chemotherapy

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The chemotherapy is a drug therapy of cancer (antineoplastic chemotherapy) or infections (anti-infective or antimicrobial chemotherapy). Colloquially (also referred to as chemo ) is mostly meant the cytostatic treatment of cancer. Chemotherapy can be carried out from a curative , adjuvant or palliative point of view.

Chemotherapy uses substances that exert their damaging effect as specifically as possible on certain disease-causing cells or microorganisms and kill them or inhibit their growth. In cancer therapy, these substances are called cytostatics ; in the treatment of infectious diseases antibiotics , chemotherapeutic agents , antivirals , antimycotics and anthelmintics . In the treatment of malignant tumor diseases , most of these substances use the rapid division of tumor cells, as these react more sensitively than healthy cells to cell division disorders ; However, they have a similar effect on healthy cells with a similarly good ability to divide, which can lead to side effects such as hair loss or diarrhea . In the treatment of bacterial infectious diseases one makes use of the different structure of eukaryotic (humans) and prokaryotic organisms (bacteria).

Cancer therapy with monoclonal antibodies and cytokines , such as interleukins and interferons , is not chemotherapy, but often cancer immunotherapy .

history

Paul Ehrlich (1915)

The term, which first appeared in the 18th century, was redefined and coined in 1906 by Paul Ehrlich . He used it to describe the treatment of infectious diseases with chemical substances that act directly against the pathogen . In 1904 he recognized Trypan Red as the first effective chemotherapeutic agent , with which he cured mice suffering from sleeping sickness. Ehrlich began further experiments on August 31, 1909 in Frankfurt am Main by injecting syphilis pathogens into rats and then treating them with the help of chemotherapeutic methods. These attempts had such a convincing effect that they were seen as the new "weapon" of medicine against infectious diseases. Ehrlich was then referred to as the "creator of chemotherapy". The drugs used are either manufactured artificially or are derived from naturally occurring substances.

sensitivity

The response to chemotherapy depends on various factors. First, a chemotherapeutic agent is broken down at different rates in humans, and the shorter the drug is effective or present in the body, the shorter it can only work. Second, the accessibility of the disease-causing cells or microorganisms is an important factor. A tumor can be very compact and have little blood supply. The result is that the drug cannot reach the actual site of action or can only reach it with difficulty. A third factor determines the response behavior of chemotherapy drugs. For example, even if the tumor can be easily reached by the cytostatic agent, the cancer cells can be resistant to the drug. These properties are known as chemosensitivity and chemoresistance .

It is possible to test the effectiveness of chemotherapy drugs on bacteria with an antibiogram . The chemosensitivity of cancer cells can also be tested in vitro ( chemosensitivity test ).

Principles of antineoplastic chemotherapy

Representation of the log-cell kill hypothesis (idealized course in the case of a solid tumor).
The blue curve shows the course after surgical tumor removal with adjuvant chemotherapy, the red curve the course after an inoperable tumor and chemotherapy.
About 30 cell division cycles are required from the first degenerate cell to the detectable tumor (= 10 9 cancer cells with a mass of 1 g). From this point to the normally fatal tumor mass of around 1 kg (= 10 12 cancer cells), only ten more cycles of division are required.
The more realistic course of chemotherapy

Intravenous administration is usually chosen because of the higher bioavailability. Some therapies are also possible orally.

A certain cytostatic dose can only ever be a certain amount, e.g. B. kill 90% of the target cells. As the treatment progresses, this proportion remains the same, i. H. two doses reach 99% of the cells, three doses 99.9%, etc. This mechanism explains why chemotherapy must not be reduced in the course of treatment, even if the visible tumor has already disappeared ( Log cell kill , Howard E. Skipper 1964 ). On the contrary: It must be expected that weak treatment will select the most resistant tumor cell clones, ie. H. left over. Modern protocols therefore try to "strike as early and as hard as possible". Chemotherapy is administered in rapid succession, and two or more cytotoxic drugs are almost always combined to make them more effective . Inadequate therapeutic success for some types of tumor and more recent theoretical and animal experimental data, however, raise doubts about the general correctness of this concept.

A chemotherapy is called adjuvant and is intended to ensure success after a complete surgical removal of the tumor. Neoadjuvant is chemotherapy before surgery. Very often adjuvant, neoadjuvant or sole chemotherapy is combined with radiation therapy ( radiochemotherapy ).

When treating the elderly, it must be taken into account that they often have reduced liver and kidney functions and a reduced bone marrow reserve and that their sensitivity to the substances is therefore increased. When estimating the dose according to body weight or body surface area, the increased percentage of body fat in old age should be taken into account.

Resistance of the tumor cells to one or more of the cytostatics used is not uncommon. In addition, one should not smoke during chemotherapy, because some standard chemotherapy drugs have been shown to be weakened by nicotine . Resistance can have many causes, for example reduced transport of the substance into the cell interior or increased transport from the cell ( multiple drug resistance ). The cell can also have inactivating enzymes . Good blood flow to the tumor ( angiogenesis ) leads to rapid growth due to the high nutrient supply, but also to a better response to chemotherapy, since the proportion of dividing cells is higher. Much of the damage caused by the cytostatics in the cells presupposes that existing control systems (for example p53 ) are still active in the tumor cells and that they notice these errors. Repair mechanisms ( e.g. excision repair ), on the other hand, must not be activated; instead, controlled cell death must be initiated. Resistances have to be recognized at an early stage so that changes in the therapy regimen can take effect in good time, otherwise mutations in the tumor will accumulate, making it more difficult to control. Finding the optimal combination therapy for the specific tumor through laboratory tests is also discussed and has been used successfully.

In principle, chemotherapy can be used in two different ways to combat cancer cells. With cytotoxins , apoptosis, that is, the programmed cell death of the malignant cells, is to be brought about. In most cases, this is the way to eradicate the tumor , that is, to remove it completely from the patient's body. Cytostatics ( Greek cyto = cell and static = to stop) are, by definition, substances that do not kill cancer cells, but stop their cell growth and cell division ( proliferation ). Conventional classical chemotherapeutic agents are essentially cytotoxic, while targeted newer therapies from the area of cancer immunotherapy , such as monoclonal antibodies , have cytostatic properties.

In many cases, however, the literature does not differentiate between cytostatics and cytotoxins. Most of the chemotherapeutic agents currently in use also have both cytotoxic and cytostatic effects.

application areas

  • Local treatment is no longer sufficient in the case of solid tumors (i.e. solid tumors , in contrast to, for example, leukemia) if metastases are already detectable.
  • Leukemia and malignant lymphomas often spread over several areas of the body right from the start. Systemic delivery of cytostatics is then necessary in any case.
  • An adjuvant (= supplementary, helping) dose of cytostatics is given before or after the surgical removal of a tumor, even without evidence of metastases , if experience has shown that the risk of relapse is high.

Contraindications

Antineoplastic chemotherapy should not be started, though

  • the tumor can be completely and curatively removed with a high degree of probability by surgery or radiation .
  • the balance shows that the expected side effects of the treatment are more severe than the expected course of the tumor without chemotherapy.
  • the general condition of the patient or the function of essential organs are too limited.

Examples of cancers where chemotherapy can lead to a permanent cure :

Choice of chemotherapy drug

The choice of chemotherapeutic agent depends not only on the organ of cancer (e.g. breast, lung, colon cancer), but also on individual criteria, which can be different for different patients with "the same" cancer. Such criteria can be, for example:

  • the type of tissue of the tumor cells (e.g. small cells, squamous epithelium, glandular epithelium, etc.)
  • Receptors that carry the tumor cells (e.g. HER2 / new)
  • certain mutations in the genome of tumor cells (e.g. KRAS, see also oncogenes )
  • the initial effectiveness of the therapy started
  • other diseases of the patient
  • the general condition of the patient

Despite these individual aspects, typical chemotherapeutic agents can be named for malignant diseases that are regularly used for these.

Selected examples
Cancer typical chemotherapy agent
or chemotherapy regimen		 additional drug therapy
Colon cancer FOLFIRI ,
FOLFOX or
XELOX 		Bevacizumab ,
cetuximab
Breast cancer 5-fluorouracil
+ anthracycline
+ cyclophosphamide,
possibly capecitabine 		Trastuzumab in HER2- positive tumors
Tamoxifen
Lapatinib
Sunitinib
Eribulin
Everolimus
Hepatocellular carcinoma 5-fluorouracil
+ folinic acid 		Sorafenib

Therapy schemes

Nowadays, chemotherapy almost always combines several active ingredients (apart from monotherapies that may have fewer side effects in palliative cytostatic chemotherapy). For this purpose, schemes have been developed in which it is specified which active ingredients are to be used in which sequence and at what intervals in order to achieve an optimal effect. The name of the scheme (usually as an acronym ) is derived from the names of the active ingredients involved :

Side effects

The side effects of chemotherapy depend on the type of therapy and individual tolerance. The individual side effects occur independently of one another and may not occur at all or appear in varying degrees (from mild to fatal).

These side effects are nausea and vomiting, exhaustion, hair loss, taste disturbances , inflammation of the mucous membranes and changes in the blood count. They are classified according to the Common Toxicity Criteria .

Many cytostatics are carcinogenic themselves , such as busulfan , chlorambucil , cyclophosphamide or semustine . Overall, the rate of cytostatic-induced leukemia is declining, but the number of diseases is still increasing in some tumor types. This includes multiple myeloma , non-Hodgkin lymphoma , esophageal carcinoma , anal carcinoma , cervical carcinoma and prostate carcinoma . While therapy-related acute myeloid leukemia (t AML ) can occur in the first two even a decade after chemotherapy , it is limited to the first ten years after treatment in the other cancers .

In many cases, an increase in tolerance through short-term fasting in the days of therapy was observed both in humans and in animal experiments .

Up to three quarters of cancer patients undergoing chemotherapy develop chemotherapy-associated anemia . Tumors such as lymphoma, multiple myeloma, bronchial carcinoma and gynecological and urogenital tumors are particularly at high risk. The frequency and severity of the anemia also depend on the tumor stage. While the side effects listed according to the Common Toxicity Criteria usually disappear when chemotherapy is discontinued, irreversible heart muscle damage and temporary or permanent infertility may occur. The administration of anthracyclines leads to permanent damage to the heart muscle cells in around ten percent of patients, which can trigger cardiac arrhythmias and / or heart failure (cardiac insufficiency). So-called cardioprotective agents have been approved since 2007, which can prevent heart damage by administering the anthracyclines doxorubicin or epirubicin .

Because of any infertility caused by chemotherapy, if the patient so wishes, the sperm can be stored (similar to the practice with sperm donors) in men before treatment. Proper storage then gives you the chance to have your own children. Fertility-preserving measures in women are possible, but are in some cases still experimental. The Fertiprotekt network endeavors in German-speaking countries to provide information about measures for men and women and to offer them.

After chemotherapy, some patients experience a mostly temporary impairment of the ability to think, remember and cope with stress, which is known as post-chemotherapy cognitive impairment (PCCI) (also chemotherapy-induced cognitive dysfunction or "chemo brain"). The cause of this phenomenon is currently being researched. According to the current state of research, it can lie either in the psychologically stressful, trauma-like situation of the diagnosis and illness itself, in the direct physical effects of chemotherapy, or in both factors.

To prevent pronounced mucositis , several local anesthesia with a vasoconstrictor in the mouth / jaw area can be administered, which reduces the flooding of the chemotherapeutic agent into the mucous membrane. In addition, cold therapy by sucking ice cubes can increase the local vasoconstriction during radiation therapy. The resulting insufficient supply of oxygen to the tissue reduces the cellular sensitivity to radiation.

In addition to the well-known side effects of chemotherapy such as hair loss and nausea, chemotherapy (or stem cell transplantation) can also lead to bleeding. In 2012 and 2015, Estcourt and co-workers conducted Cochrane reviews of these with randomized controlled trials to find out which use of platelet transfusions is most effective in preventing bleeding in patients with haematological disorders when they are receiving chemotherapy or a stem cell transplant .

effectiveness

The effectiveness of chemotherapy depends very much on the type of tumor and its stage. While there are very many studies on the effect of specific cytostatics on the corresponding tumor types, there is only one cancer registry study to date that examines the benefit of chemotherapy alone for 22 cancers in Australia and the USA . Cancer diseases for which chemotherapy is the most important treatment (e.g. leukemia or lymph gland cancer) were not evaluated, nor were the types of cancer for which chemotherapy is only used as adjuvant. According to the study, cytotoxic chemotherapy used alone should contribute an additional 2.3 percent (in Australia) and 2.1 percent (in the USA) to the respective five-year survival rate in adults . However, the study also confirms that certain types of cancer such as B. testicular cancer, Hodgkin's lymphoma or cervical carcinoma an adjuvant chemotherapy brings a 10 to 40 percent better prognosis.

The study was heavily criticized by Australian oncologists. The authors did not weight the various types of cancer (the group of cancer types in which chemotherapy works poorly and is therefore often not used is the greatest) and there are methodological deficiencies. Using the same data would increase the effectiveness to 6 percent over all cases if a clean methodology was used. In addition, some cancers that are mainly treated by chemotherapy (e.g. leukemia) and where this therapy is very effective were not considered. In addition, the data come from the 1990s and are therefore out of date. Since the effect of chemotherapy depends on the type of tumor, such a combination of all tumor types is not expedient, because it says nothing about the individual case.

The fact is that highly effective cytotoxic drugs have helped to significantly increase the relative five-year survival rate for certain types of cancer over the past 20 years - with improved prognoses in the double-digit percentage range. This applies, on the one hand, to adjuvant use, for example, in breast cancer, testicular cancer and lung cancer, and, on the other hand, to the primary use of chemotherapy as the first choice, such as in Hodgkin's lymphoma and leukemia.

literature

Web links

Wiktionary: chemotherapy  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ Duden | Chemo | Spelling, meaning, definition. In: duden.de. Retrieved August 21, 2015 .
  2. ^ Bickel: Chemotherapy. P. 241.
  3. ↑ Hans Loewe: Paul Ehrlich. Creator of chemotherapy. Stuttgart 1950.
  4. ↑ Klaus Aktories, Ulrich Förstermann, Franz Hofmann, Klaus Starke: General and special pharmacology and toxicology . 10th edition. Elsevier, Urban & Fischer, Munich / Jena 2009, ISBN 978-3-437-42522-6 .
  5. ^ OA Adam: Antineoplastic chemotherapy.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. (PDF; 1.6 MB) LMU Munich@1@ 2Template: Toter Link / wsi1.med.lmu.de  
  6. ^ HD Bruhn (ed.) U. a .: Oncological therapy. Verlag Schattauer, 2003, ISBN 3-7945-2165-X , pp. 89-92
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  19. ↑ LM Morton, GM Dores, MA Tucker, CJ Kim, K. Onel, ES Gilbert, JF Fraumeni Jr., RE Curtis: Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975-2008 . In: Blood. 2013; doi: 10.1182 / blood-2012-08-448068 .
  20. ↑ NDR: Can fasting support chemotherapy? Retrieved September 30, 2019 .
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  22. ↑ For breast and ovarian cancer: Short-term fasting probably makes chemotherapy more effective and easier to tolerate. Retrieved September 30, 2019 .
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  24. ↑ Heart protection in chemotherapy.  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. Patient's Guide: Prevention of Anthracycline-Related Heart Damage. (PDF).@1@ 2Template: Toter Link / www.novartisoncology.de  
  25. ↑ Ludwig Maximilians University of Munich: Cancer and the "Chemobrain" - When the mental abilities of tumor patients suffer. Retrieved April 30, 2011 .
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  27. ↑ Lise Estcourt, Simon Stan Worth, Carolyn Doree, Sally Hopewell, Michael F Murphy: Prophylactic platelet transfusion for prevention of bleeding in patients with Haematological disorders after chemotherapy and stem cell transplantation . In: Cochrane Database of Systematic Reviews . May 16, 2012, doi : 10.1002 / 14651858.CD004269.pub3 ( wiley.com [accessed July 9, 2020]).
  28. ↑ Lise J Estcourt, Simon J Stanworth, Carolyn Doree, Sally Hopewell, Marialena Trivella: Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation . In: Cochrane Database of Systematic Reviews . November 18, 2015, doi : 10.1002 / 14651858.CD010983.pub2 ( wiley.com [accessed July 9, 2020]).
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