Cancer: diagnosis and treatment

About the development of cancer, immunotherapy, diagnosis and treatment of cancer

Due to what it is possible to reduce the risk of cancer in the body? How are oncological diseases diagnosed today? What type of cancer is most common in humans? Post-science product manager Alina Zatonskaya talked with an oncologist about the diagnosis and treatment of cancer  Igor Samoylenko.

– Are there any tests for screening major oncological diseases?

– There is not a single tool to say with confidence: "You are doing well." When we do screening, we want to check the most common malignant tumors that affect life expectancy. But we cannot detect rare forms of cancer with high reliability in the early stages. Therefore, we all need to accept the fact that there is always a chance of getting sick. And the older a person is, the higher this probability is. 

If something bothers you or something has appeared that you cannot explain to yourself, be sure to go to the doctor. He will confirm that it is not dangerous, and you can continue to live a normal life. Or, on the contrary, he will ask you to do additional tests. Here's what you should do as an early diagnosis.

– What about prevention?

– Really effective measures: smoking cessation and vaccination against human papillomavirus. This will make a tangible contribution to the health of your family. Another important factor is the state of the environment. If we can keep the habitat in ecological balance, it will reduce the likelihood of malignant neoplasms.

– Which diagnostic methods are most effective? 

– All preventive and diagnostic interventions have different values. Some can affect life expectancy: to make sure that we detect the disease early and have time to cure it in time. Others, even very precise and detailed ones, ultimately do not affect how long a person will live.

There are diseases that can be detected using instrumental and biochemical methods even before a person feels any deviations. For women, this is breast and cervical cancer, for men – prostate cancer, for all of us – colorectal cancer. 

But there are ways about which it is not yet clear whether they can affect mortality or not. The role of biochemical screening for prostate cancer detection is being reviewed. We can detect the disease at an early stage by taking a blood test for PSA (prostate-specific antigen). 

But a number of studies show that patients will not live longer from this. It turned out that it is not always useful to interfere with the natural course of the disease by aggressive methods.

– Is everything ambiguous with mammography, too?

- yes. In some countries, the role of mammographic screening is being questioned. Do women need to have their mammary glands checked if treatment has become more accessible and better? Should every healthy woman have a mammogram every two years? Or can we wait until she herself discovers a neoplasm in the mammary gland and goes to the doctor, because the chances of curing the disease in both cases are gradually leveled?

– Can mammography be a trigger for breast cancer?

– Mammography is performed using X-rays, and this is ionizing radiation. Therefore, theoretically, it can cause DNA damage and the appearance of malignant tumors. Early studies have shown that in women who undergo mammography, cases of detection of malignant tumors are more common than in those who do not. But this was explained not so much by the harmful effects, but by the fact that we simply find additional cases that may not lead to the death of the patient. Therefore, there is no confirmation yet that mammography increases the risk of developing malignant tumors. In any case, the risk is lower than the expected benefit, and the dose of radiation received by a woman during mammography is comparable to a transatlantic flight. 

– But not with all types of cancer?

– Yes, it's the opposite with others. For cervical cancer or colorectal cancer, the role of early diagnosis is catastrophically great. Now it is possible to identify precancerous conditions, which in a few years may become malignant neoplasms. And if we cure them at the first stage, we will prevent cases of cancer development, which means premature death of a person. To diagnose cervical cancer, you need to come to a gynecologist once a year, and to detect colon and rectal cancer, you need to take a stool test for hidden blood and do a colonoscopy.

– Ultrasound of the gastrointestinal tract can detect oncological processes in the early stages?

– Can we find a tumor of the gastrointestinal tract "by touch"? Yes. Can it be at an early stage at the same time? Theoretically, yes. But ultrasound of the abdominal organs is still not the method that is required for early diagnosis of a gastrointestinal tumor. The gastrointestinal tract consists of several organs. If we are talking about tumors of the colon and rectum (colorectal cancer), then it is useless to do an ultrasound of the abdominal cavity. Starting from a certain age, you need to take a stool test for hidden blood and do a colonoscopy if the result is positive. We recommend that people over the age of 50 come for a colonoscopy once every 10 years. The examination will help to identify polyps. Depending on their number and type, the doctor will offer the patient an individual colonoscopy interval. But if there are none, then over the next 10 years, the tumor will most likely not grow.

Cancer Treatment

– How does a cancer cell deceive the immune system?

– The immune system is not a means of individual protection, but a means of protecting the population. Over millions of years of existence, we have developed a certain pattern of responding to the main threats faced by the species, and this pattern has developed into certain structures of the lymphatic system. But in order to gain a foothold in the population, the trait must be inherited. When cases of the disease occur in childbearing age, there is a chance that individuals with a poor immune system response will not pass on their signs to the next generation. But malignant neoplasms are an element of aging of the body's cells, when there is no longer a chance that something could consolidate a successful pattern of response to cancer in the population.

Factors of carcinogenesis act constantly. They can be endogenous and exogenous: caused by internal causes or external effects on the body, for example in the form of a virus. As a rule, carcinogenesis takes a long time. Tumor cells that have been recognized by the immune system are destroyed. But the evolution within the individual is also underway, and those clones are selected that for some reason may be invisible to the immune system. 

In 2018 , the Nobel Prize in Medicine was awarded to two scientists from The United States of America and Japan – James Ellison and Tasuku Honjo. They explained the mechanisms of interaction between tumors and the immune system. And these mechanisms turned out to be available for the effects of drugs. If we take the top 5 malignant neoplasms, we will see that this mechanism is universal: it occurs in malignant tumors of the lung, skin, gastrointestinal tract. But the frequency of its use by the tumor is different in one case or another.

If you take skin tumors, skin melanoma, squamous cell skin cancer – diseases that are not very common – then in about 40% of cases the body's response to such therapy will be successful. If you take lung tumors, the reaction will be slightly worse. If you take tumors of the gastrointestinal tract, the percentage of a positive response to therapy will be even lower. Apparently, in other cases we will find other mechanisms. 

This is how the concept appeared, which is being developed by several institutions, including in our country. Thanks to these evolutionary mechanisms within an individual, due to the fact that the repertoire of immune T-cell receptors (molecules capable of recognizing infected and tumor cells) is finite, clones are selected that are not able to recognize a certain spectrum of antigens. And this is a rather sad story, because if we don't have a repertoire, then we don't have a chance to activate the immune system.

– Why else can the immune response be suppressed?

– The tumor may express some factors that suppress the immune response. Lymphocytes are inactivated, despite the fact that they can recognize the disease. Or the second scenario: the tumor does not have particles on its surface that can be recognized by the body. These are the two main versions. But there are others: there may be special genetic changes in the tumor that do not allow lymphocytes to use traditional mechanisms to destroy it. This is one of the ways in which current immuno-oncological approaches do not work, because the intracellular signaling pathway in the tumor, which should be involved in interaction with the lymphocyte, is turned off and does not work. 

– With immunotherapy, how long does it take the body to learn how to correctly recognize cancer cells?

– It should be noted that immunotherapy is a collective name. We can divide it into two classes. Either you transfer effector cells, and they start working as soon as you transferred them – this is adaptive immunotherapy (from the word adoptive – "reception"). Or you can try to influence the training of lymphocytes. For many decades there has been a belief in antitumor vaccination. This was done very widely all over the world, in our institute too. 

Interest in antitumor vaccination is growing again today. We are talking about tumor antigens that you get from a patient or naturally when a fragment of a tumor is taken and an antigen is somehow released. Then, under special conditions, either in the presence of dendritic cells, or in the presence of a mixture of dendritic cells with lymphocytes, inject the antigen back into the same patient with the expectation that the loaded immune cells of a particular person began to recognize the tumor. This process is similar to vaccination against influenza or infectious diseases. This is what is called active immunization. 

– What other ways are there?

– The second way is the blockade of immune control points, an attempt to influence the receptors of immune cells that direct the immune response. The lymphocyte, depending on which receptors are activated on it, can become more aggressive or calm down. And if we block the receptors of calmness, then he begins to get excited and react to everything. 

– What side effects can there be?

– It is not safe to wake up the immune system, because the inhibitory mechanisms that have been evolutionarily selected protect our organs from the aggression of our own immune system. And if we suddenly start to eliminate them, then we open a Pandora's box. We want to ensure that the immune system responds only to tumor antigens. But we don't have a mechanism to close her eyes to everything else and point only to the tumor. An immune-mediated reaction may occur, then lymphocytes will begin to attack their own organs: skin, intestines, endocrine glands, liver, lungs. When this happens, the patient needs intensive and aggressive, now immunosuppressive treatment. 

Thus, we wanted to shake up the immune system, but when it turned out, we want the person not to die from it. But such undesirable reactions have a positive correlation with the antitumor response – this is an indirect marker that the treatment has worked.

– How fast is the field of cancer treatment developing?

– Several new classes of medicines have appeared only in my memory. When I came to the medical institute, we only knew about cytostatic chemotherapy. 

In the process of training, the first drugs appeared that began to act on mutant proteins in a targeted manner. One of the first such drugs was Imatinib. It was used to treat chronic myeloid leukemia, where there is a specific chromosomal mutation. And this mutant protein was very important for tumor cells. Therefore, if it is blocked, then leukemic cells die. Since then, the approach of blocking the process important for the tumor has led to the development of targeted drugs that are used for various malignant neoplasms.

In parallel, the story of monoclonal antibodies developed. One of the first was a drug for the treatment of B-cell lymphomas – a drug Rituximab is based on chimeric antibodies that bind to the target on tumor cells and, due to antibody-dependent cytotoxicity, trigger the process of necrosis inside cells and destroy them. Since then, three generations of such drugs have appeared. 

Today we have a large number of new classes of drugs and new targets for them. Immunological therapy is developing when we can embed new receptors in lymphocytes. An antitumor, oncolytic virus was found. In the Western world, one is used, and in China has several viruses for intra-tumor immunotherapy. This is a separate class of drugs that are used for treatment. All this represents a dynamically developing area. 

Therefore, the design of antitumor drugs and the development of methods for the treatment of malignant neoplasms is a promising area of activity where there is an opportunity to come up with something new and technological. Today we have a good understanding of the mechanisms of carcinogenesis. It only takes some time, tools and investments of effort and resources to largely translate the problem of cancer into the category of chronic diseases that may annoy a person, but do not make him terminally ill. 

Carcinogenesis is a long and complex process of pathological cell development. In order for a cell to become cancerous, a number of genetic mutations must occur in it, leading to functional reorganization within the cell. The order and nature of these changes may vary greatly in different tumors.

And which of the above is NOT included in the list of changes that can often be found in the genomes of tumor cells?

• Violation of the mechanisms of control over proliferation (cell division) and differentiation of cells.
• Violation of telomerase activity.
• Changing the mechanisms of protection against bacterial or viral infections.
• Violation of the mechanisms of programmed cell death.

Additional materials

• HPV vaccination to prevent cancer and precancerous changes of the cervix, Cochrane.
• Screening for prostate cancer, Cochrane.
• Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness, H. Gilbert Welch, M.D., M.P.H., Philip C, 2016.
• Screening for breast cancer with mammography, Cochrane.
• The Nobel Prize in Physiology or Medicine 2018 goes to James P. Allison and Tasuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation.
• Chronic myeloid leukemia.
• Imatinib, FDA.
• Rituximab, FDA.

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