Advances in Cancer Treatment

Cancer is a disease that has existed since the dawn of humanity. The first steps in modern cancer treatment were taken after World War II. The successful use of drugs in cancer treatment began in the 1970s.

The treatment of cancer with drugs is called chemotherapy, and these drugs are called chemotherapy drugs. The most important reason for using drug therapy in cancer treatment is that cancer is generally a systemic disease (i.e., a disease affecting many organs of the body). Of the three treatment methods (surgery, radiotherapy, and chemotherapy) that play a role in cancer treatment, drug therapy, or chemotherapy, is the only treatment method that can affect the entire body systemically. The common characteristic of the drugs used in chemotherapy is that they damage cells with a high rate of division/growth. Since cancerous cells are generally cells with a very high growth rate, they are damaged by these drugs. These drugs also affect the body's normal cells that have a high division rate. As a result, common side effects of chemotherapy drugs can occur: nausea, decreased blood counts, hair loss, etc. One of the most important differences between cancerous cells and normal cells is that normal cells can repair themselves, while cancerous cells cannot fully repair themselves. While normal cells can recover from the effects of chemotherapy within two to three weeks, cancerous cells cannot and can die after repeated chemotherapy treatments.

While chemotherapy alone can be curative in some cancers (such as lymph node cancers, breast and ovarian cancers, etc.), in other cases the cancerous cells develop resistance to the chemotherapy drug, and the disease reappears either immediately or after a while. There are two important reasons for this:

1. Cancer cells developing resistance to chemotherapy drugs
2. Because drugs also affect normal cells, they cannot be given in high doses to destroy all cancerous cells.

In recent years, there have been significant advances in chemotherapy drugs and applications. New, more effective drugs are being introduced into treatment (e.g., nab-paclitaxel, liposomal drugs), the side effects of chemotherapy are being reduced thanks to new supportive medications (e.g., serotonin antagonists for nausea; G-CSF for patients with low blood counts – low leukocytes), new treatments against drug resistance are being investigated (e.g., MDR modulators, drugs that increase DNA damage), and new drugs are being developed that target only cancerous cells and do not harm normal cells (antivascular drugs, humanized antibody therapies that block growth factors).

To treat cancer more effectively, in addition to chemotherapy, we need drugs that target the cause or mechanism of cancer. In the coming years, these types of treatments will be the most effective forms of cancer therapy. While some of these treatments are still in the experimental phase, others are already being used on humans, and we will have the opportunity to use many of them routinely within the next five years.

The main new treatments are as follows:

1. Drugs that prevent blood vessel formation (Angiogenesis inhibitors): Cancer cells depend on receiving oxygen and nutrients from the bloodstream to grow and multiply. To this end, cancer cells secrete certain substances to form their own capillaries. After a while, these capillaries allow the cancer cells to enter the bloodstream, reach other organs, and metastasize. Experiments have shown that if the formation of capillaries by cancer cells can be prevented, the cancer cells can neither multiply nor metastasize. One of the most important discoveries of recent years is the discovery of a group of substances that prevent cancer cells from forming capillaries, and the creation of other substances that can perform the same function. Many of these substances (angiogenesis inhibitors), numbering over ten, are currently being used therapeutically on humans. In this way, even if cancer cells are not destroyed, they will neither be able to grow nor metastasize. Thus, even if cancer is present in the body, it will not harm us. With the help of these drugs, it may be possible to live healthily even with cancer.
2. Biological medicines: One of the most important advances in cancer treatment is therapies targeting the biology of cancer. Using genetic technology, many drugs in the antibody class have been developed and are still being developed to counter certain biological mechanisms that are excessive in some cancers and make treatment difficult. The first products of this era are currently being successfully applied in some lymph node cancers and in breast, colon, and lung cancers. The most important of these drugs are immunotherapy drugs. In this method, called immunotherapy, the PD-1 molecules on the surface of body cells that fight the tumor, or the PDL-1 molecules that tumor cells use to bind to PD-1, are targeted. That is, the PDL-1 on the membranes of tumor cells binds to the PD-1 mouthpiece of immune cells, effectively putting the immune cells to sleep and rendering them ineffective. If the PD-1 on the immune cells is blocked by an antibody, these cells become stronger and more activated, attacking and destroying tumor cells. The first anti-PD-1 antibodies developed, Nivolumab (trade name Opdivo) and Pembrolizumab (trade name Keytruda), have shown efficacy in -50 patients with lung cancer. The most important indicator of which patients they are most beneficial to is the mutation burden in the tumor. A high mutational burden (i.e., a large number of mutations in the tumor) is defined as more than 18 mutations in each megabase of genetic material, and this is the best indicator to date. Genomic analysis of the tumor block is required to determine this. The second important indicator is the detection of PDL-1 expression in the tumor tissue using immunohistochemistry. The higher this expression, the higher the probability that the immunotherapy drugs will be effective.
   Immunotherapy drugs are currently used in Stage IV lung cancer patients as first and second-line treatments, and more recently, in combination with chemotherapy drugs as first-line treatment. They are also now standard treatment for various other cancer types (head and neck cancer, triple-negative breast cancer, esophageal and stomach cancers, kidney cancer, liver cancer, bladder cancer). The advantage of these drugs is that if the disease responds to them, the response time is quite long (on average over a year and a half). These drugs do not have side effects such as hair loss, nausea, or decreased blood counts. On the contrary, they can strengthen the immune system. The most serious side effect is the strengthening and activation of immune cells, leading them to attack normal tissues. This side effect, which is quite rare, occurs in patients with %2-5 and most frequently manifests as immune pneumonia, colitis, thyroiditis, or hepatitis. With cortisone treatment, the cure rate is close to 0.
3. Small molecules: The most important of these, tyrosine kinase inhibitors, can make significant contributions to treatment by affecting targets in cancer cells that differ from those in normal cells. In some types of lung cancer (such as adenocarcinoma lung cancer with EGF-R receptor mutations), the orally administered tyrosine kinase inhibitor erlotinib can be more effective than chemotherapy and exhibits a very positive profile in terms of side effects. Two new generation drugs (afatinib and osimertinib) have now been introduced to the market. These can show benefit in cases resistant to erlotinib. Osimertinib (trade name Tagrisso), in particular, is both more effective than erlotinib and effective in brain metastases. In renal cell carcinoma, which is kidney cancer, numerous tyrosine kinase inhibitors have shown much more beneficial results compared to oral chemotherapy.
4. Cancer vaccines: While partly related to the immune system, cancer vaccines, aided by recent advances in research, represent a significant breakthrough in cancer treatment. The discovery of certain substances found in cancerous cells but not in normal cells was the first step in this direction. Experimental studies have shown that by selectively stimulating the immune system against these substances, cancerous tissue can be rejected by the body. Human trials are currently ongoing. We expect these vaccines to be used within the next five years, particularly in early stages, to prevent cancer from recurring (adjuvant therapy).
5. Drugs that transform cancer cells into normal cells: It was first demonstrated some time ago that cancerous cells can be transformed into normal cells by medication, using all-trans retinoic acid in a type of blood cancer (acute promyelocytic leukemia). Studies with such drugs are being conducted on other types of cancer, and it is thought that by increasing the quality and quantity of these transforming agents, it may be possible to utilize them in more common cancers in the near future.
6. Gene therapy: Cancer is essentially a disease caused by genes within a cell failing to perform their functions for some reason. Two groups of genes play a crucial role in the cell. One group tells the cell that it needs to grow and divide. Another group tells the cell that it has grown sufficiently and that it should stop growing and perform its function. Cancer largely results from an imbalance between these two groups of genes. If the genes that promote growth work excessively, or if the genes that inhibit growth work insufficiently, or if they malfunction for any reason, then the cell continues to divide and grow, becoming a cancerous cell. The aim of gene therapy in cancer is to restore this imbalance, meaning to stop the genes that cause cancer by working harder, or to reactivate the genes that are not working and thus preventing cancer development. The most important of the genes that stop cancer is the P53 gene. When this gene is not working, it plays a significant role in the formation of many cancers (one of the most important mechanisms by which smoking causes cancer is that the substances in smoke disable P53). Experimentally, it has been shown that when a new P53 gene is introduced into a cancerous cell, the cell's cancer development stops. Following this, researchers in the US injected healthy P53 into the cancerous tissue of nine lung cancer patients, and in eight of them, the cancers almost completely disappeared. Now, the biggest obstacle for researchers is getting the healthy P53 to reach all the tissues where the cancer has spread. Studies are ongoing in this area, and it is thought that this treatment could be successful using viruses similar to the influenza virus, which are harmless to humans.

In conclusion, we hope to use new, effective, and low-side-effect treatments for cancer in the coming years. These treatments will most likely not be a cure for cancer on their own. Cancer is not a relatively simple event like a microbial disease. For a definitive cure, we will need to use all these treatments, including chemotherapy, in a specific order or in combination. Perhaps instead of completely eradicating cancer, we will learn to control it and live with it.