A new surgical technique for bone cancers

When it comes to bone cancers – such as osteosarcoma or Ewings sarcoma – surgical removal of the tumour-bearing bone is part of the standard treatment. Chemotherapy is part of the treatment, and sometimes radiotherapy, but resection of the bone is at the core of any curative program.  In days gone by this used to mean amputation of a limb, but these days a lot of work goes into limb-sparing surgery. And of course for those cases where the tumour is not in a limb, amputation isn’t an option any way.

In practice this means that very often surgery involves not just the removal of the effected bone, but also taking bone from another part of the body and slotting it into place a replacement. In my son’s case, George had three separate operations to treat the osteosarcoma in his jaw. The second and third time the ‘new’ mandible had to be replaced with a ‘newer’ one – in the end bone taken from his leg, his hip and a rib all to craft new jaw bones. While his was an extreme case, it shows what surgeons are capable off – but also gives an idea of how much trauma is involved to the patient. Some of the operations took more than 12 hours to complete. 

But what if there is a way to reduce the scale of the operation? What if the surgeons didn’t need to harvest new bone to replace the diseased one?

Surprisingly, such an approach does exist. It involves removing the diseased bone – making sure there are good margins as normal – and then the bone is treated to definitively kill the tumour cells. This is achieved by placing the resected bone in liquid nitrogen or bombarding it with very high doses of radiotherapy. Then the treated bone, now stripped of disease, is replaced in its original position. No need therefore to operate on other parts of the body to harvest bits of bone. No need for extensive remodelling.

Does this radical new treatment work? Recent papers show that the results are very good – there are lower rates of complications, low rates of disease recurrence, and of course lower risks of infection and faster recovery times.  For example in one study, published in the Bone and Joint Journal (http://www.bjj.boneandjoint.org.uk/content/96-B/4/555.abstract), no recurrences are reported at all in the grafted bones. 

That’s the good news. For patients in the UK the bad news is that this procedure, which was first used in Japan about 10 years ago, is not available. I remember asking for this for George, but got a blank look in return. So far as I know this is still not available in the UK – though I’d love to find out that someone, somewhere in the NHS has started doing this. It would make a huge difference to those people who’ve got primary bone cancers or bony metastases.

Osteosarcoma - A Proposal for Reducing the Relapse Rate

As has been mentioned on this site before, there has been little progress in the treatment osteosarcoma – the disease that killed my son,George – in the last twenty-five to thirty years. The actual figures vary by country, but generally the five year disease free survival is around 60% - 70%, though in the UK the last published figures were an absolutely appalling 43%. But these figures mask what’s really going – osteosarcoma of the extremities (the long bones in the arms and legs) has a much higher disease free survival rate than osteosarcoma at other sites. So the figures for England show that the rate is 48% for osteosarcoma of the extremities and only 16% for other sites. And, regardless of site, the prognosis for relapsed disease (whether it’s a local recurrence or a distant metastasis) is truly grim.

Looking at the patterns of relapse however shows us something really interesting and, hopefully, significant. The vast majority of relapses occur within 18 months of surgical resection (and in osteosarcoma the only way for definitive cure is to surgically remove the tumour). What is more, most of these relapses take the form of distant metastases, the majority appearing as new tumours in the lungs. This begs the question as to why this pattern? It suggests that there’s something systemic going on – and it’s a similar pattern to the relapse/recurrence of breast, lung, head and neck and other cancers. 

One possible mechanism involves the surgery itself. The body responds to the trauma of surgery by releasing different growth factors, cytokines and other inflammatory responses. This is necessary for wound healing, but it also creates an environment that is conducive to cancer growth – there are pro-angiogenic growth signals, immune suppression and so on. It all adds up to an environment that gives any microscopic pockets of cancer cells the chance to expand and grow into new tumours, particularly in the lungs.

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.