The side effects that have been associated with traditional systemic cytotoxic chemotherapy in the past are largely absent now. The newer therapies are accompanied by relatively few unpleasant side effects and may be associated with improved outcomes.
Chemotherapeutics
Chemotherapy drugs can be divided into several groups based on factors such as mechanism of action, chemical structure, and relationships to other drugs. Some therapies act in more than one way, and may belong to more than one group.
The mechanism of action of a treatment is an important factor in predicting and understanding side effects. If a combination therapy is used, the timing and order of administration of the drugs can influence the occurrence and severity of adverse effects.
Alkylating agents
Alkylating agents directly alter the DNA in order to prevent the cell from reproducing. The drugs are effective in all phases of the cell cycle. Alkylating agents have been used in a wide variety of cancer types.
Adverse effects. Because these drugs alter DNA, they can have long-term effects on the bone marrow, which can lead to acute leukemia in some cases. The risk is generally dose dependent and peaks at about 5 to 10 years after treatment.
The Platinum Agents
The platinum agents, like the alkylating agents, prevent cell reproduction by altering DNA. The platinum drugs are less frequently associated with subsequent leukemias. The platinum agents are associated with many of the adverse events listed below.
AnthracyclinesAnthracyclines are anti-tumor antibiotics that interfere with enzymes involved in DNA replication in all phases of the cell cycle. They are widely used against a variety of cancers.
Side effects. Cardiotoxicity is a concern when these drugs are given in high doses. For this reason, lifetime dose limits are often established.
Other anti-tumor antibiotics
Anti-tumor antibiotics that are not anthracyclines include:
Topoisomerase inhibitors. These drugs disrupt the S phase of DNA replication. The side effects of topoisomerase II inhibitors are related to the development of a second cancer – acute myelogenous leukemia (AML) – as early as 2 to 3 years after the anthracyclines are given.
Mitotic inhibitors
Mitotic inhibitors interrupt the M phase of the cell cycle but can alter cells in all phases by preventing the production of certain proteins.
Side effects. These drugs may cause nerve damage in a dose-dependent manner thereby limiting the maximum dosage.
General Side Effects of Ctyotoxic Chemotherapy
The general side effects of cytotoxic chemotherapy can be very serious. In some cases the side effects are intolerable to the patient. In other case the side effects weaken the patient and hasten death. In still other cases, the torturous course of chemotherapy can confer upon the patient a month or two of additional lifetime.
Performance-Based Oncology: Reduce Adverse Effects
The performance-based physician must balance the patient experience, the treatment efficacy, the cost efficacy, and other factors in recommending a treatment course for the patient. During this decision making the physician must consider the common adverse effects of cytotoxic therapy. Those can include:
- Alopecia; often as alopecia totalis, telogen effluvium, or, less often. alopecia areata.
- Anemia
- Anorexia
- Chills
- Cognitive impairment
- Diarrhea
- Dyspnea
- Fatigue
- Female infertility
- Fever
- Flu-like symptoms (chills, fever, headache, fatigue, loss of appetite, nausea, vomiting)
- General gastrointestinal distress; including nausea, vomiting, anorexia, diarrhea, abdominal cramps, colitis, and constipation, among others)
- Headache
- Hypo- or hyperthyroidism
- Immunosuppression and myelosuppression, sometimes severe
- Lethargy
- Nausea
- Nausea and vomiting; Two of the most feared cancer treatment-related side-effects for cancer patients and their families.
- Organ damage
- Peripheral neuropathy
- Pruritus
- Rash
- Recurrence
- Teratogenicity
- Tumor lysis syndrome
- Typhlitis, sometimes fatal
- Vomiting
Immunotherapy: Fewer Serious Side Effects
Side effects of the chemotherapeutic agents can include fatigue, cough, nausea, itching, skin rash, decreased appetite, constipation, joint pain, and diarrhea.
Side effects of cytokine therapy can include flu-like symptoms such as fever, chills, neuralgia, fatigue, and even low white- and red-blood cell counts. Interleukin-2, particularly in high doses, can cause clinically significant edema. In order to be cautious, high-dose IL-2 is administered only in the clinic at centers that have experience with this type of treatment.
Serious side effects seem to be more common with cytokine inhibitors than with PD-1 inhibitors. Drugs that stimulate the immune system can cause damage to other parts of the body, which can lead to serious problems. Clinicians must be vigilant for distant systemic adverse effects.
Possible side effects of monoclonal antibodies
Monoclonal antibodies are given intravenously. The antibodies themselves are proteins, so there is always some risk of allergic or anaphylactic reaction. This is more common while the drug is first being administered. The listed side effects are frequently much less severe than the identical side effect caused by a cytotoxic agent. Possible side effects can include:
- Chills
- Diarrhea
- Fever
- Headache
- Hypotension
- Nausea
- Rash
- Vomiting
- Weakness
Immune Checkpoint Inhibitors to Treat Cancer
PD-1 is a checkpoint protein on T cells. It normally acts as a type of off switch that helps keep the T cells from attacking other cells in the body. It does this when it attaches to PD-L1, a ligand present on some normal (and some cancerous) cells. When PD-1 binds to PD-L1, it causes the T cell ignore the first cell. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack.
Checkpoint inhibitors target molecules such as PD-1, PD-L1, and CTLA-4, which normally help keep the immune system in check. The checkpoint inhibitors allow the programmed death and CTLA-4 compounds to operate at full capacity. All available resources are focused on the cancer cells.
Monoclonal antibody treatments that target either PD-1 or PD-L1 can boost the immune response against cancer cells still further, and have shown a great deal of promise.
Cancer vaccines
Only one vaccine has been approved to treat cancer in the U.S. For this vaccine, immune system cells are removed from the patient’s blood and converted to dendritic cells. They are then exposed to prostatic acid phosphatase (PAP) in order to produce the desired immune response.
Side effects are usually mild and can include fever, chills, fatigue, back and joint pain, nausea, and headache
Interleukins
Interleukins are a group of cytokines that act as chemical signals between white blood cells.
Interleukin-2 (IL-2) helps immune system cells grow and divide more quickly. A man-made version of IL-2 is approved for clinical use.
IL-2 can be used as a single-drug treatment, or it can be combined with chemotherapy or with other cytokines such as interferon-alfa. Using IL-2 with these treatments might help make them more effective against some cancers, but the side effects of the combined treatment are also increased.
Side effects of IL-2 can include flu-like symptoms such as chills, fever, fatigue, and confusion. Most people gain weight. Some have nausea, vomiting, or diarrhea. Many patients develop hypotension. Rare but potentially serious side effects include an abnormal heartbeat, angina, and other heart problems. Because of these possible side effects, if IL-2 is given in high doses only on an inpatient basis.
Other interleukins, such as IL-7, IL-12, and IL-21, are currently being studied for use both as adjuvants and as stand-alone agents.
Interferons
Only IFN-alpha is used to treat cancer. It boosts the ability of certain immune cells to attack cancer cells. It may also slow the growth of cancer cells directly, or via antiangiogenesis.
The side effects of interferon can be severe and can make treatment hard for patients to tolerate. Rare long-term effects include neuropathies of the central nervous system.
Immunomodulating drugs
These agents are thought to work in a general way by boosting the immune system, although their mechanism of action is unclear.
Side effects can include fatigue, lethargy, constipation, low blood cell counts, neuropathy, and increased risk of coagulation disorders. In contrast to the vast number of wildly variable side effects experienced by patients who receive cytotoxic chemotherapy, the list of side effects of attributable to immunotherapeutic agents is relatively brief, and the signs and symptoms can often be palliated.
