Chemotherapy is the type of cancer treatment that uses one or more anti-cancer drugs,chemotherapeutic agents,in a standard combination or protocol. Chemotherapy may be given with a curative plan or it may only target to prolonging life or to reduce symptoms.Chemotherapy is one of the major categories of the pharmacotherapy for cancer(Alfarouk,KO,2015).
The term chemotherapy currently means the non-specific use of chemical agents to inhibit cell division or to induce DNA damage(Rajman,L,2018).The word “chemotherapy” usually refers to cancer treatment, but its historical meaning was broader. The term was used in the early 1900s ,meaning any use of chemicals to treat any disease, such as the use of antibiotics(De Vita,VT,2008).Today,any treatment of disease with drugs, is often expressed with the word pharmacotherapy.The first use of drugs to treat cancer was in the early 20th century, although the chemicals first used were not originally intended for that purpose.Mustard gas was used as a chemical warfare agent and was discovered to be a potent suppressor of blood production.It was reasoned that an agent that damaged the rapidly growing white blood cells might have a similar effect on cancer(Fenn,JE,2011).Therefore, several people with advanced cancers of the lymphatic system and lymph nodes were given the drug by vein, rather than by breathing the irritating gas(Fenn,JE,2011).Their improvement, although temporary, was remarkable(Chabner,BA,2005).After WWII was over and the reports assessed, the data converged and led researchers to look for other substances that might have similar effects against cancer. Since then, many drugs have been developed to treat cancer and drug development has exploded , although the principles and limitations of chemotherapy discovered by the early researchers still apply(Joensuu,H,2008).
There are also more selective agents,that block extracellular growth signals.Therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones,like oestrogens for breast cancer and androgens for prostate cancer,are now called hormonal therapies.Inhibitions of growth-signals,such as those associated with cell receptors are called targeted therapy.The use of drugs,chemotherapy,hormonal therapy, or targeted therapy,is called “systemic” therapy for cancer,since they enter into the blood stream and therefore can treat cancer anywhere in the body. “Systemic” therapy is often used along local therapy,that is treatment that works only where it is applied, such as radiation,surgery and hyperthermia(Gopu,P,2021).
Chemotherapeutic agents are cytotoxic,interfering with cell division(mitosis), but the susceptibility of cancer cells to these agents vary widely. Chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death.Many of the side effects of chemotherapy can be traced to damage also normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs.These cells are mostly found in the bone marrow,digestive tract and hair follicles.This damage results in the most common side-effects of chemotherapy:decreased production of blood cells,immunosupression, irittationa or inflammation of the lining of the digestive tract and hair loss.Because of the effect on immune cells,especially lymphocytes, chemotherapy drugs often find use also in many diseases that result from harmful overactivity of the immune system against self,the so called autoimmune diseases,like rheumatoid arthritis,systemic lupus erythematosus, multiple sclerosis and many others.
There are a number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may help to prolong life or to palliate symptoms.
Induction chemotherapy is the first line treatment of cancer with a chemotherapeutic drug with a curative target.
Combined modality chemotherapy is the use of drugs with other cancer treatments,such as surgery,radiation therapy or hyperthermia therapy.
Palliative chemotherapy is given after remission in order to prolong the overall disease-free time and improve overall survival.
Combination chemotherapy involves treating a person with a number of different drugs simultaneously. The drugs differ in their mechanism and side-effects.The biggest advantage is minimising the chances of resistance developing to any one agent. Also, the drugs can often be used at lower doses, reducing toxicity(Bayat,M,2017).
Neoadjuvant chemotherapy is given prior to a local treatment such as surgery, and is designed to shrink the primary tumor.It is also given for cancers with a high risk of “micrometastatic disease”. Adjuvant chemotherapy is given after a local treatment,radiotherapy or surgery. It can be used when there is little evidence of cancer present, but there is risk of recurrence.It is also used in killing any cancerous cells that have spread to other parts of the body.These “micrometastases” are treated with adjuvant chemotherapy to reduce relapse rates caused by these disseminated cells(Untch,M,2011).
Maintenance chemotherapy is a repeated low-dose treatment to prolong remission. 
Salvage chemotherapy or palliative chemotherapy is given without curative intent, but simply to decrease tumor load and increase life expectancy (Neugut,AI,2017).
The administration of all chemotherapeutic drugs requires that the recipient is capable of undergoing the treatment.”Performance status” may be used as a measure to determine whether a person can receive chemotherapy or whether dose reduction is required. Because only a fraction of the cells in a tumor die with each treatment,repeated doses must be administered to continue to reduce the size of the tumor.Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity.
The effectiveness of chemotherapy depends on the type of cancer and the stage.At high doses the percentage of normal and cancer cells killed is very similar. For this reason, doses are chosen where anti-tumour activity exceeds normal cell death(Corrie,PG,2008).Providing if the dose is too low, it will be ineffective against the tumor, while, at excessive doses, the side effects will be intolerable to the patient receiving it,it is necessary to employ the proper dosage of chemotherapy (Corrie,PG,2008).It has been posited that, due to pharmacokinetic variability among people ,many people do not receive the right dose to achieve optimal treatment effectiveness with minimized toxic side effects.Some people are overdosed while others are underdosed (Kaestner,SA,2007).For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard,68% were underdosed and 17% were overdosed (Kaldate,RR,2012). Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced(Capitain,O,2012).In the 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA(Gamelin,E,2008).For optimized treatment effectiveness with minimized toxicities,dosing can be achieved by personalized approach for optimal results in each one individual case.Clinical trials on this base resulted in significantly improved treatment outcomes (Canal,P,1998).
Types of chemotherapy agents
Alkylating agents
Originally derived from mustard gas, there are now many types of alkylating agents in use(Corrie,PG,2008).They are so named because of their ability to alkylate many molecules, including proteins,RNA and DNA. This ability to bind to DNA via their alkyl group is the primary cause for their anti-cancer effects(Lind,MJ,2008). DNA is made of two strands and the molecules may either bind twice to one strand of DNA or may bind once to both strands.If the cell tries to replicate crosslinked DNA during cell division or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis(Siddik,ZH,2005).Alkylating agents will work at any point in the cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug(Malhorta,V,2003).
Antimetabolites
Antimetabolites are a group of molecules that impede DNA and RNA synthesis. Their building blocks are nucleotides,molecules comprising a nucleobase, a sugar and a phosphate group.The nucleobases are divided into purines(guanine and adenine) and pyrimidines,cytosine,thymine and uracil.Anti-metabolites resemble either nucleobases or nucleosides,that is nucleotides without the phosphate group, but have altered chemical groups (Parker,WB,2009).These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA.They inhibit the enzymes involved in DNA synthesis and prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA,DNA damage can occur and programmed cell death,apoptosis,is induced.Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case the DNA synthesis phase. For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses (Pillwein,K,1986).
Anti-microtubule agents
Anti-microtubule agents block cell division by preventing microtubule function. Microtubules are are hollow, rod-shaped structures that are required for cell division, among other cellular functions (Rowinsky,EK,1991).Microtubules are structures, which are permanently in a state of assembly and disassembly.Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents.Although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are opposite.Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrope in the cancer cells(Vitale,I,2011).Following this, cell cycle arrest occurs, which induces programmed cell death.These drugs can also affect blood vessel growth , an essential process that tumours utilise in order to grow and metastasise (Yue,OX,2010).Taxanes are natural and semi-synthetic drugs. The first drug of their class,paclitaxel , was originally extracted from the plant Taxus brevifolia.Now this drug is produced semi-synthetically from a chemical found in the bark of another tree, Taxus baccata(Croteau,R,2006).
Topoisomerase inhibitors
Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and II.When the DNA double-strand helix is unwound, during DNA replication or transcription,the adjacent unopened DNA winds tighter, like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes.Topoisomerase inhibitors cause breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during the phases of replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes(Goodsell,DS,2002).
Cytotoxic antibiotics
The cytotoxic antibiotics are a group of drugs that have various mechanisms of action,mainly interrupting cell division.
Delivery
Chemotherapy is administrated intravenously or orally.According to a systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans.Depending on the person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis (Greer,JA,2016).
Side effects
Chemotherapy medications most commonly affect the fast-dividing cells of the body, such as bone marrow cells and the epithelial cells lining the mouth, stomach, and intestines.Chemotherapy-related toxicities can occur acutely after administration,within hours or days, or chronically, from weeks to years (Rachel,A,2009).
Virtually all chemotherapeutic regimens can cause depression of the immune system, often by paralysing the bone marrow and leading to a decrease of blood cells.Anemia and thrombocytopenia may require blood transfusion.In severe myelosupression, which occurs in some regimens, almost all the bone marrow stem cells,which produce white and red blood cells,are destroyed, damage which may indicate bone marrow cell transplantation necessary.Some people ,also, develop diseases because of this interference with bone marrow.Patients receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps,since they are vulnerable to systemic or localized infections.Sometimes, chemotherapy treatments are postponed because the immune system is suppressed to a critically low level(Elad,S,2010).
Nausea,vomiting,anorexia,diarrhea, abdominal pains and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells. Malnutrition and dehydration can result when the recipient does not eat or drink enough or when the patient vomits frequently because of gastrointestinal side effects. This can lead to a rapid weight loss or ,sometimes, in weight gain, if the person eats too much in an effort to ease nausea or heartburn. Weight gain can also be caused by some steroid medications(Gibson,RJ,2006). Due to immune system suppression, enterocolitis ,especially “typhlitis” may be a gastrointestinal complication of chemotherapy.Typhlitis is an intestinal infection which may manifest itself through vomiting,diarrhea, distended abdomen, fever, chills. abdominal pain and tendernessss. and may be a medical emergency.(Keidan,RD, 1989).
Anemia can be a combined outcome caused by myelosuppressive chemotherapy. Treatments which suppress the bone marrow may cause a tendency to bleed easily and or an impaired blood cell production, leading to anemia.Such chemotherapy medications kill the rapidly dividing normal cells and can reduce significantly the number of platelets in the blood, so that patients are vulnerable to bruises and bleeding. Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover(Sekhon,SS,2006).Low physical stamina may be a consequence of the cancer or its treatment, and can last for months to years after treatment.The most common cause of easy fatigue is anemia, which can be caused by chemotherapy, radiotherapy,primary and metastatic disease(Franklin,DJ,2006).
Chemotherapy induced nausea and vomiting are common with many treatments and some forms of cancer.Nausea and vomiting are two of the most often cancer treatment-related side-effects for cancer patients.It has been demonstrated that people receiving chemotherapy ranked nausea and vomiting as the first and second most severe side-effects, respectively.Some people receiving agents,causing intense nausea,postponed and even refused cancer treatment by these agents.Several classes of antiemetic drugs have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens,helping to successfully manage these symptoms in many people. Effective mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the recipient and more efficient treatment cycles, due to less stoppage of treatment due to better tolerance and better overall health(Gill,P,2006).
Hair loss can be caused by chemotherapy that kills rapidly dividing cells These are often temporary effects: hair usually starts to regrow a few weeks after the last treatment,but sometimes with a change in color, texture, thickness or style. Severe hair loss occurs most often with drugs such as doxorubicin, paclitaxel, cyclophosphamide.Permanent thinning or hair loss can result from some standard chemotherapy regimens.Chemotherapy induced hair loss is usually associated with the high mitotic rate of hair follicles and is more reversible than androgenic hair loss,although permanent cases can occur. Chemotherapy induces hair loss in women more often than men (Chadha,V,2003).
Secondary malignant neoplasms after effective chemotherapy or radiotherapy treatment for the primary tumour can occur. The most common secondary neoplasia is acute myeloid leukemia, which develops primarily after treatment with alkylating agents or topoisomerase inhibitors.The long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published was investigated.About 6,000 patients with HL treated with chemotherapy in Britain from 1963 to 2001 were followed,of whom 3,432 also received radiotherapy,to assess second primary malignancy risks compared with general population-based expectations.Second malignancies occurred in 459 of them. After chemotherapy alone, there were significantly raised risks of lung cancer, non-HL, and leukemia. When chemotherapy was combined with other “systemic” therapies, there were raised risks of these and several other cancers. Second cancer risk peaked 5 to 9 years after chemotherapy alone, but it remained raised for 25 years and longer after combined modalities (Swerdlow,AJ,2011).The survival of breast cancer patients with second primary malignancy and to evaluate the impact of chemotherapy on the risk of different cancer sites were explored. The incidence of second primary cancer for all sites was significantly higher in breast cancer patients.Chemotherapy was associated with increased incidences for all sites, except lymphoma, myeloma, and chronic lymphocytic leukemia.It was concluded that female breast cancer patients showed higher incidence of second primary malignancy, which was associated with poorer prognosis and that Chemotherapy benefits should be weighed against the risks of second primary malignancy (Wei,JL,2019).
It has also been observed that advances in diagnosis and therapeutic technologies have paradoxically increased the risk of second primary malignancies. Cancer patients,who seem to have been successfully treated, have a higher risk of developing a new primary cancer than the general population. This suggests that more studies are needed to develop screen and management programs for cancer survivors, especially patients with gastrointestinal cancers (Park,JY,2019).The long-term risk of second malignancies after breast cancer treatment was studied at the Curie institute, Paris, between 1981 and 2000. It was calculated the cumulative incidence of second malignancies and the risk of developing each type of second malignancies over a period of 10 to 15 years and the incidence rates in the entire patient population were then compared to the expected incidence in the general population of French women. It has been demostrated that patients treated for breast cancer had a significantly increased risk of various kinds of second malignancies compared to the general population(Bazire,L2017).
Some types of Chemotherapy are toxic to genital system and may cause infertility. Chemotherapies with high risk include procarbazine and other alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil and chlormethine.Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin.Female infertility by chemotherapy appears to be similar to premature ovarian failure due to loss of ovarian follicles(Brydoy,M,2007).
Chemotherapy may be teratogenic during pregnancy,especially during the first trimester, to the extent that abortion usually is recommended if pregnancy in this period is found during chemotherapy.Second- and third-trimester exposure does not usually increase the teratogenic risk,but it may increase the risk of various complications of pregnancy and of fetal myelosuppression (Arnon,J,2001).Female patients of reproductive potential should use effective contraception during chemotherapy and for a few months after the last dose(Tichelli,A,2013).In women previously having undergone chemotherapy,miscarriage and congenital malformations are not increased in subsequent conceptions. However, when in vitro fertilization and embryo cryopreservation is applied shortly after treatment, possible genetic risks to the growing oocytes exist(Arnon,J,2001).
Between 30-40% of people undergoing chemotherapy experience suffer from peripheral neuropathy(PN),a progressive, enduring, and often irreversible condition, causing pain, tingling, numbness and sensitivity to cold, beginning in the hands and feet and sometimes progressing to the arms and legs.Chemotherapy drugs associated with PN include vinca alkaloids, taxanes and platinum-based drugs (Beijers,AJ, 2012). Whether PN arises, and to what degree, is determined by the choice of drug, duration of use and the total amount consumed.Motor nerves and the autonomic nervous system are affected,though the symptoms are mainly sensory.PN often appears after the first chemotherapy session,gets aggravated as treatment continues and some PN cases appear are irreversible (Windebank,AJ,2008).Some people receiving chemotherapy report fatigue or non-specific neurocognitive problems, such as an inability to concentrate, a condition called “post-chemotherapy cognitive impairment”(Tannock,IF,2004).
In particularly large tumors and cancers with high white blood cell counts.such as lymphomas,teratomas and leukemias,some patients develop the so called “tumor lysis syndrome”.The rapid breakdown of cancer cells by cytotoxic agents may cause the release of chemicals from the inside of the cells, leading to high levels of uric acid,potassium and phosphate in the blood.High levels of phosphate induce secondary hypoparathyroidism, resulting in low levels of calcium in the blood (Adeyinka,A,2022).This causes kidney damage and the high levels of potassium can cause cardiac arrhythmia,that is irregulare pulse rate.Though preventive measures are available and are often applied in people with large tumors, tumor lysis syndrome is a very dangerous side-effect,that can lead to death if left untreated (Wood,M,2005).
Cardiotoxiciy,that is toxic action on heart, may be especially prominent with the use of anthracycline drugs(doxorubicin,epirubicin,etc). The cause of this is most likely due to subsequent DNA damage.Other chemotherapeutic agents that cause cardiotoxicity, but at a lower incidence, are cyclophosphamide and docetaxel (Shaikh,AY,2012).The spectrum of cardiac side-effects of cancer chemotherapy has expanded with the development of combination, adjuvant and targeted chemotherapies.Their administration in multiple combination regimens has increased significantly in older patients and in patients suffering from cardiovascular and/or coronary artery disease (CAD). High doses of the alkylating drugs cyclophosphamide and ifosfamide may result in heart failure and in life-threatening arrhythmias.Myocardial ischemia may be induced by the antimetabolites,like 5-fluorouracil.Severe arrhythmias may complicate administration of microtubule inhibitors.Targeted therapies with the antibody-based tyrosine kinases (TK) inhibitors may induce heart failure or asymptomatic LV dysfunction,hypotension,severe hypertension and venous thromboembolism (Monsuez, JJ, 2010).
Liver damage can be caused by many cytotoxic drugs.The susceptibility of an individual to liver damage can be altered by other factors such as the cancer itself,immunosupression and nutritional deficiency.The liver damage can consist of damage to liver cells, obstruction of the veins in the liver,cholostasis,whe bile does not flow from the liver to the intestine and liver fibrosis(Thatishetty,2013).
Kidney damage can also be caused by “tumor lysis syndrome” and also by direct effects of drug clearance by the kidneys.Different drugs will affect different parts of the kidney and the toxicity may cause acute kidney injury(Thatishetty,AV,2013).
Damage to the inner ear is a common side effect of platinum based drugs that can produce symptoms such as dizziness and vertigo(Rybak,LP,2009).Children treated with platinum analogues have been found to be at risk for developing hearing loss(van As,JW,2019).
It has been demonstrated that ,besides chemotherapy,other therapies can cause cardiotoxicity, such as, immunotherapy, antibody therapy and radiotherapy. If these side effects remain undetected, the patient may develop heart failure or severe heart valve damage (Anker,MS,2020).While newer targeted agents provide "on-target" anticancer activity, their "off-target" drug effects encompass also a wide range of cardiovascular toxicities(Bhave,M,2014).Specific chemotherapeutic agents are associated with organ-specific toxicities, including cardiovascular disease,lung disease and occasionally secondary neoplasm,like it may happen in chemotherapy for Hodgkin's disease (Shannon,VR,2019).Less common side-effects include red skin, dry skin, damaged fingernails, a dry mouth,water retention or allergic reactions.Nutritional problems are also often observed in cancer patients through chemotherapy treatment (Waed,EJ,2015).

The incidence and risk of septic complications in 382 patients treated for small cell lung cancer(SCLC) with combination chemotherapy at a single centre have been analysed. Full protocol doses were employed throughout with no dose reduction after episodes of severe or life-threatening sepsis (SLTS). 50 (13%) patients experienced 66 episodes of SLTS associated with 1978 cycles of chemotherapy (3.2% cycles affected). 20 (5.2%) patients died due to sepsis (SD) of whom only 4 had experienced SLTS with a previous cycle of treatment. The others died as a result of their first septic episode. It has been proposed that high-risk patients receive 50% of protocol doses in the first cycle of treatment with escalation to 75% and eventually 100% doses in subsequent cycles if sepsis dose not supervene(Radford,JA,1993).In a large series of patients with SLCL an increased risk of death in the second week after commencing the first cycle of chemotherapy was observed, suggesting that of the 10% of patients who died within 3 weeks of starting chemotherapy, half may have been treatment-related. Much less additional risk was associated with subsequent cycles of chemotherapy, and no additional risk with either initial surgery or radiotherapy.A high risk group of patients was identified with an excess death rate of more than 15% in the second week after starting chemotherapy.It has been concluded that Radford et als' suggestion that high risk patients be given half doses of drugs at the first cycle should be tested in a randomised clinical trial(Stephens,RJ,1994).

Deaths within 30 days of chemotherapy during a 6-month period were identified from the Royal Marsden Hospital electronic patient records. Treatment intention--curative or palliative, cause of death and number of previous treatments--were documented. Between April 2005 and September 2005, 1976 patients received chemotherapy with 161 deaths within 30 days of chemotherapy (8.1%). Of these, 124 deaths (77.0%) were due to disease progression. Of the other 37 deaths, 12 (7.5%) were related to chemotherapy, six each for solid tumours and haematological malignancies, of which seven (4.3%) were due to neutropenic sepsis. For the remaining 25 deaths (15.5%) there was insufficient information. There were more deaths after third and subsequent lines of therapy than with first and secondlines of therapy.It has been suggested to audit mortality within 30 days of chemotherapy and that this should become a benchmark for standard practice(O’Brien,2006).

The relative influence of increasing age and other clinical parameters was evaluated on the occurrence of treatment-related death in elderly patients with intermediate- or high-grade Non-Hodgkin Lymphoma(NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy.From 1982 to 1991, 267 consecutive patients were treated. Median age was 70 years (range, 60 to 94 years). There were 35 toxic deaths. Sixty-three percent of the deaths occurred after the first cycle. Infection accounted for 82% of the toxic deaths.It was concluded that the results show that in elderly patients with NHL treated with doxorubicin-based chemotherapy the risk for treatment-related death is associated with poor performance status rather than with increasing chronologic age(Gomez,H,1998).
It has been reported that Chemotherapy does not always work and,even when it is useful, it may not completely destroy the cancer cells.For instance,the blood-brain barrier poses an obstacle to delivery of chemotherapy to the brain.Drug transporters can pump out drugs from the brain and brain's blood vessel cells into blood circulation.Drug transporters are integral membrane proteins that play a critical role in drug disposition by affecting absorption, distribution, and excretion.They translocate drugs, as well as endogenous molecules and toxins, across membranes using ATP hydrolysis, or ion/concentration gradients.These transporters pump out most chemotherapy drugs, which reduces their efficacy for treatment of brain tumors (Gerstner,ER,2007).Also,blood vessels in tumors are very different from those seen in normal tissues.The newly formed tumor vasculature is poorly formed and does not deliver an adequate blood supply to all areas of the tumor. This leads to issues with drug delivery because many drugs will be delivered to the tumor by the blood (Minchinton,AI,2006).Besides,ressistance is an important cause of chemotherapy treatment failure .There are a few possible causes of resistance in cancer, one of which is the presence of small pumps on the surface of cancer cells that actively move chemotherapy from inside the cell to the outside. Many chemotherapy drugs also cause DNA damage, which can be repaired by enzymes in the cell that carry out DNA repair.Drugs used in chemotherapy can induce cell stress, which can kill a cancer cell; however, under certain conditions, cells stress can induce changes in gene expression that enables resistance to several types of drugs(Moschovi,M,2015).
Most chemotherapeutic drugs work by impairing cell division,,effectively targeting any fast-dividing cells in the organism,without any discrimination if they are neoplasmatic and normal.As these drugs cause damage to normal cells, they are termed “cytotoxic”.They prevent mitosis by various mechanisms including damaging DNA and inhibition of the cellular machinery involved in cell division (Lind,MJ,2008).One theory as to why these drugs kill cancer cells is that they induce a programmed form of cell death known as apoptosis.As chemotherapy affects cell division,tumors with high growth rate are more sensitive to chemotherapy.Malignancies with slower growth rates tend to respond to chemotherapy much more less(Corrie,PG,2008).
Targeted therapies are a category of cancer drugs that may overcome the issues emerging with the use of cytotoxic drugs.The massive toxicity seen with the use of cytotoxics is due to the lack of cell specificity of the drugs,since they kill any rapidly dividing cell, tumor or normal.Targeted therapies are schedulled to affect cellular processes that are utilised by the cancer cells alone.This approach allows a higher dose directed to cancer tissues with a relatively lower dose to other tissues. Although the side effects of targeted therapies are often less severe than those of cytotoxic chemotherapy, life-threatening effects can also occur(Gerber,DE,2008).
Some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders.In some cases they are often used at lower doses, which means that the side effects are minimized(Montaudie,H,2011).while in other cases doses similar to ones used to treat cancer are used.Methotrexate ,for example is used in the treatment of rheumatoid arthritis,psoriasis,ankylosing spondylitis and multiple sclerosis(Gray,OM,2006).Chemotherapy drugs are also used prior to bone marrow transplantation to suppress the recipient's immune system in order to allow a transplant to engraft. Cyclophosphamide is a common cytotoxic drug used in this manner . Chemotherapeutic drugs may be used at high doses to permanently remove the recipient's bone marrow cells or at lower doses that will prevent permanent bone marrow loss (Bacigalupo,A,2009).
Antibody-drug conjugates are comprised of an antibody,a drug and a linker between them.The antibody will be targeted at a preferentially expressed protein,an antigen, in the tumour cells or on cells that the tumor can utilise, such as blood vessel endothelial cells.They bind to the tumor antigen and are internalised, where the linker releases the drug into the cell. These specially targeted delivery vehicles vary in their stability, selectivity, and choice of target, but, in essence, they all aim to increase the maximum effective dose that can be delivered to the tumor cells(Teicher,BA,2011).Reduced systemic toxicity means that they can also be used in people who are sicker and that they can tolerate chemotherapeutic agents that would have been much more toxic to deliver through ordinary systemic approaches(Mokhtari,RB,2017).
Nanoparticles are 1–1000 nm sized particles that can promote tumor selectivity . Nanoparticles can be targeted passively or actively.Passive targeting exploits the difference between tumor blood vessels and normal blood vessels. Blood vessels in tumors have wide openings and are "leaky" because their wall gaps range from 200 to 2000 nm, which allow nanoparticles to pass through them and reach to the neoplasmatic cells. Active targeting uses biological molecules to preferentially target the nanoparticles to the tumor cells.Nanoparticles made of magnetic material can also be used to concentrate agents at tumor sites using an externally applied magnetic field (Chidambaram,M,2011).
Electrochemotherapy is a treatment, in which the systemic administration of a chemotherapeutic drug is followed by direct local application of high-voltage electric pulses to the tumor. The treatment enables the chemotherapeutic drugs, which otherwise cannot or hardly go through the membrane of cells to enter the cancer cells. This way greater effectiveness of antitumor treatment is achieved(Larkin,JO,2007). The method has been reported as safe, simple and highly effective in all reports on clinical use of electrochemotherapy.Recently, new electrochemotherapy modifications have been introduced for treatment of internal tumors through endoscopic routes ,surgical procedures or percutaneous selective approaches to the indicated treatment area(Soden,DM,2006)
Hyperthermia therapy is heat treatment for cancer that can be a powerful tool when used in combination with chemotherapy or radiation for the control of a variety of cancers. The heat can be applied locally to the tumor site, which will dilate blood vessels to the tumor, allowing more chemotherapeutic medication to enter the tumor.Hyperthermia also helps to prevent or reverse chemotherapy resistance,which may develop over time as the tumors adapt and can overcome the toxicity of the chemo medication.It was showed that chemoresistance against several anticancer drugs (e.g. mitomycin C, anthracyclines, BCNU, melphalan) could be reversed at least partially by the addition of heat(Yi,GY,2022)


Radiation therapy
Radiation therapy or radiotherapy is a treatment using ionizing radiation , applied as part of cancer treatment, to either kill or control the growth of malignant cells.Radiation therapy is more effective in types of cancer that are localized to one area of the body and have not spread to other parts.It may also be used as part of adjuvant therapy to prevent tumor recurrence after surgery for removing a primary malignant tumor. Radiation therapy may be combined with chemotherapy and has been used before, during, and after chemotherapy.
Radiation therapy works by damaging the DNA of cancer cells and suppressing mitotic activity.Cells have mechanisms for repairing single-strand DNA damage ,while double-stranded DNA breaks are much more difficult to repair and can lead to advanced chromosomal abnormalities and genetic deletions. Cancer cells reproduce more than most healthy differentiated cells and have a diminished ability to repair sub-lethal damage.Single-strand DNA damage is then passed on through cell division; damage to the cancer cells' DNA accumulates, causing them to die or reproduce more slowly(Vitale,I,2011).
Radiation therapy is used in the conventional treatment of the cancerous tumor because of its effectiveness to control cell growth by damaging the DNA of cancerous tissue and leading to cellular death.To protect normal tissues,which radiation must pass through to affect the tumor, specific techniques are employed, providing a much larger absorbed dose at the site of the cancerous tumour than in the surrounding normal tissue.Besides the tumor itself, the radiation fields may also include the draining lymph nodes if they are clinically or radiologically involved with the tumor, or if there is thought to be a risk of subclinical malignant spread.Radiation may be used as “palliative” treatment for local disease control or symptomatic relief or as therapeutic treatment,where the treatment is expected to have survival benefit and to be curative(Yeramilli,D,2020).
It is common to combine radiation therapy with surgery, chemotherapy, hormone therapy,immunotherapy or some combination of these four kinds of treatment.The precise treatment intent,curative, adjuvant or palliative depends on the tumor type, location, and stage,as well as the general health of the patient.
Highly radiosensitive cancer cells are rapidly killed by modest doses of radiation.These include leukemias,most lymphomas and germ cell tumours.The majority of carcinomas,which constitute the vast majority of malignant neoplasias,are only moderately radiosensitive and require a significantly higher dose of radiation (60–70 Gy) to achieve a radical cure. Some types of cancer are notably radioresistant, that is, much higher doses are required to produce a radical cure than may be safe in clinical practice. Combining radiation therapy with immunotherapy is an active area of investigation and has shown some promise for some kinds of malignancies(Maverakis,E,2015).
The response of a tumor to radiation therapy is also related to its size.Large tumors respond less well to radiation than smaller tumors or microscopic disease. Various strategies are used to overcome this effect.The most common route is surgical resection prior to radiation therapy,as this is most commonly applied in the treatment of breast cancer with wide local excision or mastectomy followed by adjuvant radiation therapy. Other alternatives is to shrink first the tumor with chemotherapy before radiation therapy is administered or to enhance the radiosensitivity of the cancer by giving certain drugs during radiation therapy (Seidlitz,A,2016).The impact of radiotherapy varies between different types of cancer and different groups.For example, for breast cancer after breast-conserving surgery , radiotherapy has been found to halve the rate at which the disease recurs(Darby,S,2011).In pancreatic cancer, radiotherapy has increased survival times for inoperable tumors (Reyngold,M,2019).
Side effects of Radiation Therapy
Radiation therapy(RT) is in itself painless.Higher doses can cause varying side effects during treatment (acute side effects), in the months or years following treatment (long-term side effects), or after re-treatment (cumulative side effects). The nature, severity, and longevity of side effects depends on the organs that receive the radiation, the treatment itself (type of radiation, dose,concurrent chemotherapy), and the patient.Serious radiation side effects occur in about 5% of Radiation Therapy cases Acute (near immediate) or sub-acute (2 to 3 months post RT) radiation side effects may develop after 50 Gy RT dosing. Late or delayed radiation injury (6 months to decades) may develop after 65 Gy(Cooper,JS,2022).Most side effects are predictable and expected,usually limited to the area of the patient's body that is under treatment. Side effects are dose-dependent; for example, higher doses of head and neck radiation can be associated with cardiovascular complications, thyroid dysfunction and hypophysis dysfunction (Mahmood, SS, 2016).
Modern radiation therapy intends to reduce complications to a minimum.The most common observable side effects reported are fatigue and skin irritation, like a sun burn.The low stamina often commences during the middle of a course of treatment and can last for many weeks after the treatment ends. The irritated skin will heal, but may not be as elastic as it was before(Lee,VH,2012).Depending on the area being treated, damages may include the skin, oral and pharyngeal mucosa and intestinal mucosa. The rates of onset of damage and recovery from it depend upon the turnover rate of epithelial cells.Typically the skin starts to become pink and sore several weeks into treatment. The reaction may become more severe during the treatment and for up to about one week following the end of radiation therapy, and the skin may break down. Skin reactions tend to be worse in areas where there are natural folds in the skin, such as underneath the female breast, behind the ear, and in the groin(Yang,X,2020).
Nausea and vomiting is not a general side effect of radiation therapy and is associated only with treatment of the stomach or abdomen or with radiation therapy to certain nausea-producing structures in the head during treatment of certain head and neck tumors(Lee,VH,2012).As with any distressing treatment, some patients vomit immediately during radiotherapy, or even in anticipation of it, but this is considered a psychological response(Hall,EJ,2000).

When head and neck areas are treated, soreness and ulceration usually occur in the mouth and throat,which can affect swallowing(Hall,EJ,2000).The esophagus can also become sore if it is treated directly, or if, as commonly occurs, it receives a dose of collateral radiation during treatment of lung cancer. When treating liver malignancies and metastases, it is possible for collateral radiation to cause gastric, stomach, or duodenal ulcers(Carretero,C,2007).The bowel may be treated directly with radiation or be exposed by radiation therapy to other pelvic structures,like prostate, bladder and female genital tract. Typical symptoms are soreness, diarrhoea, and nausea. Nutritional interventions may be able to help with diarrhoea associated with radiotherapy.Studies in people having pelvic radiotherapy as part of anticancer treatment for a primary pelvic cancer found that changes in dietary fat, fibre and lactose during radiotherapy reduced diarrhoea at the end of treatment (Ηenson,CC,2013).

Infertility is a major risk,since the ovaries and testicles are very sensitive to radiation. Treatment planning for all body sites is designed to minimize, if not completely exclude dose to the gonads if they are not the primary area of treatment.There is a dose-dependent relationship between ovarian radiation therapy (RT) and premature menopause. Patients treated with RT must be aware of the impact of treatment on fertility and explore appropriate options(Wo,JY,2009).

Late side effects occur months to years after treatment.They are often due to damage of blood vessels and connective tissue cells. Many late effects are reduced by fractionating treatment into smaller parts.Tissues which have been irradiated tend to become less elastic over time due to a diffuse scarring process.Hair loss may occur on any hair bearing skin with doses above 1Gy.It only occurs within the radiation field/s. Hair loss may be permanent with a single dose of 10Gy, but if the dose is fractionated permanent hair loss may not occur until dose exceeds 45Gy(Freites-Martinez,A,2019).The salivary glands and tear glands have a radiation tolerance .which is exceeded by most radical head and neck cancer treatments. Dry mouth and dry eyes can become irritating long-term problems and severely reduce the patient's quality of life. Similarly,sweat glands in treated skin tend to stop working and the vagina is often dry following pelvic irradiation.Radiation therapy treatments to the head and neck regions can cause chronic sinus tract draining and fistulae from the bone(Cooper,JS,2022).
Lymphedema,a condition of localized fluid retention and tissue swelling, can result from damage to the lymphatic system sustained during radiation therapy. It is the most commonly reported complication in breast radiation therapy patients who receive adjuvant axillary radiotherapy following surgery to clear the axillary lymph nodes(Meek,AG,1998).

Radiation is a potential cause of cancer, and secondary malignancies are seen in some patients.Patients,who have survived after cancer treatment are more likely than the general population to develop malignancies due to a number of factors including radiation treatment(Kamran,SC,2016).Malignancies start to occur 4–6 years following treatment, although some haematological malignancies may develop within 3 years.It is well known that radiation is also a carcinogenic agent. The increased number of long term survivors from cancer treatment face the burden of developing therapy-related cancers.the so called second malignant neoplasms. Consequently, practitioners are increasingly faced with the necessity to evaluate the risk of cancer induction as a late effect of radiation treatment(Toma-Dasu,I, 2017).The complex changes induced by radiation therapy in the tumour environment can also increase the metastatic risks,that may counteract the long-term efficacy of the treatment (Blyth,BJ,2018).

“Radiation therapy”(RT) can increase the risk of heart disease and death as observed in previous breast cancer RT regimens.”Therapeutic radiation” increases the risk of a subsequent cardiovascular event,like heart attack or stroke by 1.5 to 4 times a person's normal rate,aggravating factors included(Weintraub,NL,2010).The increase is dose dependent, related to the RT's dose strength, volume and location.Use of concomitant chemotherapy is an aggravating risk factor.The occurrence rate of RT induced cardiovascular disease is estimated between 10 and 30%(Benveniste, MF,2019).Cardiovascular late side effects have been termed radiation-induced heart disease (RIHD) and radiation-induced cardiovascular disease (RIVD).Symptoms are dose dependent and include cardiomyopathy,myocardial fibrosis,valvular heart disease,coronary artery disease,heart arrhythmia and peripheral artery disease (Klee,NS,2017).Most radiation-induced cardiovascular diseases occur 10 or more years post treatment, making causality determinations more difficult (Weinttraub,NL,2010).

Radiation treatments may damage nerves near the target area or within the delivery path as nerve tissue is also radiosensitive. Radiation-induced polyneuropathy occurs in approximately 1–5% of those receiving radiation therapy(Delanian,S,2012).In cases of radiation applied to the head,radiation therapy may cause cognitive decline,which was especially apparent in young children, between the ages of 5 and 11.The gastrointestinal tract can be damaged following abdominal and pelvic radiotherapy.Atrophy, fibrosis and vascular changes produce malabsorption, diarrhea, steatorrhea and bleeding.Pelvic radiation disease includes radiation proctitis, producing bleeding, diarrhoea and urgency and can also cause radiation cystitis when the bladder is affected(Hauer-Jensen,M,2014).

According to a report in the journal “Radiotherapy and Oncology”,depending upon the irradiated zone, late effect neuropathy may occur in either the central nervous system (CNS) or the peripheral nervous system (PNS). For example,in the CNS cranial nerve injury typically presents as a visual acuity loss 1–14 years post treatment,while in the PNS injury to the plexus nerves presents as radiation-induced brachial plexopathy or radiation- induced lumbosacral plexopathy appearing up to 3 decades post treatment with symptoms including pain,muscle weakness, and sensory deficits. Also.muscle cramping, spasms or twitching may develop. Radiation-induced nerve injury and chronic compressive neuropathies are the most common cause of involuntary muscular movements, usually visualized on the skin as vermicular or continuous rippling movements.Common areas affected include the arms, legs or face depending upon the location of nerve injury (Delanian,S, 2012).
Radiation necrosis is the death of healthy tissue near the irradiated site,that occurs because the radiation directly or indirectly damages blood vessels in the area, which reduces the blood supply to the remaining healthy tissue, causing it to die by ischemia ,similar to what happens in an ischemic stroke. Because it is an indirect effect of the treatment, it occurs months to decades after radiation exposure. Radiation necrosis most commonly presents as osteoradionecrosis, vaginal radionecrosis, soft tissue radionecrosis, or laryngeal radionecrosis(Cooper,J,2022).
During the first two weeks after fertilization, radiation therapy is lethal but not teratogenic.High doses of radiation during pregnancy may induce anomalies,impaired growth and intellectual disability and there may be an increased risk of childhood leukemia and other tumors in the offspring.(Arnon,J,2001). Supression of the functions of hypophysis may develop after radiation therapy for sellar and parasellar neoplasms, extrasellar brain tumors, head and neck tumors, and following whole body irradiation for systemic malignancies.Radiation-induced suppression of hypophysis mainly affects growth hormone and gonadal hormones,FSH and LH(Fernandez,A, 2009).