Systemic Cancer Therapy

Cytotoxic drugs damage DNA and kill many normal cells as well as cancer cells. Antimetabolites such as fluorouracil and methotrexate are cell cycle–specific and have a nonlinear dose-response relationship. In contrast, other drugs (eg, DNA cross-linkers, also known as alkylating agents) have a linear dose-response relationship, killing more cancer cells at higher doses. At high doses, DNA cross-linkers damage the bone marrow.

Single drugs may cure selected cancers (eg, choriocarcinoma, hairy cell leukemia). More commonly, multidrug regimens incorporating drugs with different mechanisms of action and different toxicities are used to increase efficacy, reduce dose-related toxicity, and decrease the probability of drug resistance. These regimens result in substantial cure rates (eg, in acute leukemia, testicular cancer, lymphomas, and, less commonly, solid cancers such as lung and nasopharyngeal cancers). Multidrug regimens typically are given as repetitive cycles of a fixed combination of drugs. The interval between cycles should be the shortest one that allows recovery of normal tissues. Continuous infusion may increase cell kill with some cell cycle–specific drugs (eg, fluorouracil).

For each patient, the probability of adverse effects should be weighed against the likelihood of benefit. End-organ function should be assessed before giving drugs with organ-specific toxicities. Dose modification or exclusion of certain drugs may be necessary in patients with lung disease (eg, bleomycin), kidney failure (eg, methotrexate), liver dysfunction (eg, taxanes) or heart disease (daunorubicin, cyclophosphamide).

Despite these precautions, adverse effects commonly result from cytotoxic chemotherapy. The normal tissues most commonly affected are those with the highest intrinsic turnover rate: bone marrow, hair follicles, and the gastrointestinal epithelium.

Imaging (CT, MRI, PET) is frequently done after 2 to 3 cycles of therapy to evaluate response. Therapy continues in responders or patients with stable disease. In patients whose cancer progresses, the regimen is often changed or stopped.

Endocrine therapy uses agonists or antagonists to influence the course of cancer. It may be used alone or combined with other therapies.

Endocrine therapy is particularly useful in prostate cancer, which grows in response to androgens. Other cancers with hormone receptors, such as breast and endometrial cancers, can be controlled by endocrine therapy such as estrogen receptor binding (tamoxifen). Other endocrine therapies suppress the conversion of androgens to estrogens by aromatase (letrozole) or inhibit the synthesis of adrenal androgens (abiraterone). The most common use of endocrine therapy is in breast cancer. Tamoxifen and raloxifene are typically given for several years after breast cancer surgery (adjuvant therapy) and substantially reduce risk of cancer recurrence.

All hormone blockers cause symptoms related to hormone deficiency, including hot flashes, and the androgen antagonists also induce a metabolic syndrome that increases the risk of diabetes and heart disease.

Immune therapy is the newest systemic cancer therapy (see also Immunotherapy of Cancer Immunotherapy of Cancer A number of immunologic interventions, both passive and active, can be directed against tumor cells. (See also Immunotherapeutics.) In passive cellular immunotherapy, specific effector cells... read more ). Immune therapy is divided into two forms:

Active immune therapy can involve vaccines Vaccines Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more , modified T-cells Modified T cells Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more from the patient (eg chimeric antigen receptor (CAR)-T-cells), or certain types of monoclonal antibody Monoclonal antibodies Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more that activate the patient's immune system against the cancer (eg, checkpoint inhibitors). Another example of active immune therapy is instilling bacille Calmette–Guérin (BCG) in the bladder of patients with bladder cancer.

Adoptive immune therapy often involves giving monoclonal antibodies Monoclonal antibodies Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more produced in the laboratory or giving modified T cells Modified T cells Systemic cancer therapy includes chemotherapy (ie, conventional or cytotoxic chemotherapy), hormone therapy, targeted therapy, and immune therapy (see also Overview of Cancer Therapy). The number... read more or natural-killer (NK) cells from a healthy person to someone with cancer. Sometimes these cells are genetically modified by inserting an anticancer chimeric antigen receptor (CAR). Other forms of adoptive immune therapy include lymphokines and cytokines such as interferons and interleukins. These forms are less widely used in cancer therapy.

These drugs induce differentiation of cancer cells. All-trans-retinoic acid and arsenic are capable of curing acute promyelocytic leukemia. Other drugs in this class include hypo-methylating drugs, such as azacitidine and decitabine, and drugs with target mutations that block differentiation. Examples include enasidenib and ivosidenib, which counteract mutations in IDH2 and IDH1. Another approach uses venetoclax, which reverses a differentiation block caused by BCL2. Differentiating drugs are ineffective in most cancers.

Solid cancers produce growth factors that form new blood vessels necessary to support cancer growth. Several drugs that inhibit this process are available. Bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), is effective against renal cancers and colon cancer. VEGF receptor inhibitors, such as sorafenib and sunitinib, are also effective in kidney and liver cancers.

Most targeted therapies are directed against tyrosine kinase–mediated cell signaling pathways. The best example are tyrosine kinase inhibitors, including imatinib, dasatinib, and nilotinib, which are extremely effective in chronic myeloid leukemia. Many epithelial cancers have mutations that activate signaling pathways without the need for a receptor-ligand interaction, resulting in continuous proliferation of cancer cells. These mutated genes include those for growth factor receptors and the downstream proteins that transmit messages to the nucleus. Examples of such targeted therapies include erlotinib, gefitinib, and osimertinib, which inhibit the epidermal growth factor receptor (EGFR) signaling pathway. These drugs are especially useful in lung cancer. Poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors are used to treat ovary and hereditary breast cancers and include olaparib, rucaparib, niraparib, and talaparib. Other examples include the nonspecific JAK1/2 inhibitors ruxolitinib and fedratinib, which are used to treat myeloproliferative neoplasms, and selinexor, which inhibits transport of proteins from the nucleus to cytoplasm, decreases cell proliferation, and is effective in multiple myeloma.

A new direction in targeted cancer therapy is to use drugs that inhibit the gene product of a mutation independent of cancer type. Examples are drugs such as vemurafenib, dabrafenib, and encorafenib, which inhibit the protein produced by a mutation in BRAF. This mutation is common in melanoma but also occurs in some leukemias. Another example is drugs that inhibit abnormal proteins resulting from MEK mutations, including trametinib, cobimetinib, and binimetinib.

Gene therapy of cancer has not been successful so far except for the development of chimeric antigen receptor (CAR)-T-cells.

Some viruses, termed oncolytic viruses, appear to selectively or relatively selectively kill cancer cells, stimulate the immune system to target cancer cells, or both. The only available oncolytic virus is talimogene laherparepvec which is injected into the cancer in patients with melanoma. This virus, a modified herpesvirus, is engineered to produce a protein that stimulates an immune-mediated anticancer response and to express a protein that has similar effects. Because the virus is genetically engineered, it might be regarded as an indirect form of gene therapy.

In some cancers with a high likelihood of recurrence after surgery and/or radiation therapy, chemotherapy drugs, hormones, and/or targeted therapy drugs are given to reduce recurrence risk even when there is no evidence of residual cancer. This strategy is effective in many cancers and is termed adjuvant therapy. Radiation therapy can also be given after surgery or chemotherapy and is referred to as adjuvant radiation therapy.

Sometimes therapy with chemotherapy, hormones, and/or targeted therapy drugs is given before definitive surgery or radiation therapy, in which instance it is termed neo-adjuvant therapy. There are several objectives of neoadjuvant therapy. One is to reduce size of the cancer, allowing for less extensive surgery and/or a smaller radiation therapy field. Another objective can be measuring response to neoadjuvant therapy and/or assessing the cancer when it is removed surgically, allowing for a more accurate prediction of the potential value of adjuvant therapy. Neoadjuvant therapy is increasingly used in breast, ovary, colorectal, lung, gastric, and other cancers. Sometimes a cancer that could not otherwise be removed by surgery is operable after neoadjuvant therapy.

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

National Cancer Institute's up-to-date list of drugs used to treat cancer