It has been 1350 days since cancer declared war on my body.
Actually, it’s probably been quite a while longer than that, because it invaded under cover of darkness, so it took a bit of time for me to get the memo. Either way, for 3 years and 8 months we have been on a war footing. Normal service has been suspended while we have mounted defence, and aggressive counter attack with traditional, chemical and nuclear weapons. There have been lengthy battles, heavy losses, and hard-fought victories; a grinding war of attrition, with the occasional time off for good behaviour, all in pursuit of a lasting and permanent ceasefire. But while I’m the Squadron Leader of my own personal battlefield, I’m just one of millions of soldiers, called up against our will, caught up in a larger campaign. The real heroes of this conflict are not the patients – though we occasionally have to screw our courage to the sticking place we’re mainly just doing what we’re told to stay alive. The unsung heroes, as in any war, are the brains behind the operation; the Watts, the Wilkins, and the Widdowsons; the Turings and the clever codebreakers of Bletchley Park*. In this case it is the oncologists locked in a lab, trying to crack cancer’s code, to find the chink in its armour, and develop the superweapons that will see it off for good. Now there may finally be cause for cautious optimism, because oncology might just be on the brink of a breakthrough…
If you haven’t yet heard of immunotherapy, then I urge you to quickly get acquainted, because immunotherapy is getting oncologists excited, and if the people who deal in cancer every day – not known for their overstatement – are getting excited, then the rest of us should probably be throwing our hats in the air and whooping for joy. For the first time in medical history, oncologists are successfully using the immune system to treat cancer.
An enemy of apparently overwhelming might
Cancer is the aggressor; an expansionary force that will stop at nothing to increase its territory. It has many tactical advantages, not least its vast army of stormtrooper cells, able to multiply and advance at speed. But cancer’s key strength is its capacity to hide in plain sight; the ability of cancer cells to masquerade as innocent and healthy, so our bodies don’t recognise them as a threat, and they are free to proliferate at will. Our traditional weapons – surgery, chemotherapy, and radiotherapy – are all applied externally, once we have detected that a tumour has formed, to either slay them, starve them, or carpet-bomb them out of existence. Immunotherapy comes from a different perspective – it seeks to make the body recognise the cancer as a disease and mobilise the full power of the immune system to obliterate the threat from within.
The immune system is the most powerful weapon we have; it has the potential to kill us much more rapidly than any disease, and so it is also extraordinarily clever, using molecules called ‘checkpoints’ to control the strength and the duration of the responses that it makes, to minimise the collateral damage to healthy tissue. But cancer cells are extraordinarily smart too. They are able to produce their own checkpoint molecules – their own invisibility cloak – which fools the immune system into thinking they are innocent and healthy, and protects the tumour from immune system attack.
Checkpoint inhibitors are a new class of cancer drugs which target these checkpoint molecules in the tumour, effectively removing the invisibility cloak from the cancer cells, so the full power of the immune system is unleashed against them. They also tend to have names which are completely unpronounceable. By 2015, 3 checkpoint inhibitors – ipilumumab, nivolumab and pembroizumab – had been approved in the US for the treatment of advanced melanoma, and the highly effective combination of ipilumumab and nivolumab was approved for use in the UK in June last year. Checkpoint inhibitors are now achieving sustained periods of remission for patients who would otherwise have run out of treatment options. As well as advanced skin cancer, they are prolonging survival for patients with the most common form of lung cancer, with fewer adverse side effects than chemotherapy. They have also been shown to be effective in kidney, liver, head and neck cancers, and recurrent Hodgkin lymphoma, with exciting trials underway for recurrent ovarian cancer. These gains, however incremental, represent a true breakthrough for cancers which have hitherto had few, if any, treatment weapons in their arsenal.
A Hot and Cold War
Immunotherapies are thought to be so effective in melanomas and lung cancer because they tend to be ‘hot tumours’. They have a high level of mutation, and produce a lot of malfunctioning proteins which act as a flashing red beacon to the immune system. The immune system despatches its fighter cells to the tumour, but the cunning little cancer cells put on their invisibility cloaks, and the fighter cells are fooled into lying dormant. As soon as the checkpoint cloaks are destroyed – by checkpoint inhibitors like nivolumab – these immune cells WITHIN the tumour are mobilised, and can get to work taking the cancer cells out. You’ll notice I haven’t mentioned breast cancer yet, and that’s because breast cancers are typically cold. Cold tumours are more camouflaged to begin with, so they don’t contain many immune system cells, which is why checkpoint inhibitors have – so far – had limited effect. Which is not to say that they won’t…the newest front of research in immunotherapy is investigating what combination of factors determine the ‘heat’ of a tumour, and – more importantly – how can we turn a ‘cold’ tumour ‘hot’ to make sure our immune system troops are dispatched to the tumour and lying in wait. Or, in other words, how can we get the immune engine running within the tumour, so the Spitfire takes off into battle as soon as the brakes are released.
We shall fight on the beaches….
Immunotherapy is perhaps the most promising of recent breakthroughs, but it’s just one of multiple fronts on which advances are being achieved. On 1st Feb the American Society of Clinical Oncology (aka the society for elite forces against cancer) published its 12th Annual Report on Progress Against Cancer, and – aside from Winston’s wartime speeches – bedtime reading genuinely does not get more spine-tingling than this. It tells of the other types of immunotherapy – like CAR-T therapy – where a patient’s T-cells are genetically reprogrammed to become assassins which seek and destroy hard to treat blood cancer cells. It tells of the discovery of new genetic mutations which increase the risk of ovarian cancer, and can be used for screening and prevention. It tells of targeted therapies which focus on specific types of cancer cell and the molecular-level features which help them to grow and thrive, and how these precision weapons are making gains against breast, ovarian and kidney cancer. It tells of new chemotherapy combinations proving successful against pancreatic cancer. It tells of the analysis of millions of patient records to provide crucial insights and spark new ideas. The list goes on and on; research is ongoing into every conceivable aspect of every kind of cancer, from the genetic factors which cause it, to the lifestyle and environment factors which aid it, and the vaccines and treatments which will most effectively work against it.
Science is fighting on the beaches, the landing grounds, the fields and the streets and the differentiator today – the crucial advantage that is starting to make all of the difference – is that we live in an age of powerful technologies like big data, robotics and artificial intelligence, which have the potential to rocket-launch us into an era of personalised, precision medicine, and finally turn the tide in our favour.
The precipice of caution
You have to run risks. There are no certainties in war. There is a precipice on either side of you – a precipice of caution and a precipice of over-daring” – Winston Churchill, 1954
So far, so exciting, but how do these many and various discoveries on the front line of science translate into real gains on the ground? At times of war, the War Ministry is established to oversee operations, make strategic decisions, and steer the alliance to victory. In the war against cancer this is the job of the regulatory bodies which oversee clinical research, trials, licensing and practice. They are responsible for defining the rules of engagement, protecting the safety of citizens, and deciding whether the gains the trials and treatments bring are worth the costs and risks that they pose.
In war timing is everything. Supply lines matter, and air drops of the latest weaponry make all the difference. The US’s own war ministry – the Federal Drug Administration – has recognised this and created a process for accelerated review of ‘breakthrough’ therapies which offer significant advantages for serious or life threatening illness. Most of the latest cancer therapies have been approved under this process, including Palbociclib – a new targeted therapy for late stage breast cancer – which was awarded this ‘breakthrough’ status and approved by the FDA in early 2015. However, while patients across the Atlantic started benefitting from this powerful new treatment just months after trials concluded, their comrades in Europe were not so fortunate. The European Medical Agency finally approved palbociclib for use in Europe in November 2016, after 15 long months of deliberation. That may not seem like a particularly long time in the grand scheme of government, but time is relative, and at the very front of a life-threatening illness it is measured in days and weeks, not years and decades. Fifteen months is time that some patients simply don’t have – they are being left to bleed out on the battlefield while the officers at HQ wait to rubberstamp the order to send out the cavalry. There are no certainties in war, but timing is everything, and indecision is fatal. We have to run risks, and as our medicine is becoming more imaginative and daring, so too must the Ministry.
Coventry, and other ethical dilemmas
On 14th November 1940, Operation Moonlight Sonata was unleashed on Coventry, killing 568 people, injuring over a thousand others, and leaving the city and its factories crippled. It is claimed that intelligence on the air raid had been intercepted at Bletchley Park, and Churchill was faced with the ‘Coventry dilemma’ – to warn and attempt to evacuate Coventry, thereby revealing that the ENIGMA code had been cracked, or to take no special defensive measures, and to sacrifice Coventry for the greater good.
The new generation of cancer therapies is forcing us to confront our own Coventry dilemma, and tackle agonising ethical questions: How do we balance the urgent needs of the few against the long term needs of the many? What is the value of a life? What is the value of a year of a life? How expensive is too expensive? And how much can we reasonably afford?
In England and Wales NICE has the job of answering these questions, and it values a year of life at £30,000, but it will spend up to £50,000 for end of life drugs. I don’t know about you, but I personally value a year of my life at significantly more than the cost of a high spec Volkswagen Golf. Equally I realise that resources are limited, that cancer is not the only disease in town, and that NICE has the unenviable task of achieving a level of spending that is sustainable in the longer term. Which is why NICE has just announced its decision to reject Palbociclib for use on the NHS…
Palbociclib is effective for oestrogen-positive breast cancer that has spread to other parts of the body, and has been hailed as “one of the most important advances in treating the most common type of breast cancer in 20 years”. It also costs £80,000 per patient per year. So while I don’t welcome the decision, I get it (and I also very much appreciate that the people at NICE have had their Weetabix so took less than 3 months to reach a conclusion). Like most of the new generation of targeted treatments coming to market, this drug costs more than the NHS can afford, and the amount the NHS can afford is less than the drug company demands to recover its R&D, satisfy its shareholders and to continue to invest in future therapies. It is a classic stand-off. The warring parties will hopefully – eventually – negotiate a workable settlement, but in the meantime the patients who need Palbociclib are trapped in no-man’s land, and the message to them is bleak: “We have the means to help you, but not the money. You are on your own, and should you die, it is because we can’t afford to help you live.”
Palbociclib is by no means the first example of this kind of impasse, and it won’t be the last. The highly targeted nature of the latest cancer therapies means they can be extremely effective, but for a much smaller subset of people, and they therefore have a high cost per patient. A new kind of warfare calls for a new kind of strategy, and so the entire system now needs to adapt to reduce the cost of drug development and licensing, and to ensure treatments are cost-effective. These therapies ultimately have the potential to transform cancer into a chronic, manageable disease, like antiretrovirals for HIV. If (or when) they eventually deliver on that promise, they will need to be sufficiently affordable for millions of war veterans to access them over the course of a much longer lifetime. In other words, the war may be expensive, but we haven’t even considered yet how we will pay for the peace.
Keep calm and carry on
We shall not fail or falter; we shall not weaken or tire. Neither the sudden shock of battle, nor the long-drawn trials of vigilance and exertion will wear us down.- Winston Churchill, 1941
When you live on a war footing, you quickly learn to keep calm and carry on; to do as instructed, to wait patiently for updates, and remain constantly alert to the next air raid or ambush. However far from the battlefield you have come, you only have to close your eyes to flashback to your time in the trenches – the endless exhaustion, the crippling fear, and the physical hardship. And in the relative luxury of the Home Front you must adapt to the inconvenience of long term side effects, the rationing of the anti-cancer lifestyle, and the abiding uncertainty of what tomorrow might bring. Whether in the white heat of treatment, or the ‘long drawn trials of vigilance’, morale is everything. I simply can’t convey how essential it is to know that however tough the day, however punishing the regime or however costly the sacrifice, you are on the best possible treatment to make and keep you well.
I have been fortunate to be in that position. I received chemotherapy targeted at patients with a BRCA defect months after the trials completed; my hormone therapy was modified within weeks of the trial results indicating that there was a more effective treatment; and I write this with a needle in my arm, receiving a preventative therapy which was recently proven to protect against the spread of cancer to the bones – though others who live in different parts of the country are struggling to get access because of confusion at the Ministry over how it should be funded (http://breastcancernow.org/news-and-blogs/news/27000-women-being-denied-43p-osteoporosis-drug-that-can-prevent-breast-cancer-spread).
I know from first-hand experience that every moment and discovery counts. Had genetic science arrived just 10 years earlier it might have prevented me getting embroiled in this sorry fiasco in the first place. Nevertheless I have been the lucky recipient of the latest, greatest medicine, and that knowledge has helped me go over the top and charge the enemy when there was nothing else left in the tank. I also know that every report from the front about a new drug which has failed or been rejected is more than a headline – it means something utterly devastating to someone, and there but for the grace of today’s good fortune go you or I.
The end of the beginning?
Confronting cancer has made me acutely aware of the tightrope we all tread; the knife edge between health and illness, benign or malignant, treatment that is successful, and treatment that is ineffective. We none of us know when or how we might fall off the edge, and what kind of help we might need to catch us and help us back on our feet. The best we can hope is that whatever reinforcements we require are ready and available and deployed to give us a fighting chance to survive. There is no silver bullet; we won’t all wake up one day to find that cancer has been cured. But, on the bleeding edge of medicine there are therapies being developed that might just form a fleet of rescue helicopters, which can pick us up from even the direst of circumstances on the front line, and evacuate us to the relative safety of a prolonged and durable remission. Our enemy will not procrastinate; it will continue to evolve and outsmart us, and so our research must keep pace because it is our only path to victory. The road ahead is long, and there is so much yet to discover, but in the remarkable advances of the last few years Churchill’s ‘bright gleam of victory’ looks like it has caught the white coats of our oncologists, and that should warm and cheer all our hearts.
“This is not the end. It is not even the beginning of the end, but it could be, perhaps, the end of the beginning” – Winston Churchill, 1942
*Robert Watson-Watt and Arnold Wilkins were pioneers of early radar technology, and instrumental in the creation of ‘Chain Home’ – a system of aircraft tracking and detection along the south coast of England, which proved vital during the Battle of Britain.
Elsie Widdowson was a pioneer of nutritional research. Together with Robert McCance she devised a safe wartime rationing diet, and it is thanks to Elsie that our humble white loaf is fortified with vitamins and minerals.
Alan Turing needs no introduction. Among his many extraordinary achievements he led the team of Hut 8 at Bletchley Park, cracking enemy ciphers. It has been estimated that this work shortened the war in Europe by more than two years and saved over fourteen million lives. As the father of artificial intelligence his work is now starting to play a crucial role in today’s war against cancer. Turing died in tragic circumstances, aged just 41, but his legacy lives on and the eventual tally of lives that he has helped to save will far outstrip fourteen million.
Links & References
ASCO’s 12th Annual Report on Progress Against Cancer
Pioneering drug combination approved
http://www.icr.ac.uk/news-archive/the-icr-responds-to-decision-by-nice-not-to-recommend-palbociclib