Quo vadis oncologia or how far to the moon?

Quo vadis oncologia or how far to the moon?

When talking about the future of oncology it’s impossible not to mention two significant historical events. On December 23, 1971, the National Cancer Act, which was signed into law by American president Richard Nixon, envisioned a multi-billion dollar “bypass budget” that was designed to forgo administrative procedures to ensure that money was spent more effectively to combat cancer and to create new methods to achieve and implement these programmes. 45 years have passed, yet people are still suffering and dying from cancer, no matter how emphatically the media has trumpeted the never-ending progress and significant achievements that have been made in oncology. Not unlike the spectre of communism, a bright and cancer-free future has taken root in our collective consciousness and science has been left with the task of once again proving that the emperor is indeed clothed. That is how President Barack Obama’s grand Cancer Moonshot[1] programme, which he inaugurated with the words “let’s make America the country that cures cancer once and for all,” arose with an impressive multi-billion dollar budget designated to promote early screening, immunotherapy, tumour resistance, the limiting of side effects, a variety of innovations, clinical studies and a number of new potential solutions to the problem of cancer.

Cancer mortality statistics are often a standard benchmark for progress in each respective branch of study. Today, in large part due to achievements in science, technology and the pharmaceutical industry, we can significantly prolong life and reduce the spread of tumours and the suffering of patients, but we have yet to eliminate cancer as the cause of death for the vast majority of patients. In the United States the average age of mortality from heart disease has decreased steadily since 1980, while mortality from tumours has only dropped slightly since 1993[2]. The mortality curve has been nearly flat since 1958. The latest estimates from the EU’s 28 member nations, which is available for year of 2014 [3], illustrates that from 2004 to 2014 death from cancer in men has decreased by 12.3% for men and 6.9% for women. A much larger decrease was observed in ischemic heart disease – 32.7% in men, 36.8% in women. In Latvia, premature mortality (in people aged 0 – 64) from malignant tumours is higher than the average for EU nations and continues to increase in both the group under 64 as well as the total population [4].

 

How the future of oncology is seen throughout the world and how that will help to solve the cancer problem here in Latvia.

 

Diagnostics

Liquid biopsy

Over the course of an illness it may be necessary to repeatedly test tissue samples to ensure that the biological nature of the relapsed or metastasised tumour has not changed from the original, which is not uncommon, as this could necessitate a completely new treatment strategy. Although today’s current invasive technologies theoretically allow us access to every part of the body, this can often be unpleasant, painful, dangerous and even complicated for the doctor to perform. Unfortunately, frequent testing of metastasised tissue is not common practice in Latvia. A liquid biopsy enables doctors to extract cancer cells or their DNA from blood samples and to investigate further when appropriate. In the future, liquid biopsies should be commercialised, so they could be available to anyone who requires them. One such clinic in Latvia would be sufficient to cater to the needs of all of the nation’s patients

.

Real-time diagnostics

The intelligent scalpel (iKnife) is a well-known, tried and tested method. The so-called electric knife can now not only be used to cut tissue, but also to test samples of that tissue. When the tissue is burned, the steam that is released can be captured and analysed in a mass spectrometer, so information about chemical compounds in the organic material can be immediately tested to see if it is benign or malignant.

 

Molecular diagnostics

The driving force behind this is a supposition that therapy can be customised to the genetic changes in each patient’s tumour. If genetic sequencing has until now been largely an academic pursuit, in the future it could well be more important than the histological method. This is certainly an interesting direction of study, but could possibly be at odds with the assertion that tumours are genetically unstable and are more susceptible to new mutations than healthy tissues.

An algorithm created by artificial intelligence

Accumulated information about tumours and the unique features of each patient’s organic material could be processed using artificial intelligence technologies, which could, for example, create a prognosis algorithm that could allow doctors to make a custom-tailored treatment plan for each individual patient. This Big Data system would help doctors to more precisely choose the most suitable method of therapy, especially in oncology, where drugs are expensive and often toxic. The goal is to gain the largest potential patient data to create the best and most precise therapy algorithm. Patients will become information donors, while the accumulated data from around the globe will complement the opinions and personal experience of doctors. Although this will allow doctors to be more confident, as I mentioned before, tumours are extremely cunning and unparalleled in nature as masters of change in every possible way. I’ve personally seen a patient being prescribed concrete drugs on the basis of genetic sequencing, which were supposed to be the most effective. However, the patient received the treatment and the disease continued to progress. These methods will definitely help in choosing between different treatment methods, but we have to bear in mind that there will be patients for whom this method will not guarantee any significant shrinking of their tumours or their complete disappearance.

 

Surgery

Robot-assisted surgery

Modern technology will eventually replace that classic symbol of the surgeon’s profession – the scalpel – in all operating theatres. The combination of artificial intelligence and other technologies will allow surgeons to carry out all manner of manoeuvres with maximum accuracy. This will potentially make surgery less invasive, hence lessening the risk of post-op infections, guaranteeing faster recovery times and less scarring.

The first attempts at robot-assisted surgery were made at the end of the 1980s, when laparoscopic surgery was used in gall bladder operations. Robot-assisted surgery is still often referred to as computer-assisted operations. This was a significant contribution that allowed tumours that were found deep within the body and difficult to reach via traditional methods to be seen. The da Vinci robot-assisted surgery system already offers experience with precision surgery. During the operation, the surgeon sits at an ergonomically designed console and uses instruments guided by high-resolution 3D cameras. The advantages of the da Vinci surgery system include greater surgical accuracy, more precise movements, better visibility and an improved approach. Methods of robot-assisted surgery continue to advance. Naturally, this doesn’t mean that all oncology operations will be replaced by the robotic method in the near future, but the larger the proportion of early diagnoses we see, the more this method will be justified, especially since it lessens damage to the surrounding tissue.

 

Robot-assisted radiosurgery or the CyberKnife

This is an alternative to invasive cancer surgery, which aims concentrated doses of radiation at tumours, with unique precision, at a wide variety of locations throughout the body. A high-resolution CT determines the location and size of a tumour and these data are sent to the CyberKnife work station, where a treatment plan is created. In Latvia, a new-generation CyberKnife is available at the Stereotactic Radiosurgery Centre in Sigulda. The advantages of this method include a more accurate targeting of high radiation doses in a tumour, minimal damage to surrounding tissue, shorter treatment time and greater comfort for the patient. Although the method is as yet not subsidised by the government, I sincerely hope that, given its positive results, it will eventually be funded by the state for all Latvian cancer patients, as there already is ample experience with this method in our nation. There is an enormous difference between destroying tumours of the brain with the aid of robot-assisted radiosurgery (if possible) or via traditional neurosurgery. The same can be said of smaller tumours or metastases such as those found in the liver or kidneys.

 

Radiation therapy

Intensive study will also provide solutions in radiation therapies. One of the most significant goals is high selectivity in the destruction of cancer cells with the least damage to healthy cells. In essence, how do we make this treatment method as safe as possible for the patient and the healthy tissue that surrounds the tumour’s lair. One of the solutions of the future is radiogenic therapy (RGT) and Equivalent Uniform Dose (EUD) in combination with intensity modulated radiation therapy (IMRT). In the future, we can expect that radiation therapy will be complemented by precise radiation intensities and doses, which have been calculated based on the tumour’s metabolic and molecular characteristics.

 

Personalised radiation

Today we already live in an era of personalised therapy and this also applies to chemotherapy and biotherapy, as well as radiation therapy. The more we learn about radiobiology and the identification of predictive biomarkers for radiosensitivity and radioactivity, the easier it will be to make an effective radiation treatment plan that will achieve more positive results for the patient.

 

Image guided radiation therapy

This method (IGRT) allows an even more accurate beam of radiation to be directed at a tumour in real time, while protecting the surrounding tissue. This method is also referred to as 4D therapy and its technical solutions continue to advance and improve.

Latvia has a number of excellent specialists in a variety of fields of medicine. This combined with the renovation of the radiation therapy unit and the promotion of the latest technologies is an essential step in improving the overall treatment of cancer patients, because this method can be applied to both early-stage as well as late-stage tumours and metastases with only a minimal impact on the general health or well-being of the patient.

 

Drug therapy

In 2016, five of the 15 best-selling medications in the world were cancer treatment drugs[5] (rituximab, lenalidomide, bevacizumab, trastuzumab, filgrastim). At the same time, it appears that the era of medical guidelines in cancer (one therapy for all similar cases) has ended and this will gradually be replaced by the selection of a specific therapy method based on a patient’s immunogenic, genetic, epigenetic, proteomic, metabolic, microbiological and phenomic profiles, instead of on the tumour’s histological characteristics. Today, precision [also personalised or individualised] medicine is at a complicated juncture, where enthusiasm is combined with disappointment and incomprehensible contradictions. Furthermore, it all comes at an enormous cost. It has been calculated that the cost of cancer treatments (including diagnostics, surgery, hospitalisation, palliative and hospice care) will increase by 53% from $106.5 billion to $162.9 billion from 2015 until 2020[6]. The goal of cancer therapy has always been a cure, but even with today’s available selection of drugs, this has not been achieved for even the most common tumours and every new round of therapy brings new financial burdens for treatments that offer no guarantee of success. The future of cancer treatment may be linked to panomics, that is, the use of a range of molecular biology technologies or a combination of these to model a therapy method for each individual patient. Achievements in genomics already allow us to create a personalised genetic and epigenetic pathology map, to find the most appropriate therapy. However, that unfortunately still doesn’t guarantee 100% effectiveness.

 

Precision medicine

Until now the single biggest achievement in personalised medicine has been imatinib (Glivec®), which is used to treat chronic myelogenous leukaemia (CML). If its diagnosis was a death sentence in the 1980s, since the mid-1990s the average life expectancy for a patient being treated with imatinib is no longer measured in months, but in years and perhaps even decades. People with this specific genetic defect finally had real hope at recovery. However, the effects of imatinib proved difficult to replicate in treating other types of cancers. Each tumour contains a unique bouquet of genetic mutations, which, not unlike snowflakes, are completely different from one another. In addition, this heterogeneity not only distinguishes one histological type of tumour between different patients, but also within the same tissue of the tumour, not to mention metastases, which may in fact be a completely different disease. Today we’re aware of the most common mutations in specific tumours. This knowledge is also taken into account in many studies by randomising patients in subgroups. But tumours are so innately mercurial or, to use more scientific terminology, genetically unstable, that by attempting to fight one mutation, we enter a vicious cycle and the disease continues to progress. Many patients respond well to genetically-targeted therapy, but unfortunately this is often short-lived. This is why a combination of the precision method with immunotherapy seems hopeful.

Another problem with the precision method is that clinical trials are often conducted on patients with widespread illnesses or metastatic tumours, whose range of genetic anomalies is even greater. Moreover, the tumour, being genetically unstable, constantly adapts to new conditions often replacing one mutation with another. Therefore, the next challenge could be – the correct drug at the correct time, but how to get there? There’s still a long road ahead involving the dynamic study of tumours (cells, DNA, DNA fragments). Today metastases aren’t tested often, given the assumption that the tumour is the same as when it was first diagnosed and treated. A commercialized liquid biopsy could be the solution. A laboratory was even created for the detection of circulating cancer cells a few years ago, but it didn’t gain favour with local oncologists and was closed.

 

Resistance

We have discovered over 500 genes, which could be linked to the origin of the disease and its progression. Approximately 100 drugs that target specific mutations are currently available. However, even in so-called wealthy nations, where patients have good access to diagnostics and methods of therapy, mortality rates for cancer are decreasing only slowly and much of this is due to early detection.

From a Darwinist point of view, a tumour is a complicated ecosystem of diverse cells, which are forced to adapt to survive and they do this by mutation. As a result of therapy, many cells are destroyed, but others remain and continue to grow and multiply. By discovering genetic adaptation mechanisms, it’s possible that this problem could also be solved in the future. Not unlike the heads of the dragon in that old fairy tale – we cut off some, but others grow in their place. Furthermore, no one really knows for sure if the changes that make a circulating cancer cell develop metastases in other organs are purely genetic. It is estimated that we can offer an appropriate therapy for roughly 5% of gene mutations today. If we can’t address the remaining 95%, then how do we find a cure?

 

A tumour’s micro-environment

Neighbouring healthy tissue certainly plays a large role in a tumour’s development and progression. Where were they earlier? Why don’t they intervene? Why did they allow the tumour to develop? Until now, all clinical research and therapy has been focused on the cells of a tumour and how to best destroy them, bypassing the micro-environment and its no less complex ecosystem. Cells that are in the so-called G0 phase, or resting phase (cells that aren’t actively involved in the division process), are less susceptible to traditional chemotherapy, whose target is a cell in the process of division. What prompts these dormant cells to come to life after a successful initial course of therapy (surgery, radiation, drug therapy) and where at that moment are neighbouring healthy cells looking? Only in recent years has this caught the attention of scientists who have begun actively studying the immune system. Our bodies are such complicated systems that even today scientists have more questions than answers.

 

Immunotherapy

Tumour cells have been very successful in adapting to circumvent the immune system – by releasing biologically active substances, which interfere with the functioning of competent immune cells, and by creating what can be described as “antigen wigs” that fool the immune system. We now know that the longer the cancer cell mutation cascade has continued, the more foreign antigens are located on the surface of the tumour, which the immune system should be able to recognise, but instead it becomes confused. How can we help the immune system? Is the key to a successful therapy, the sequential or simultaneous use of precision therapy and immunotherapy?

Today, immunotherapy is usually considered to be a narrow group of drugs called checkpoint inhibitors, which “remove the breaks”, so to speak, from the immune system’s monitoring function. However, these drugs also fall short of helping all patients and often have the disadvantage of dubious side effects such as autoimmune reactions, which can be severe and difficult to deal with. Furthermore, the very word immunotherapy often has the suggestive connotation of an alternative to chemotherapy, which patients view as toxic and poorly tolerated. This is why new methods are constantly being researched, which would be less toxic to the effectiveness of the immune system’s monitoring functions. One of these methods is oncolytic virotherapy, which is known to not only destroy cancer cells, but also to influence and activate a dormant anti-cancer reaction. Currently there are a number of these viruses, both natural and genetically modified, which are successful at their given tasks.

 

Metabolic therapy

Tumour cells metabolise glucose, lactates, pyruvates, hydroxybutyrates, acetates, glutamine and fatty acids more intensively than healthy cells. That said, the tumour’s metabolic ecosystem is extremely complicated. The metabolic phenotype of cells within a tumour’s tissue is heterogeneous and can be significantly different from healthy tissue. Therefore, a targeted focus on the varied metabolism of the tumour could be a hopeful direction for research[7]. We already know that metformin users are much less likely to suffer from malignant tumours. However, efforts by doctors and scientists to use this well-known drug as a cancer treatment have met with great resistance.

 

Microbiome modulation

In recent years studies have shown that a person’s microbiome is related not only to the development of a tumour, but also to its reaction to therapy.  Therefore, microbiome modulation may be another new direction in tumour therapy. Great expectations have been placed not only on diet, but also on the specific role of probiotics in the treatment and potential prevention of cancer.

 

Personalised cancer vaccines

The patient’s own cancer cells are extracted, mixed with immunity stimulating substances and injected back into the body to stimulate the body’s response mechanism to the presence of cancer. This is not a preventative, but rather a therapeutic vaccine as it is injected directly into the patient himself. Until now, much of the interest in this therapy was related to dendritic cells and one could hope that this interest won’t wane.

 

Oncolytic viruses

Only recently, scientists believed viruses introduced into the body were simply eliminated by the immune system. Today, after 100 years of experience, it turns out that viruses can achieve long-term remission, because they have the power to influence a tumour’s micro-environment. Research has shown that the simultaneous use of checkpoint inhibitors and other immunotherapy methods in conjunction with virotherapy garners a synergistic interaction. Therefore, it’s possible that the next seismic wave in clinical studies could be focused on the potential combination of viruses with other immunotherapy methods. Combined therapy currently dominates oncology as it attempts to simultaneously affect a variety of factors that promote the growth and spread of tumours. Tolerability, safety and toxicity are of paramount importance. In this way, oncolytic viruses, introduced at the correct moment, can be suitable allies to a diverse number of therapy methods.

 

3D models to plan therapy

On the other hand, 3D printing has opened new opportunities for testing drugs, expediting their trial time. For example, by printing nephrons, which functionally bear a resemblance to a real organ, it will be easier to predict a drug’s effect on the body. Three-dimensional cultures, or organoids, obtained from a patient’s tumour can precisely simulate the original cancer cells and be used in research studies[8].

 

The use of nanoparticles

Chemotherapy essentially destroys fast-dividing cells, including healthy ones (germ cells, mucous membranes, hair follicles, etc.). Systemically administered drugs use the same transport network the body uses for its own physiological needs. As a result, the drugs affect all of the cells along the way. The use of tumour-specific mechanisms once seemed promising. However, the tumours proved to be smarter and better capable of adapting. Unfortunately, on a larger scale, the Trojan horse tactic wasn’t successful. We currently have two antibody-linked chemical agents that act as selective deliverers of poison – brentuximab vedotin (FDA approved in 2011) to treat certain lymphomas and trastuzumab emtansine (FDA approved in 2013) used by breast cancer patients who no longer respond to conventional chemotherapy.

A future vision of oncology would also include the idea of using nanoparticles to transport effective drugs to the tissues of the tumour, while sparing the healthy cells. However, at present there are simply too many unanswered questions regarding its safety in humans. The primary as yet unsolved problem is the heterogeneity of tumours. No matter how perfectly and safely these toxic, yet effective drugs are administered (without harming the surrounding cells), there will always be cells that will not respond to the treatment.

 

How will 2017 enter the history books of oncology in Latvia?

At a time when the world’s leading media (The Guardian, CNN, The Telegraph, The Daily Mail et al.) and medical journals (BMJ, JAMA, The Oncologist et al.) are assessing and analysing the excessive cost, toxicity and questionable effectiveness of oncological medications, our own local media space has oddly enough been inundated with one unmistakable viewpoint – Latvia lacks both the money and the desire to pay for these innovative resources whose efficacy has garnered divided reactions abroad. Society has been methodically misled to believe that only expensive innovative remedies can solve the cancer problem in Latvia.

Recently, unmistakable pressure has been placed on Latvian society to accept the erroneous idea that only the latest (innovative) medications will help. For a long time “lifesaving drugs” have served as a perfect marketing trick to gain sympathy with the public. As we can see from the news in the Latvian press, the sums are staggering. For example: NRA, July 14, 2016, Inga Paparde about T.B. – “The council of doctors decided that from now on she had to be treated with drugs that cost €9,106 per month.”; website nra.lv, October 22, 2016, Inese Blažēviča about A.K. – “… the only hope is expensive chemotherapy (€54,000). The family doesn’t have that kind of money.”; website nra.lv, October 1, 2017, “The council of doctors decided in favour of the drug Vemurafenib, whose cost isn’t compensated by the state. A. has been given a fixed sum of €14,228 which will be compensated by the state, but the remaining sum of €50,507 necessary to cover the year-long treatment will have to be paid by A. himself. His family doesn’t have the resources.” Are those really our own doctors, who so cold-heartedly exploit a patient’s despair, encouraging them to contact the charity www.ziedot.lv, knowing full well that the advanced tumour is untreatable? Essentially, doctors, industry specialists and journalists manipulate public opinion by saying look how evil our country is, not caring for its grievously ill citizens by not buying those expensive, good drugs. The Ziedot.lv database offers information about numerous cases of money donated to specific patients, who are now deceased, being divided among other cancer patients (and there are many such cases).

Miracle cures for cancer simply don’t exist, but this intentionally orchestrated publicity alarms cancer patients as well as their friends and family. “Patient stories” are published with enviable regularity on these websites nearly every week detailing their struggle, the inclusion of innovative drugs on the government’s list of subsidised medications and the unwillingness of the state to help. I was recently on a TV show, where a journalist with unfeigned amazement asked why we need a so-called “green corridor” (expedited cancer treatment) if we can’t cure our patients. We can forgive a journalist for thinking this way, but not a doctor. The state must think about all of its patients and ensure that the largest possible number are diagnosed early when the chances of a full recovery, or at least the potential to limit the progression of the disease, are greatest. Currently, metastatic tumours (with rare exceptions) can’t be cured. For now, this unfortunately is an axiom. The state cannot allow a situation where resources are not invested in prevention, screening diagnostics, early detection diagnostics and early stage treatments. I am in no way against innovative drugs, especially when used locally on tumours, as drug therapy options are currently limited. However, I do support a balanced distribution of funds to ensure the availability of diagnostic tests (PET/CT), to modernise radiation therapy (including stereotactic radiotherapy) and to fund palliative care, rehabilitation and the development of human resources. However, on a national level it would be inexcusable to not treat those who could be potentially cured, but rather to focus on exceedingly expensive innovative drugs to treat metastases, which are neither effective, nor cost effective for everyone and whose cost would consume the lion’s share of the state’s oncology medication budget.

It appears that the most avid participants in these debates are often doctors, the media and some more dubious players whose motives seem to be less than objective. Even well-respected medical journals are not above publishing bald-faced lies. We can read gynaecologist Ronalds Mačuks’ opinion, who is supposedly deeply concerned about melanoma patients (!), on p.48 of the December 2017 issue of Medicus Bonus: “Patients ask me, for example, about the efficacy of virotherapy. Although there are very few clinical studies, or ones that aren’t of a questionable nature, patients receive these state-subsidised drugs. At the same time, there is a shortage of funds for drugs that have been studied and recognised as effective. If four million of the medication budget weren’t wasted every year on unproven therapy, we would have enough money to prescribe proven, evidence-based drugs that are used around the world to the few patients suffering from disseminated or unresectable melanoma, no matter how expensive they are.” It appears that my colleagues have no idea how much of the budget is actually spent on Latvian melanoma patients, which is available on the National Health Service website, yet they all have an opinion about it. If one patient’s metastatic melanoma therapy costs €100,000, then you don’t have to be a mathematician to understand that, even with the current amount of money allotted to subsidise cancer medications, we wouldn’t have enough to cover all of these patients. In Latvia, roughly 11,000 people are diagnosed with a wide variety of tumours each year. Should we treat only the melanoma patients and ignore the rest? It’s sad that a gynaecologist and oncologist would think that.

The result is that the patient’s interests are left in the background, because the primary objective is to include new drugs in the state’s list of subsidised medications. What happens to the patient when the new, innovative drug no longer works, or if it doesn’t work from the very beginning? It appears that no one is concerned about this. Well, it is cancer after all. Yes, there will be a new generation of innovative drugs and even greater costs, which even wealthy and very wealthy nations won’t be able to afford.

However, in these situations you usually come across that hallowed phrase in the patient’s chart – “henceforward, observation by the general practitioner” – which supposedly absolves the doctor of all responsibility by placing it on the shoulders of another colleague who is now accountable for the progression of the disease and for the fact that there are no more effective drugs to prescribe. Unfortunately, as Latvia celebrates its centenary, we will be left with the methodically and intentionally implanted idea that, here in Latvia, nothing can be done.

That said, I would like to finish this article on an optimistic note. Right now, there are more than 70,000 cancer patients in our nation, who have been operated on by Latvian surgeons (using the operating theatres and the technology that we have), who have been irradiated by Latvian radiologists (with the devices available to us), who have been treated by Latvian chemotherapists (with drugs that are in keeping with the World Health Organisation’s list of essential medicines and with ones that surpass this). The majority of these patients feel nothing but gratitude to their doctors for the lives, which they have saved or at least prolonged. Let’s be proud of ourselves and of our colleagues who are capable of helping, even in the most hopeless situations, with the resources that are available to us.

[1] https://www.cancer.gov/research/key-initiatives/moonshot-cancer-initiative

[2] National Vital Statistics Reports, June 30, 2016; Vol.65, No 4.

[3] http://ec.europa.eu/eurostat/statistics-explained/index.php/Causes_of_death_statistics/lv

[4] European Health for All Database (HFA-DB), WHO. URL: http://data.euro.who.int/hfadb/

[5] https://www.genengnews.com/the-lists/the-top-15-best-selling-drugs-of-2016/77900868

[6] Global Oncology Trend Report: A Review of 2015 and Outlook to 2020, IMS Institute for Healthcare Informatics, June 2016

[7] Martinez-Outschoorn UEPeiris-Pagés MPestell RGSotgia FLisanti MP. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017 Feb;14(2):11-31.

[8] Van de Wetering, Hayley E. Francies, Joshua M. Francis, Gergana Bounova et al.: Prospective derivation of a Living Organoid Biobank of colorectal cancer patients.// Cell May 7, 2015; 161, 933–945.

Comments are closed.