courage my son showed in facing those long, complex operations, but he had every confidence in Nick Hyde and the maxillofacial team at St Georges. And for George the thing that made it bearable was that there was something definitive about surgery - it lead to the physical removal of the tumour assuming that the margins were clear. In this he was not alone, many cancer patients would rather opt for a surgical option rather than rounds of toxic chemotherapy or being blasted with radiotherapy.

However, it is becoming increasingly clear that surgery itself could well be contributing to the metastatic spread of disease, no matter how good the surgeon or how clear the margins are. It is not the surgery itself that seems to be at issue, but the use of opiate-based pain relief (morphine, fentanyl and so on). It's a topic that I have covered a number of times on this site already:

http://www.anticancer.org.uk/2013/09/ketorolac-and-breast-cancer.html

http://www.anticancer.org.uk/2012/03/opiates-cancer-and-naltrexone.html

The culprit is the mu-Opioid Receptor (MOR) pathway that is the main target of the opiate-based pain-killers and which cause increased levels of tumour growth and metastases. We know this from epidemiological studies (looking at what happened to cancer patients after surgery based on what pain relief they had), from studies in animals and from studies in the test tube. The effect is likely due to a number of factors, including the fact that the opiates increase angiogenesis, cause immune suppression and activate a number of pro-cancer pathways.

Another epidemiological study has just been published which looks at the rate of disease progression and overall mortality in prostate cancer patients who have had a radical prostatectomy. The study, 'Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study' has been published in the British Journal of Anaesthesia. The authors used a large sample of patients, matched for age, surgical year, pathological stage, Gleason scores, and presence of lymph node disease and type of anaesthesia - those treated with neuraxial anaesthesia (which has lower use of opiates) and general anaesthesia (using the 'normal' amount of opiate-based pain relief).

The results are clear and in line with the previous studies I have written about. Increased use of opiates is associated with increased risk of disease progression and higher overall mortality.

The question we need to be asking ourselves now is not whether opiates in surgery are risky for cancer patients, the evidence is there in plain sight. The question we need to be asking now is how can we ensure that clinical practice changes and changes soon? One step in the right direction is the clinical trial being run by Dr Patrice Forget in breast cancer patients:

http://www.anticancer.org.uk/2013/09/q-with-dr-patrice-forget-ketorolac-and.html

But at the same time, if I was a cancer patient about to have surgery I know that I would be wanting to speak to my surgical team and pointing them in the direction of these various results. At the very least I would be wanting to explore the use of methylnaltrexone if there is no option but opiate-based pain relief.

Osteosarcoma - A Small Step Forward?

In the past I have written about Dr Stefano Fais in Italy and his work on the use of anti-acid drugs in relation to cancer, for example here and here.In particular his work using proton pump inhibitors (PPI), some of them over-the-counter drugs, to change the tumour micro-environment shows huge potential for therapeutic benefit to patients. One example of this was work done using lansoprazole and standard chemotherapy to treat pets afflicted with cancer, to quote from my previous article:

...this study uses a cheap and readily available drug that is widely used, thus short circuiting many years of safety testing. It is part of a welcome trend in using existing drugs for tackling cancer and cancer-related conditions – other notable examples include the anti-diabetic drug metformin, beta blockers, celecoxib and aspirin. Finally, as with many of the other off-label drugs listed, the target here isn't cancer cells directly, but the tumour microenvironment.  Without a supportive microenvironment, cancer cannot thrive and prosper, which is exactly what we want. In this case, by attacking the microenvironment it means that existing chemotherapy drugs can work more effectively and kill the cancer cells. The hope now is that these results can be replicated in a wide range of human cancers, making them susceptible again to the chemotherapy that all too often stops working.

In a new paper Dr Fais and colleagues report a small clinical trial that combined a PPI drug with the standard treatment for osteosarcoma (the bone cancer that killed my son, George). Now the standard treatment for osteosarcoma is multi-drug chemotherapy followed by surgical resection of the bone tumour. A key prognostic marker for this treatment is to look at the degree of cancer cell death in the tumour after it has been removed. A good response is normally when there is greater than 90% tumour necrosis, less than 90% is counted as a poor response to the chemotherapy. So, for this trial Dr Fais and colleagues added pre-treatment with the anti-acid drug Esomeprazole to the standard four drug chemotherapy treatment for osteosarcoma.

The results show that there was a higher rate of good responses in patients taking the esomeprazole prior to chemotherapy compared to historical controls. In the case of the chondroblastic subtype of osteosarcoma the difference in the number of good responders is truly striking. Overall though across all types of osteosarcomas the difference was 47% good responders in the control group versus 57% in the PPI group.

This was a small study, not randomised (due to the fact that osteosarcoma is a relatively rare cancer), and it was looking at response to chemotherapy and not overall survival, but with those caveats this is an important step forward. It adds significantly to the evidence that adding PPI to existing treatments can have positive effects. And, in terms of osteosarcoma, it shows that there is something that can be done to incrementally improve treatments for a disease that remains stubbornly hard to treat.

Losartan - High-Blood Pressure Drug Helps Fight Cancer

We treat cancer with the most vicious, toxic and carcinogenic drugs available to science in the form of chemotherapy. But the fact is that the chemotherapy drugs are brutally effective at killing cells - at least initially, and at least when they can get to the cells we want to target. But, as we all know, most chemotherapy drugs are not easily targeted and end up killing plenty of non-cancerous cells. Not only that, cancer cells are also able to find various methods of shielding themselves from the poisonous brew or they mutate and become resistant. This means that no matter how good chemo drugs are at killing cells, if tumour cells are able to hide or adapt then that killing power is ultimately useless (not to say downright dangerous to the rest of the body). The upshot of this is that finding ways of getting more chemotherapy to more cancer cells is a hugely useful strategy if we can do it.

One mechanism by which cancer cells cells are shielded from chemotherapy (and other treatments, including radiotherapy), is through the decreased blood supply inside solid tumours. As tumours develop they constrict blood vessels into the interior of the tumour, stopping nutrients and oxygen getting to the cells deep inside the mass. With the vessels so constricted it's also the drugs carried in the blood supply - like chemotherapy drugs - which are cut off from the cells at the heart of the tumour. Furthermore, in response to this restrict supply of food and oxygen, the cancer cells adapt and become more aggressive and able to cope with the harsh conditions that surround it. These adapted cells are also more likely to form metastases, spreading the cancer to other parts of the body where conditions are easier, at least initially.

One possible way to stop this is to look at 'tumour vasculature normalisation' as a therapeutic strategic. The idea behind this is that by reducing the constriction of blood vessels into the tumour, then blood, oxygen and blood-borne drugs can make it into the heart of the tumour. In this way there is a reduced push towards more aggressive mutations, reduced risk of metastases and of course a greater delivery of cancer-killing drugs like chemotherapy. It seems counter-intuitive to want to make it easier for tumours to have a blood supply, but sometimes it's the counter-intuitive ideas that work the best in practice.

Campaign For Earlier Bone Cancer Diagnosis

I have written before about the poor record we have in the UK regarding osteosarcoma, the disease that ultimately killed my son George. It  is a scandal that survival rates have not improved for more than 25 years in this country, and that the figures are lower than for comparable countries in Europe and North America, (see for example my article on dismal bone cancer statistics). Figures from Cancer Research UK suggest that survival for many common cancers has doubled in the last 40 years, but there has been no change in the 54% overall survival rates for bone cancers (osteosarcoma and Ewings sarcoma) in 25 years. I don't know about you, but I find that shocking.

In a bid to address this the Bone Cancer Research Trust, in alliance with the Royal College of GPs, has launched a new e-learning module to help doctors recognise and diagnose bone cancers earlier. The idea being that earlier disgnosis will lead to better outcomes as there is less disease and lower risk of metastates at diagnosis. I know from our own experience with George that it took many weeks of visits to a number of oncology departments before even the experts were able to diagnose osteosarcoma of the jaw. Admittedly this is a rare cancer, but too many doctors were not alerted to the possibility that a numbness of the lips is a warning of cancer in the jaw. Bone cancers are more common in the long bones of the arms and legs, but we know from other parents that we met that even in the more common cases there were long delays in their children being diagnosed.

While we should welcome the campaign to get earlier diagnosis and improve the recognition of the key symptoms, we also need to make sure we do more to research on new treatments. As with many cancers, it is often metastatic disease that kills, not the primary tumour. So it's with some interest that we note that one of the cancers that has a bimodal pattern of recurrence is osteosarcoma. As with breast cancer, there is a spike of metastases/recurrence in the first couple of years after surgical treatment. This is the trigger for the work of Dr Patrice Forget, who has found that treatment with the anti-inflammatory pain-killer ketorolac at the time of surgery massively reduces the rate of recurrence in breast cancer patients. Perhaps it's time we looked at osteosarcoma in the same way. Can the pattern of metastases/recurrence be massively reduced by the use of ketorolac (or other similar drugs) before and during surgery?

Q & A With Dr Patrice Forget: Ketorolac and Breast Cancer

In the previous article on this site I wrote about recent work that showed that the use of a cheap, safe and generally available anti-inflammatory pain killer (ketorolac) had the potential to massively reduce the incidence of cancer relapse following surgery. This extraordinary result was discovered by a Belgian anaesthesiologist Dr Patric Forget and colleagues. Now working on a clinical trial to put this finding under test, Dr Forget kindly agreed to respond to a short interview to give us more of background to his research.

PP: What prompted your initial investigations - did you expect to find the results that you found?

PF: The diverse long term effects of anaesthetic techniques and analgesic medications have been suspected for many years. Discrepancies exist about the effect on outcome in humans. Concerning opioids, many data exist, but results are inconsistent. Concerning NSAIDs, animal data are consistent, but no human data are available. Therefore, we investigated it in the prospective patients listing existing in our Cancer Centre. Nevertheless, the magnitude and the repetition of the NSAIDs data were relatively unexpected.

PP: What are the clinical factors that influence the choice of ketorolac versus other medications?

PF: The anaesthesiologists have to make choices for which there are not always evidence-based guidelines. This is the case with single NSAIDs dose in the perioperative period. The usefulness of this single dose in terms of analgesia improvement is still matter of debate. The American Society of Anesthesiology has no definitive recommendations about it. Consequently, in many centres, including ours, some anaesthesiologists use it systematically, and others not.

PP: Your findings suggest that other interventions - such as taking a surgical biopsy - could also have a negative influence on cancer outcomes. What is your view on this?

PF: Inflammatory pathways are implicated in the development of cancer. It is probable that the degree of tissue injury during surgery is associated with cancer outcome. Nevertheless, whether  this effect is mediated by an influence on tumours cells, tumours cells spreading and/or immune suppression is not clear. In all cases, many arguments exist to limit as far as possible the extent of tissue attrition and surgical procedures in cancer patients.

PP: Although the emphasis of your work is on breast cancer, there is evidence that a similar bimodal pattern of relapse occurs in other cancers. Do you think that peri-operative ketorolac can have a similar reduction in relapse in these cancers?

PF: Yes. We have done the same observation in non-small cell lung cancer (NSCLC) (Forget et al, Ann Surg Oncol 2013). In NSCLC, the bimodal pattern of relapse was shown by Demicheli et al. Out data shows that the NSAIDs effect is also present. In contrast, in prostate cancer, no NSAIDs effect was observed (Forget et al, Eur J Anaesthesiol 2011). Concommitantly, no bimodal patter of relapse was shown, in my knowledge, arguing for a different pre-, intra- and/or postoperative cancer pathophysiology.

Ketorolac and Breast Cancer

Most cancer papers, even the ones with really interesting and important results, are not exactly an easy read. Aside from the technical content, they’re written in a deliberately dry and unemotional style that suggests objectivity and cautiousness. Which is why the paper ‘Promising development from translational or perhaps anti-translational research in breast cancer’, published in the journal Clinical and Translational Medicine stands out from the crowd. It’s an open access paper available here: http://www.clintransmed.com/content/1/1/17. If you only ever read one cancer paper make it this one. It’s written a highly accessible style, raises key questions and contains a result that, if confirmed, could reduce breast cancer mortality by 25% - 50%. That would be a massive step forward, truly massive.

And what is this finding that holds the promise of reducing breast cancer deaths by such a massive amount? It’s not a new drug, not a new form of therapy not even a new type of treatment. It’s simple, cheap and easily available and, best of all, easy to slot into place in existing treatment protocols. The starting point for all of this is the observation that the pattern for cancer recurrence following mastectomy occurs in two waves (it’s bimodal in stats jargon). The first wave happen in the immediate period (the first four years), and then there is a second peak of relapses that happens much later, around six years and stretching out to 10 – 15 years. This pattern of relapse has been confirmed in numerous countries and studies now, and seems to also be common in some other cancers, including prostate, lung, and pancreatic cancer, as well as osteosarcoma and melanoma.

This pattern of relapse could not easily be explained by existing theories of cancer growth. In fact, it was a down-right inconvenient finding with huge and controversial implications. Chief among these was that it suggested that surgery to remove the primary tumour was often triggering spurts of metastatic disease. To quote from the paper directly: Between 50% and 80% of relapses result from surgery initiated growth. That is a truly shocking result. It means that many breast cancer deaths are caused by the surgery meant to remove the initial small tumours.

Aspirin To Treat Liver Tumours?

There were a number of really interesting papers that popped up over the summer, and I'll be blogging about them in the next few days. For today though I'll focus on an open-access paper in the World Journal of Hepatology (and in case you're wondering, hepatology is the branch of medicine focused on the liver, pancreas and gall bladder). The paper is entitled 'In vivo assessment of intratumoral aspirin injection to treat hepatic tumors' and looks at what happens when you inject aspirin directly into liver tumours. Given the very high levels of interest in the anticancer properties of aspirin, taking it to the next level and injecting it directly rather than swallowing it seems such an obvious idea that it's a suprise that no one has tried this. But then it's often the case that it's the simple, obvious ideas that get over-looked.

And the results? Stunning, to be honest. The experiment took place in rabbits implanted with liver tumours and then injected with a solution of sodium bicarbonate and aspirin. Firstly there seemed to be no ill-effects - the rabbits showed no physical changes aside from changes in the tumours injected. And here the results were clear - the tumours collapsed and seven days after the treatment had disappeared completely, whereas in the control group the tumours continued to grow as expected. Furthermore, there was no evidence that the tumours started to recur or regrow.

Clearly this is a small study in rabbits and not humans, but the result is really striking and it cries out for follow up research. Given the low toxicity of aspirin, the obvious follow-up is for a small human trial. If the results are as fast and as positive we should know very quickly whether this is a viable treatment option to explore further.

Unfortunately I've not been able to contact the researchers (in Brazil), but hopefully this isn't destined to be one of those interesting results that sits languishing on the shelves and goes no where.