MTA.hu 31st August 2016, PÉTER TÁTRAI
In the past six decades’ medication’s approach towards tumours was with the intention of demolition. But in almost all cases, there are some tumour cells, which survive even the most drastic therapy, and for the second time they rebuild a tumour which is much more difficult to attack. The limitations of the traditional strategy raise the possibility of that cancer actually should not be defeated, but kept at bay.
The traditional cancer-healing strategies all build on the theory, that the best solution for the patient is the minimalized demolition of the tumour, and for this purpose, with the therapies one needs to “reach the wall”. The tumour removal surgeries are carried out in the spirit of surgery radiality, delicately balancing between the possible fullest removal of the tumour, and maintaining the functions of the surrounding soft tissues; and during the planning of the radiation and medical therapy they tend to set such a high therapy intensity, which is barely, but still endurable for the patient. All this is done in the hope of killing even the smallest trace of the tumour by the end of the therapy. But according to the experiences; this is almost an impossible mission; on the contrary, it seems like the aggressive treatment actually actively contributors to the recrudescing of the tumour.
A change of paradigm in oncology after sixty years?
After six decades of efforts – producing both significant results, but from the aspect of the final aim full of failures – part of the researchers and medical doctors are urging a change of paradigm in oncology. In their opinion, instead of striving for the full healing of cancer, tumour illness should be formed into a kind of chronic condition, with which one can live with for decades. The future of cancer healing might not be the final victory over tumours, but the “taming” of the tumour as an illness – to live with a tumour should be equal to living with well-maintained diabetics. According to the new strategy, in order for the tumours to be controllable in a long run, they should not be attacked so frontally as it had been done until now. In the past few years Robert Gatenby, the research professor of the Lee Moffitt Cancer Center of Florida has developed a significant theoretical frame for the foundation of the new way of the “more tender” treatment of tumours. As the representative of the school propagating the Eco evolution of tumours; Gatenby considers tumours to be ecosystems, in which there is an evolution process based on the Darwinist selection. Tumours, similarly to a real symbiosis are heterogenous: both the tumour cells, both the micro-environment they experience differ from place to place.
It is known, that the basis of tumours is genetical deformities, mutations, and during the evolution of the tumour; new and new mutations keep emerging. Therefore, the differences between the tumour cells – at least partly – can be explained by the differing mutational patterns of the individual sub-populations of the tumour. But the tumour cells can adapt to their environment and the challenges they face without acquiring new mutations: it is enough for them to re-regulate the expression level of their ready-coded protein in the genome.
Metastatic melanoma tumour cells
Source: Flickr/NIH Image Gallery/Julio C. Valencia, NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health
Diversity, detoxication and competition – the three great weapons of tumour cells
Gatenby’s treatment model is based on three main theories, all of which are well-founded by convincing experimental data. At first, he starts off from the hypothesis, that the tumour cells already vary before the beginning of the treatment, regarding their responsiveness towards the therapy. Due to the above-mentioned heterogeneity of the tumour cells, some tumour cells will react better and some will react less to medical treatment. The second theory is that after the beginning of the treatment, the tumour cells do not necessarily need to acquire new mutations in order to become more resistant, but it is enough for them to activate the detoxicating metabolism-routes naturally existing in the cells. This is important, because by setting their already existing tools in; the cells are able to become therapy-resistant much faster, then if they had to wait for a “lucky” mutation. Due to its essence, the occurrence of mutations is a random process, and even though the mutations securing resistance secure a selective advantage to their carriers, the occurrence of the new mutations and the process of selection assume a series of cell divisions. Contrary to this, the “top flight” of the detoxicating metabolism does not even require cell division, inly the switching on of the appropriate genes. At last, Gatenby builds into his model the third theory, that the sub-populations of tumour cells – similarly to the members of a natural symbiosis – are competing with its other within the tumour for the living-space and nutrient. Taking these three basic theories as a basis, it is possible to deduct substantial conclusions regarding the inner dynamics of tumours. During chemotherapy, tumour cells resistant to the therapy obviously enjoy a selective advantage compared to their mates which are receptive towards the therapy, namely, the resistant cells are more able in the presence of the therapy; as an external selection pressure – their reproduction ability is better –, then the one of the sensitive ones. This has not been a very important surprise so far. But Gatenby calls the attention to the extremely significant fact, that in the absence of chemotherapy, the ability relations are exactly the reverse: the resistant cells are less reproductive then the ones which are receptive.
The root-cause of this is to be found in the mechanism of resistance.
Versatile pumps – stubborn tumour cells
The most common trick among tumour cells, with which they avoid the effect of the chemotherapy substances, is that they place a large amount of so called. multidrug resistance-pump on their surface. The multidrug resistance-pumps are such proteins, which – impregnated into the cell-membranes - vigilantly guard over the strange molecules which try to penetrate from outside, and if they discover any of such, they throw it out before it could penetrate into the inner part of the cell. The name of the pumps indicate that they are able to identify and remove numerous, chemically not related cell-foreign compounds, and thorough this, they make the cell to become resistant towards uncountable possible medicines. Naturally, this protection is not for granted: the cell pays in hard energy-currency for the job of the pumps. It has been proven, that the tumour cells might use up to one third of their entire energy production for the operation of the pumps. This giant cost pays back though – it provides selective advantage in the efficiency competition –, if the pumps have something to protect against. But during “times of peace”, namely at the lack of chemotherapy, cells not being in the possession of pumps can use all the energy their competitors use for feeding their pumps for their own growth and reproductivity. And since both the resistant and the sensitive sub-populations are competing for the same limited resources, in the absence of therapy; the resistant cells wasting their energies in wain; come of worst from the battle.
The disadvantages of intensive chemotherapy
So, the model forecasts that in the absence of medicine; the tumour cells receptive to therapy as a result of the competition roll back and keep at bay the sub-populations resistant to the therapy. But the intensive chemotherapy which almost exceeds the maximally endurable dose radically changes the balance of forces, and turns the status quo prior to the therapy completely upside down. Under such circumstances, when the cells sensitive to the therapy die in masses, the resistant populations which had been kept under control until then start to expanding explosively.
Ecology knows this phenomenon very well, under the name competitive release, as is well aware of its sometimes-catastrophic consequences. What happens if a newly introduced weed-killer only demolishes some of the plant species being in natural competition with each other? The rest of them, as a result of competitive release; overflow the entire living-space, and we cannot protect ourselves from them with the same weed-killer again. A very similar process happens inside our bowels during a significant antibiotics cure: the medicine decimates the mostly innocent, but sensitive bowel bacterial, and opens the way for the much more unpleasant disease agents, which have been naturally regulated by the competition. And if the latter one’s cause illness as they proliferate, we will have to remove some entirely different antibiotics against them from our shelf – until there is a choice to pick from. Gatenby makes his conclusion: the drastic, dose intensive chemotherapy, unless it is able to defeat the resistant cells too, is not only doomed, but it literally cuts the wood beneath itself. By providing a selective advantage to the resistant cells, and demolishes their natural competitors, it elevates the “special forces” of the therapy resistant cells, which re-develop the tumour sometimes just months after the ending of the therapy, but at most within a few years. And we shall not forget: this recurrence tumour is no longer sensitive to the previously applied treatment. The blotter of sins of intensive chemotherapy is actually much longer then this: we are well aware of its other unwanted side effects, as a result of which it does not keep under control, but enhances the development of the tumour. The bone marrow – due to its rapid cell division is one of the main sufferer of the side effects of the chemotherapy substances, and since this tissue is responsible for the reinforcement of the soldiers of the immune system, the white blood cells; its damage leads to the set-back of the immune-protection. Yet, the immune-system plays a very important role in limiting the growth of tumours, therefore the eroding of the immune competency is no good news for the body battling with cancer. We also have to recall, that tumours are not only made up of tumour cells, but they are organized around a so-called stroma – a kind of frame – which consists of connective tissues and veins; and immune cells also penetrate into their frame. Chemotherapy substances do not spare the non-malicious components either: they distract the structure of the veins, as a result of this they lose their normal permeability, and they also eliminate the white blood cells battling against the tumour on the spot. The abnormally structured veins provide bad blood supply, and the lack of oxygen ignites such mechanisms in the tumour cells; which enhance their exit from the tissues structure, namely the metastasis. Upon all this, the bad veins cannot secure that the medicine reaches the tumour cell effectively, so while the healthy part of the body is suffering from the side effects, the inner part of the tumour enjoys some kind of protection.
The drastic, dose intensive chemotherapy, unless it is able to defeat the resistant cells too, is not only doomed, but it literally cuts the wood beneath itself.
Tumour therapy with a gentle approach
What would the alternative be then? Gatenby – reaching to the tradition latent in tumour-healing for actually decades now – recommends the gentler form of chemotherapy. Such and adaptive therapy, which only uses high doses, until its stops the exponential growth of the tumour; and afterward, continuously following the size of the tumour, it modifies the doses in a way, that the sensitive balance between the cell populations sensitive to the therapy and those which are resistant to it should not be disarrayed. So instead if intending to completely eradicate the tumour, it is his expressive intention to reserve the tumour cells therapy responsive fraction, which it plays out as an “insider enemy” against the potentially dangerous, resistant cell substance. The applied lower dose intensity also does not endanger the intactness of the stoma, therefore the stable veins of the tumour and the immune cells penetrating into the tumour can be turned to the advantage of the therapy.
Gatenby and his team finally had the chance to try this promising theory in practice in the near past. Their study, in which they prove with the support of an animal test model that the adaptive therapy can keep tumours at bay compared to the traditional high doses chemotherapy, was published in the February 2016 edition of the Science Translational Medicine. Following the achievement of the tumour control at the beginning – breaking the exponential growth – they experimented with two types of the reduced dose modification of the traditional therapy on mice injected with human breast cancer cells. In the first version, the regularity of the dosage was not modified, but the dosage was reduced depending on how the tumour responded to the therapy. In the second variation, in response to the shrinking of the tumour, not the dose used by each of the treatments was reduced, but the therapy occasions were made less frequent. The control group received the traditional, timewise pre-set, continuously high dose and unchanged frequency chemotherapy.
In the group treated with standard chemotherapy, the size of the tumour was reducing at a fast pace at the beginning, but at the end of the defined dosage period, in the lack of further therapy it started growing again almost instantly, and during the approximately two months’ observation period it was growing in an intensifying rate. Contrary to this, in the first adaptive therapy group, in which the treatment was maintained with low dosage fitted to the size of the tumour, the tumour did not only refuse to start growing again, but out of 7 cases, in 6 cases the size of the tumour reduced to be under the size which is set to be treated, which made it possible to completely seize the dosage. And what is even more important; these adaptive treated tumours remained steadily small, giving a hint, that as the result of the treatment they became self-controlling. The results of the second group, with skipping therapy occasions were less convincing.
In his comment attached to the article in the same edition of the journal, Giannoula Klement, the child oncologist of the Tufts University Clinique of Boston enthusiastically welcomes the new therapy approach, adding that: until we do not have respect for the eco-evolution laws of the growth of tumours; we will only be able to continue playing the cat and mouse game with cancer.
Living together with cancer – even for decades
Klement emphasises, that the stable living together with tumours is not only a theoretical option, but it is an existing, and for a long time known phenomena. In young and middle aged women dissected for other reasons; they found malicious breast-tumours in an amazingly high frequency, which did not produce any clinical effects during the lives of the patients. Likewise, while in more than 40% of men above 60 years, histologically proven malignant prostate lesions are present, the frequency of prostate cancer breaking through the clinical horizon is only 1%. All these indicate, that tumours often have a sort of self-controlling dynamism without external intervention, and it is possible, that an unthoughtfully applied early treatment disarrays this inner balance. This observation reflects in the strategy used in the case of the less aggressive cases of prostate cancer, called the watchful waiting strategy: in such cases the doctor closely follows the way the size of the tumour changes, and only interrupts if it noticeably starts to grow.
Epithelioma tumour cells
Source: Flickr/NIH Image Gallery/Markus Schober and Elaine Fuchs, The Rockefeller University
Support from a spiritful researcher
Local researchers also join the efforts of Gatenby in a broader sense: a Hungarian team of researchers strives to turn the vulnerability of the chemotherapy resistant tumour cells for the advantage of healing in a slightly different way. Gergely Szakács, the head of the “Lendület-group” of the Natural Sciences Research Center of the Hungarian Scientific Academy discovered molecules with a unique behaviour during his years he sent in the United States as a doctorands. He named these molecules MDR-selective compounds. In a paradox way, these compounds attack exactly those tumour cells, which – due to their above mentioned multi drug resisting- (MDR-) pumps – are completely resistant to most of the chemotherapy substances. Returning from the US, Szakács intensely continued the studying of the MDR-selective compounds, and got to the conclusion, that they actually utilize their cell-damaging effect as a result of the operation of the pumps – but he has not been able to fully clarify how this process is happening. However, the appliance of these compounds for therapy purposes could multiply the strength of the strategy of Gatenby: in their presence, the maintenance of the pumps for the tumour cells would not be disadvantageous indirectly, due to their high-energy demands, but also because of the direct damage as well, which the MDR-selective compounds cause to the pumping cells. „The excellence program of the EU, our results supported by the application of the ERC made it clear, that the cancer cells which are resistant to therapy can be selectively attacked by the compounds discovered and tested by us – summarizes Szakács. –In the Enzymology Institute of Natural Sciences Research Center of the Hungarian Scientific Academy we patented such medicine-to be molecules, which target the Achilles-heel of the most hardly demolish able cancer cells. In accordance with the theory of the adaptive therapy, our objective is the fine-tuning of the therapy protocol. The method works perfectly in the cell-culture dish; currently we are working on the adaptation of a special animal model, which enables examination of the spontaneously developing tumours’ evolution, biopsy and response to therapy.”
September is the month of the struggle against child cancer; its symbol is the golden ribbon.
By wearing the golden ribbon, you show the entire society that you stand by the ill children.
Our foundation works for increasing the recovery chances of children suffering from cancer every month, but in this month, we would like to call the attention of even more people to these children suffering from this serious illness, who fight for their lives every day of the year.
Just a few km-s from Lake Balaton, the cancer patient children had the chance to spend their vacation on weekly turns. The fully equipped, comfortable guest house of our Foundation provides a full recreation for the little- and bigger ones recovering from the illness, who can enjoy the summer holiday in Veszprém with their siblings and parents. The Zoo, castle, several museums, galleries, excursion, and of course the inevitable bathing await our guests. Our Foundation covers the expenses of the holiday instead of the families, in the recent period we took care of the vacation of 27 persons.
The vacation spent with family members, providing meaningful recreations is not only important for the children recovering from cancer, but it is essential for their siblings and parents too, since the long-lasting illness wears out the entire family both financially and mentally, spiritually.
Michelle with her girlfriend and mother once again chose the cabana of Our Foundation in Veszprém for a weekend time-out.
We received the following letter and photo from them:
Dear Foundation, Dear Uncle István,
We really had a great time! Once we got completely soaked in the rain, but otherwise everything was so good and nice.
We visited the Zoo, the Castle, and Herend as well. :)
Thank you for the opportunity of being there!
Michelle and Gabriella
nlcafe.hu 31st May 2016.
His arm was amputated at the age of fourteen, because of cancer, but this did not stop him from becoming an onco-Olympics champion in swimming. Péter Sipos was taught by his illness, that is it only worth living consciously. Her is twenty years old now and is the junior coach of the Zuglói Sasok, ha is a university student, and aspiring for an international para-swimming competition in the meantime. Now, after five years he is waiting to be finally qualified as recovered from the cancer
You appear in the interviews of the reports of the Children Cancer Foundation among others, on a regular basis. This is obviously not by accident, you have always been giving interviews in a very matured way. Isn’t this “Ambassador’s” role sort of a burden to you?
When I have to stand up for the right cause, for the ill children to be supported by more people then it is not. Or when I am asked about sports (Péter made it to the Olympics to Warsaw through the Foundation), it also isn’t. When they want to make sort of a sensation from me, because a deadly illness left a very visible mark on me, well, I don’t like that. A few years ago, I was regularly disturbed by the media, which I very much disliked after a while, because I felt that I was only being used.
Why do you think you were highlighted among your fellow sufferers?
I think it was because mine was quite an extraordinary case. At the age of 14 I had to make a decision; whether to have my arm amputated for the sake of my recovery. This made me to become an adult, and to realize many important things. For example, to realize what was it that I really wanted in life. I don’t spend time with anything which I don’t like, because that is only a waste of time. And I also learned that goals can swing you out of the lowest points in life. Sports is excellent for this. And this is the reason why onco-Olympics is organized.
Where you made it to championship in swimming. But why did you choose swimming with one arm?
Before the amputation, I already started preparing, and never ceased to give up afterwards. Besides, I had the most chances to prepare for swimming. My physical education teacher helped me a lot, there is a swimming pool right next to the school and that was where I was training. We could adjust to each other. I was durable and felt that I was developing fast. I was in Warsaw at the age of16 and 18 too, and won several medals on each occasion in backstroke and breaststroke, as well as in freestyle swimming, all the other competitors being unimpaired, I was the only person with a missing arm. I used to be quite a good swimmer earlier too, but I had to learn it all over again, with one arm.
I guess you had to re-learn many things. Especially taking the fact that you were right-handed into consideration, if I am not mistaken.
Yes, I was, and yes, I had to re-learn even very every day and ordinary things too. For example, I can tie my shoelace with one hand. It is only the question of patience and endurance for one to learn it. And the compulsion of course, that is a large force. When you realise that you cannot cut a slice of bread. Then I met people in similar situations as mine and learned a lot from them. There is solution to almost everything. And not only when it comes to sliced bread. People came up with all kinds of tricks and solutions, such as nocking a nail into the cutting board; and fix the bread on it in order for it not to slip away.
Would you tell me how you got to know that you had cancer?
I was 12 years old, when during a basketball training I fell down and my elbow got wounded. When the P.O.P. was removed from it after a few weeks; I was unable to stretch my arm, and we realized that there was an intergrowth in the curve. The doctors were trying to calm us down for some time, that it can’t be anything extra, that it was only an encapsulated lot of muscle. I used to go to a physiotherapist for treatment, but it did not cease to exist, it rather became more and more unpleasant and painful. They kept sending me from one hospital to another for months, but they couldn’t really do anything with me. At last a number X doctor recommended, that a sample should be taken from the intergrowth with needle biopsy test, to eliminate maleness. Well, that was when we found out that there was a carcinoma in my arm. They performed a surgery on me almost instantly, cut the ingrowth out. Following the surgery, I had to attend chemotherapy for half a year.
Did you also have to stop going to school?
I was supposed to repeat grade seven, but at last I went to a new school; to a 6 grades secondary school, because my parent got divorced in the meantime, and me and my younger brother moved to my mother and her new partner to Rákospalota.
This surely worn you down, so many changes at the same time. It can as well be said that your entire life turned upside-down.
Yes, until then my entire life consisted of the school and playing basketball. Switching schools wasn’t bad at all, by the way, many of my basketball buddies attended the same secondary school. The switch did wear me down if course, but I was quite preoccupied with my own problem. Perhaps the worst part of it was the chemo, but even though it made me feel really sick, I was forced to go through it all the way. Nothing was hidden from me, that was the first time in my life that I ever felt like I was taking responsibility for my own life as an adult. I knew quite well that I could die of this illness, and followed all instructions orderly. I remember, the worst part was that I was throwing up so often and felt nausea all the time. That was the period when I really hot to hate many dishes, which I am still unable to even took at, ever since. For example, one of them is the rice-porridge, I threw that up once. Never ate it again since.
And when did you find out that the amputation was necessary?
During the second half-year control after the chemotherapy. We were told that the tumour recrudesced. They wasted no time at all, took me to the surgery room instantly. I spend five days in the hospital, thinking that the ingrowth had been removed. I was only told by my parents at home, that when my arm was excavated; the concluded that the tumour could not be removed without causing destruction, and there was also a very high chance that it would reoccur again. The doctors recommended that the best solution was to amputate my arm. But what they wanted was to let me know all this in a relaxing environment. I got to know about everything at home, from my parents. Naturally, they let me make the final decision, but there was no much time to waste.
So, you were the one who said the final verdict, that your arm should be cut down? How old were you at that time?
Fourteen. It was my decision, yes. My parents were supporting me in it, but did not enforce anything. We discussed it, that it should be amputated. We cried throughout the night, then we went back to the hospital. My mother tried everything possible, had me checked in a hospital in Austria too, but even there they could not come up with a better solution.
How did you manage the first period after the amputation?
I was depressed, was afraid to go to where there were other people, but I was really longing to get out, not to be behind the four walls, especially because it was summer time. In between two treatments, when I was feeling slightly better, we went to an aquapark with my friends. I remained in a t-shirt, but many people still looked at me, and whispered behind my back. Since then I got used to this, it doesn’t affect me anymore, but that time, being the first time it was way too much, like a cold shower for my already torn-down soul. During the period of my illness, I also found out who my real friends were, many fell out, which was also difficult to cope with. But at least I know who the honest people are, the ones I can count on. With the seven of those my friends my relationship remined very good ever since.
Photos by: Róbert Érdi
In every interview, I saw you like this, with one arm. Didn’t you want a prosthetic limb?
I actually have one, but I don’t wear it in everyday life, I don’t like it, I don’t find it practical. I only clip it on, when I put on a suit, because it looks better like that. Or if I go for having a dinner out with my girlfriend. But many people helped to gather the money for it, for which I am really very grateful.
Since when do you have a girlfriend?
For three years now, she was my classmate in secondary school.
That is a serious relationship. I guess you have plans already.
Yes, we are planning to move in together, once things get straight with the university, work, and we can afford to pay for an apartment.
So you are working and in the meantime attending university too?
On one hand, I really need to get a diploma, because I will not be able to do any physical jobs. On the other hand, I must make money and gain experience. I stich very much to basketball and coaching, that is what I see sense in, and do coaching in Zugló three times a week. This is the most important thing for me, but it cannot provide a living, that was why I had to find a job. I applied to many places, especially for administrative jobs, but I didn’t want the case to be employed alongside with other people living with disabilities because they are entitled to a tax reduction after me. Of course, I wasn’t told anywhere that they are not hiring me because I have only one arm, but it was obvious. I wouldn’t say that I am capable of doing everything, but I am able to solve most problems. But you know; you wouldn’t walk up to anyone trying to prove that you are able to slip the paper into the binding bag. Then luckily one of my good acquaintance found out about that I was searching for a job, and offered me work in his own company. I didn’t have to prove to him that I was trustworthy and hones. I do not stand up at the end of the working hours, if there is anything left to do. On top of everything, I really like the job, safety technology, CCTV systems; I want to understand and learn everything. I feel that I am being valued, they send me for training, and I am being educated and trained. During the summer, I am preparing for my German language certification exam, I need the language for the job.
If I am not mistaken, in the meantime you are also preparing for another competition too.
Yes, in July in Rijeka, I am participating in the European University Game, in Para swimming, now with more equal chances, not against unimpaired ones, But I am also having my basketball coach examination too in June. I would like to be a youth team coach.
Aren’t those who go for training for the first time surprised when they see you for the first time?
It does happen, but I am able to manage such things well, and they quickly realize that I am able to perform a training of full value even with one arm. By now I am experienced enough to ease uncomfortable situations, for example humour is always a friend in such cases. When I say, I was so good I feel like giving you an applause; at first, they are surprised, but then we laugh over it together; and they realize that they have nothing to do with this.
Index.hu Ltd. was ordered to pay 7 million HUF by the Metropolitan Court.
The Children Cancer Foundation sued Index.hu for infringement of privacy rights, seeking compensation for damages.
The Metropolitan Court found that Index had tarnished the reputation of Children Cancer Foundation by its allegations. In 2013, Index made and spread false statements and presented true facts in false light in several of its articles. These offending allegations were taken over by most of the printed and electronic media in Hungary, causing significant moral and material damage to the Foundation.
At first instance, the Court banned Index.hu from further infringement and made it pay 7 million HUF as non-material compensation.