Chemotherapy and Targeted Drugs

Chemotherapy (sometimes called "chemo") is a type of cancer treatment that uses drugs to kill cancer cells.

Rapid growth and multiplication characterize cancer cells. Chemotherapy stops or slows cancer cell growth and multiplication. However, it can also damage rapidly multiplying normal cells, causing chemotherapy side effects such as diarrhea or hair loss.

Chemotherapy and beyond: targeted drugs

Targeted treatments emerged from understanding cancer cells and intracellular growth signaling pathways at the molecular level, and successfully blocking the signals stimulating these growth pathways from inside and outside cells with various drugs. The most striking successes in this field have been achieved in lung adenocarcinoma. Treatments developed against all these steps are called "targeted treatments or smart drugs".

Genetic mutations are the underlying cause of signaling pathways that increase growth uncontrollably during cancer development (carcinogenesis).

Identifying these mutations is extremely important in clarifying which treatment will benefit which patient.

As we understand molecular pathways and abnormal changes (mutations) within them, the number of drugs targeting these mutations increases. These drugs have prolonged survival and improved quality of life in patients with metastatic disease. The limited survival achieved with chemotherapy in these cancers is significantly extended in patients suitable for targeted treatments.

These specific molecular changes in cancer cells are revealed through analysis of tumor DNA. In patients diagnosed with cancer, mutations, and therefore potential suitability for targeted drugs, are identified in two ways. The first is molecular testing of tumor tissue obtained from the patient by biopsy. The second approach, whose reliability and use have increased in recent years, is liquid biopsy. These tests use a blood sample without requiring a biopsy from the patient. They identify tumor DNA circulating in the blood and look for mutations suitable for targeted treatment. Liquid biopsies prevent repeat biopsies, particularly in patients who have previously undergone biopsy but have insufficient tissue remaining.

After mutation analysis, chemotherapy is preferred for patients unsuitable for targeted treatment. Another important development in recent years has been in immunotherapy . Drugs eliminating a kind of insensitivity, or blindness, of the cancer patient's defense system toward cancer cells generated excitement after 2012 and, following successful results, received approval from the United States Food and Drug Administration (FDA) for the treatment of malignant melanoma skin cancer, non-small cell lung cancer, kidney cancer, Hodgkin lymphoma, head and neck cancers and bladder cancer. Currently, these drugs are recommended for patients who have received first-line chemotherapy without an adequate response, or whose disease subsequently progressed despite a response. Research into their use as the first treatment choice in newly diagnosed patients continues. Initial studies suggesting success with their use alone or combined with chemotherapy have been published and found promising.

Their extremely high cost is the main disadvantage. Many countries have been unable to provide reimbursement because of the expense and fears of a threat to their economies.

Cancer differs not only between types. Even the same cancer type varies among individuals who have it. Each person's treatment tolerance and accompanying illnesses differ. Particularly as treatment options have increased, differences between tumor types and individuals have led to greater selectivity in cancer treatment and the development of personalized treatments.

The image shows targeted cancer drugs approved by the United States Food and Drug Administration (FDA). Notably, many targeted drugs were approved in 2010 or later. This is another sign of the accelerating pace of developments in cancer medicine. (Note: although every country has its own approval, licensing and reimbursement mechanisms for new drugs, the FDA is the leading institution worldwide in this area.)

History for a Better Understanding of Chemotherapy and Cancer

Cancer remains among us today, as it did thousands or even millions of years ago. In research published in Nature on 5 July 2016, a study identified a tumor in a dinosaur fossil, the earliest known cancer case (approximately 70-80 million years ago). The earliest human cancer is a bone cancer dating back approximately 1.6 million years. Yet cancer is discussed today as a disease of the modern world and thought to threaten humanity more than in the past. Both shorter average lifespans in the past and limited written statistical records make a definitive judgment difficult.

Since cancer predates even human history, attempts to treat it must also have a considerable history. Attempts to treat superficial tumors by cutting them out (surgery) or cauterization (hyperthermia) date back approximately 5 thousand years.

The use of herbal products or chemicals (copper, lead, sulfur, arsenic and others) to treat cancer can be described as the most primitive chemotherapy methods, far from effective and not yet fully evolved.

With European surgeons of the 17. century, cancer ceased to be something that should not be touched. The term "hematology" was first used in 1743 by Thomas Schwenke. Blood cells were identified in the late 17. and the 18. century. Erythrocytes were described by Anton von Leeuwenhoek (1632-1723) in 1674, leukocytes by Joseph Lieutaud (1703-1780) in 1749, and lymphocytes by William Hewson (1739-1774) in 1774.

The findings of these scientists in times when the microscope was not yet in use are remarkable. Invented by Zaharias Jansen in 1590, the microscope completed its historical development through Kepler in 1611, Chistiaan Huygens in 1684 and later Ernst Abbe (1804-1903), and only began to be used in medicine in the early 19. century by very few physicians. Until then, diseases were believed to result from impaired consistency and elasticity of solid organs (solid pathology), or imbalance between bodily fluids (humoral pathology). The idea that neoplastic proliferation of blood cells infiltrating bone marrow and other tissues caused leukemia did not yet exist.

In England in 1802, the Society for Investigating the Nature and Cure of Cancer raised questions such as “What are the diagnostic signs of cancer?”, “What causes cancer?”, “Is cancer a primary disease or does it develop from other diseases?” and “Is cancer hereditary?”

The influence of lifestyle habits on cancer development was demonstrated by isolating the carcinogenic hydrocarbon in tobacco smoke in 1950, showing high rates of mouth and esophageal cancer among Indian men chewing betel (pepper tree), and finding an association between eating smoked fish and stomach cancer in Japan.

One of cancer's most typical features is its increasing incidence with age. The observation that cancer is mainly a disease of old age dates back to Hippocrates (born 460 BC, Kos - died 370 BC, Larissa). Increasing average lifespan and improved living conditions explain the rising incidence of cancer.

The Discovery of Chemotherapy

One turning point in cancer history is, of course, the discovery of modern chemotherapy. In the 1950s, reports that various plants were effective in cancer treatment began appearing in the press. Interestingly, cancer treatment with plants can still become a popular subject of debate today as though it were a new idea... The synthetically produced antibiotic puromycin was shown to act against breast cancer in animal experiments (1954).

Lissauer, in 1865, showed that arsenic, first used by Thomas Fowler in 1786 for fever and headache (%1 arsenic trioxide: Fowler's solution), was beneficial in some chronic leukemias(a type of blood cancer). After treatment, the spleen shrank, leukocyte counts fell and anemia improved. This is considered cytotoxic therapy's first step.

Chemotherapies are cytotoxic, meaning cell-killing drugs. Cytotoxic drugs aim to stop cell growth and multiplication. Cancer cells generally grow and multiply rapidly, which makes chemotherapy drugs effective in cancer treatment.

Treating chronic leukemias with arsenic continued until radiotherapyentered treatment in 1903. Eight years after William Roentgen discovered X-rays in 1895, radiotherapy was used to treat leukemia by Nicholas Senn (1903).

Chemotherapy used to treat leukemia and many cancers was discovered in the early 1940s

During World War II, after a ship carrying 100 tons of gas mustard (mustard gas) sank, research by Dr. Alexander (1943) identified leukopenia (reduced white blood cell counts) among soldiers. In the same year, Dougerty and White found that steroids caused lymphopenia. These observations paved the way for nitrogen mustard, a component of mustard gas, to be used in lymphoma treatment successfully.

Not long after nitrogen mustard was discovered, aminopterin was found to achieve complete remission in childhood acute leukemia by acting against folic acid, a vitamin with a key role in cell division. This drug blocks a critical chemical required for DNA replication and is the precursor of methotrexate, widely used in cancer treatment today. Whether chemotherapies successful in blood cancers would work in cancers of other organs (solid cancers) immediately became a question, and studies began rapidly in the 1950s. For example; cisplatin , a platinum analogue, brought cure rates close to %100 in highly lethal testicular cancer, particularly at early stages. New drugs inhibiting different stages of cell growth and multiplication began to be discovered. Thus, the era of chemotherapy in cancer treatment began.

Developments in chemotherapy can be divided into three periods:

1. The 1946-1960 period: This period generally saw the development of single-drug chemotherapy on an experimental basis, effective new drugs, and the determination of toxicity, performance and optimal tolerated doses.
2. The 1960-1970 period: Knowledge of cell kinetics developed during this period. Kinetic concepts entered clinical chemotherapy. The first developments in combination chemotherapy occurred. Meaningful results in leukemia treatment increased markedly.
3. The period from 1970 to the present: The concept of combination chemotherapy developed during this period. Cooperation between surgery, radiotherapy and chemotherapy increased. Advances in imaging made it easier to determine treatment plans. The field of medical oncology developed.