Chemotherapy is a category of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim to prolong life or to reduce symptoms (palliative chemotherapy). Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

Cancer treatment is targeted at its proliferation potential and its ability to metastasise (cancer that spreads to a different part of the body from where it started); hence, the majority of chemotherapy drugs take advantage of the fact that cancer cells divide rapidly. Chemotherapy agents can be divided into several categories based on the factors such as how they work, their chemical structure, and their relationship to another drug. 

The most important categories of chemotherapeutics include:

  • alkylating agents (e.g., cyclophosphamide, ifosfamide, melphalan, busulfan)
  • antimetabolites (e.g., 5-fluorouracil, capecitabine, methotrexate, gemcitabine)
  • antitumour antibiotics (e.g., daunorubicin, doxorubicin, epirubicin)
  • topoisomerase inhibitors (e.g., topotecan, irinotecan, etoposide, teniposide)
  • mitotic inhibitors (e.g., paclitaxel, docetaxel, vinblastine, vincristine). 

Most chemotherapeutic drugs target the cell cycle machinery relying on the difference in the frequency of cell division to differentiate between the cancer clones and normal cells. Within this process slow-growing cancer clones will survive and evolve into new fast growing strains. Chemotherapy is able to kill off most of the susceptible tumorous cells succeeding to send cancer into remission for weeks or months after which it reemerges as a more aggressive organism. In fact, the more chemotherapy is given, the higher is the aggressiveness of relapse. In these cases, chemotherapy may indirectly select the most resistant mutant cell for clonal expansion (production of daughter cells all arising originally from a single cell).

The Chemotherapy Process

Step 1: Blood tests

Prior to chemotherapy treatment, a series of blood tests must be run. These blood tests determine the risks and the benefits of taking chemotherapy for the patient. The blood test focuses on blood counts and liver health. Blood counts indicate if the immune system is healthy enough to aid in the healing process after chemotherapy is administered, while the liver results indicate whether the liver is healthy enough to remove chemotherapy toxins from the body. If either of these results are off and the patient is healthy enough to wait for treatment, treatment may be held until results improve. 

Step 2: Administration of Chemotherapy

Chemotherapy kills both healthy cells and cancerous cells, as it cannot differentiate between the two. Chemotherapy medications attack all cells that multiply quickly by altering the cell’s structure so it can no longer multiply. Once it is determined that the patient is healthy enough to undergo treatment, the treatment method is decided. There are several ways chemotherapy drugs can be administered to the patient. 

  • Oral medications - Some forms of chemotherapy are administered orally as pills or tablets. The drugs are absorbed into the blood stream where they are delivered to all parts of the body. 
  • Intravenous medications - Chemotherapy can also be administered intravenously (Pic. 1). This method involves either an injection or a cannula that introduces the drug directly into the vein. This method allows the medication to drip slowly and directly into the patient’s bloodstream.
  • Implanted port - Chemotherapy drugs may also be administered through an implanted port. A port is a device implanted permanently under the skin connecting to a vein. This method allows medication to be administered directly into the blood stream. The benefit of using an implanted pump is that it reduces the number of injections needed and a patient can receive treatment at home with the use of a special pump. Once the treatment is complete, the pump may be removed.
  • Catheters - A catheter is a tube system that allows medication to be administered to the body. There are two types of catheters that can be used to administer chemotherapy. A catheter can be directly connected to a vein near the heart, called a skin tunnelled catheter, or directly connected to a vein in the arm, called a peripherally inserted central catheter. Similarly to a port, a catheter reduces the number of injections needed, and can be left in until treatment is complete.

Symptoms

The most common acute complaints of cancer patients undergoing chemotherapy are fatigue, nausea, vomiting, malaise, diarrhoea, mucositis (inflammation and ulceration of the mucous membranes lining the digestive tract), pain, rashes, infections, headaches, and other problems (Pic. 2). 

Associated diseases

  • non-obstructive azoospermia (no sperm in the semen)
  • premature ovarian failure (POF)
  • menopause

Complications

Although the desired goal of chemotherapy is to eliminate the tumour cells, diverse ranges of normal cell types are also affected, leading to many adverse side effects in multiple organ systems. Such debilitating effects are a major clinical problem, whereas the toxicity often limits the usefulness of anticancer agents.

Suppression of immune system

Most cytotoxic drugs have immune suppressive side effects. Many chemotherapeutics results in decreased immunity, increased susceptibility to infections, and elevated risk of bleeding. Coming from the requirement of the bone marrow to repopulate white cells and platelets in the blood, drugs are often administered episodically followed by the drug-free intervals of 2-3 weeks. Such scheme helps to minimise the chance of infection or bleeding but allows also the tumour to recover.

Neurological side effects

Cancer patients frequently complain of neurological side effects. Such effects range from abnormalities in brain volume and integrity detected by magnetic resonance imaging (MRI) on patients after chemotherapy to different clinical symptoms; manifesting acutely or as delayed neurotoxicities only becoming apparent years after treatment. Neurological complications include memory loss and cognitive dysfunction, seizures, vision loss, dementia, and other problems. These symptoms are commonly referred to as Chemo Brain affecting some 4–75% of cancer patients following with chemotherapy. Nearly all frequently used chemotherapeutic agents can cause adverse neurological effects. 

Long-term health complications

The most common long-term health problems of adjuvant chemotherapy include poor memory and concentration, visual deterioration, musculoskeletal complaints including early onset osteoporosis (weak bones), poor sleep patterns, skin changes, sexual dysfunction, and chronic fatigue. This complex of problems is suggestive of accelerated aging leading potentially to early onset frailty. Such long-term toxicity can have an impact on the quality of life of cancer survivals that could last for years.

Pregnancy complications

If pregnancy is established, there are several potential risks to a fetus conceived after cancer treatment. Both radiation and chemotherapy may theoretically increase the risk of birth defects and genetic disease in offspring. However, when considering the half-life of treatments and the duration of time for oocyte maturation, it has been recommended to delay pregnancy for at least 6 months after treatment with chemotherapy and 12 months following completion of radiotherapy to minimize risks to offspring.

Multiagent chemotherapy

Current treatment protocols often apply multiagent chemotherapy and this may even increase the extent of adverse side effects since it combinates chemotherapy with more than one chemotherapy agent. Several serious complications can cause discontinuation of therapy, prolong the duration of stay in hospitals, and may affect the overall prognosis and outcome of the disease. It is important to bear in mind that, in general, older cancer patients are more susceptible to treatment-related complications than younger individuals. 

Risk factors

The type of chemotherapy drug will determine what side effects may develop and how severe they may become. Part of the difficulty in counseling patients regarding the risk of infertility and/or subsequent pregnancy complications is that the risks are dependent on several factors. These risks include the dose and duration of treatment, other risk factors for infertility, the age of the patient, and the patient’s baseline ovarian reserve at the time of initiation of treatment.

Prevention

Intervention with dietary agents in chemotherapy has several aims. It increases the efficacy of treatment and decreases its side effects, improves cancer killing through apoptosis (programmed cell death) rather than necrosis (unprogrammed cell death), reduces drug resistance or increases drug accumulation within cancer cells, detoxifies body of chemotherapeutics, decreases weight loss and malnutrition, improves the quality of life, and reduces severity of comorbid conditions.

Female fertility

The primary impact of chemotherapy on fertility is related directly to the loss of ovarian function secondary to the gonadotoxicity of many chemotherapeutic agents (Pic. 3). The greatest risk is in women over age 40 years receiving alkylating agents with up to 80% of patients having permanent amenorrhea (absent period) after treatment. However, in women under 30 years, the risk of permanent amenorrhea is substantially decreased to less than 20%. 

The effect of chemotherapy will also depend on whether it is radical (seeks to control rather than destroy tumours) or adjuvant, single agent, or combination. Unfortunately, estimates in the impact on fertility vary widely dependent on various factors, and, therefore, there is no definitive predictor prior to treatment making counseling on future fertility challenging for health care providers.

The peak number of oocytes is found in females at 20 weeks of fetal life, and this number declines until menopause. The number of primordial follicles (first stage in follicle development) is approximately 500,000 at menarche; menopause occurs once that pool is nearly depleted. Although chronologic age is the most important predictor of oocyte quality and quantity, there is variability in the rate of ovarian aging. The term “ovarian reserve” is used to describe remaining ovarian oocyte quantity. Although menstrual cycles do not start to become irregular until a mean age of 45 to 55 years, endocrinologic changes associated with ovarian aging have been demonstrated for women age 35 to 40 years and at earlier ages after cancer treatment. Assessment of a patient’s ovarian reserve both before and after cancer treatment may provide valuable information for patients in discussion of fertility preserving option prior to treatment and future fertility after treatment.

Further research is needed to determine the impact of cancer treatments on markers of ovarian reserve and any correlation with future fertility. It is important to consider that most research has evaluated these markers in relation to success of ovarian stimulation for IVF (in vitro fertilization); therefore, caution must be used in counseling patients on the likelihood of spontaneous pregnancy or with other fertility treatments.

Male fertility

In male patients, prepubertal status does not provide protection from gonadal damage and alkylating agents at high doses induce germ cell injury although Leydig cell (produces testosterone in testes) function is commonly preserved. Because most chemotherapy agents are given as part of a combination regimen, it has been difficult to quantify the gonadotoxicty of individual drugs.

Fertility preservation is a rapidly evolving field that includes medical and surgical treatments to decrease the impact of cancer treatments on future fertility. Traditional fertility preserving techniques for patients undergoing radiation treatment included pelvic shielding or surgical repositioning of the ovaries out of the pelvis. Medical treatments to suppress ovarian function during chemotherapy have also been reported to decrease the effect on cancer treatments on future ovarian function. These modalities still rely on residual ovarian function after cancer treatments to conceive. Newer techniques to preserve ovarian reserve, oocytes, and embryos prior to cancer treatments have been developed to provide an opportunity to conceive in the event that cancer treatments result in permanent loss of ovarian function.

Ovarian suppression during chemotherapy

It has been well documented that chemotherapeutic agents, particularly alkylating agents, have high levels of ovarian toxicity. Oocytes are contained in ovarian primordial follicles, and it is estimated that hundreds to thousands of these follicles initiate the maturation process each month and are susceptible to the gonadotoxic effects of chemotherapy. Primordial follicles are stimulated to initiate maturation through a complex process that is initiated by follicle stimulating hormone (FSH) release from the pituitary in response to hypothalamic gonadotropin releasing hormone (GnRH). Suppression of ovarian function through manipulation of GnRH has been evaluated as a mechanism to decrease the loss of primordial follicles.

Embryo cryopreservation

The basic principle of cryopreservation is to store cells or tissue for future use. Damage to cells during the cryopreservation process has been a barrier to the general use of this technology. Cryopreservation is typically performed by incubation in a low concentration of cryoprotectant to minimize ice crystal formation during freezing; however, oocytes are particularly vulnerable to damage. Embryos are composed of multiple blastomere cells and are more stable for cryopreservation. 

Embryo banking has several advantages for patients interested in preserving fertility. It provides reassurance to a patient that she will have some potential to conceive if the cancer treatments result in permanent amenorrhea. A disadvantage of embryo banking is the need to administer ovarian stimulation medications to obtain oocytes for fertilization. Ovarian stimulation is a particular concern for patients with hormonal sensitive tumors such as breast cancer and will be addressed further in this review.

Oocyte cryopreservation

Recent advances in oocyte cryopreservation technology have expanded the use of this technology for fertility preservation. Disadvantages are similar to those of embryo banking including the risk of ovarian stimulation for patients with hormonally responsive cancers and the potential delay in starting cancer treatments. Oocyte banking is preferable over embryo banking for patients that do not have a partner and/or are not interested in utilizing donor sperm or have ethical concerns regarding cryopreservation of embryos.

Until recently, the primary disadvantage of oocyte banking has been the lower success rate compared to embryo cryopreservation. 

Ovarian Tissue Cryopreservation

Ovarian tissue cryopreservation has also been evaluated as a modality to preserve future fertility. A portion of ovarian cortex is cryopreserved and then transplanted back to the pelvis, or other location (arm or abdominal wall has been reported). 

Patients undergoing ovarian tissue cryopreservation may still require future ovarian stimulation with gonadotropins and/or in vitro fertilization. Options that have been investigated to eliminate the risk of exposure to gonadotropins include in vitro maturation (IVM) or in follicle maturation (IFM) of oocytes. These techniques require surgical removal of immature oocytes followed by in vitro exposure to gonadotropins to mature oocytes outside the body. There has been limited success with this approach utilizing immature oocytes aspirated during either the follicular or luteal phase of the menstrual cycle and matured in vitro. 

Sperm banking for male patients

As many children are born after fertility treatments using frozen-thawed sperm, the cryopreservation of ejaculated semen is regarded as an established fertility preservation method in adult patients and pubertal boys. Traditionally, sperm banking by cryopreservation of at least three semen samples with an abstinence period of at least 48 hours in between the samples has been recommended for adult males desiring to preserve their fertility.

Testicular tissue cryopreservation

This technique involves removal of testicular tissue from the male patient before cytotoxic therapy is initiated. Cryopreservation of gonadal tissue offers hope to childhood cancer survivors, however it also raises several medical and ethical questions. Experimental methods for fertility preservation should only be offered to patients at specialized centers working with ethics board-approved research protocols and only in case when the recognized risks associated to the procedure are minimal.

Conceiving after cancer and the risk of pregnancy complications

The likelihood of conceiving after cancer treatments is dependent on the type of cancer, age at diagnosis, treatments with gonadotoxic agents including type and duration, and various other fertility factors. The chance for conception at best can only be estimated based on individual patient history and characteristics. It also appears that future fertility may also be influenced by gender. Overall, the likelihood of future children was found to be lower for female cancer survivors than male survivors either spontaneously or with fertility treatments. 

When stratifying for age at diagnosis and estimating from probability charts, men with a cancer diagnosis prior to age 30 years had the highest overall chance of future parenthood (50%), followed by women diagnosed at age 30 years or younger (32%), then males diagnosed after age 30 years (12%), and then females diagnosed after age 30 years (<5%). For female patients the likelihood of pregnancy was dependent on the type of cancer and was highest for patients after uterine choriocarcinoma (65%), followed by lymphoma (23%) and malignant melanoma (22%), all other cancers (<5%).

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Sources

Chemotherapy ―sourced from Wikipedia licensed under CC BY-SA 3.0
Chemotherapy ―sourced from Wikispace licensed under CC BY-SA 3.0
Side Effects of Chemotherapy ―by Halycon licensed under CC0 1.0
Chemotherapy bottles NCI ―by unknown licensed under CC0 1.0
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