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Systemic Cancer Therapy

By

Robert Peter Gale

, MD, PhD, Imperial College London

Last full review/revision Sep 2020| Content last modified Sep 2020
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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 of approved cancer therapies is increasing rapidly. The National Cancer Institute maintains an up-to-date list of drugs used to treat cancer. The list provides a brief summary of each drug's uses and links to additional information.

The ideal drug would target only cancer cells and have no adverse effects on normal cells. Although older chemotherapeutic drugs are often toxic to normal cells, advances in genetics and cellular and molecular biology have led to development of more selective drugs.

Most cancer drugs are given systemically, usually intravenously or subcutaneously, but some are given by mouth. Frequent dosing for extended periods may necessitate intravenous implanted access devices.

Resistance to cancer drugs is common. Mechanisms include

  • Over-expression of target genes

  • Mutation of target genes

  • Development of alternative drug metabolic pathways

  • Drug inactivation by cancer cells

  • Defective apoptosis in cancer cells

  • Loss of receptors for hormones

For chemotherapy drugs, one of the best characterized mechanisms is overexpression of MDR1, a cell membrane transporter that causes efflux of certain drugs (eg, vinca alkaloids, taxanes, anthracyclines). Attempts to alter MDR-1 function and prevent drug resistance have been unsuccessful.

Chemotherapy

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 no linear 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.

Hormone Therapy

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

Hormone 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 hormone therapy such as estrogen receptor binding (tamoxifen). Other hormone therapies suppress the conversion of androgens to estrogens by aromatase (letrozole) or inhibit the synthesis of adrenal androgens (abiraterone). The most common use of hormone 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 risks of diabetes and heart disease.

Prednisone, a glucocorticoid, is used in some cancers such as lymphatic leukemias, lymphomas, and multiple myeloma. In these instances, the effect of prednisone is more like a drug than a hormone.

Immune Therapy

Immune therapy is the newest systemic cancer therapy. Immune therapy is divided into two forms:

  • Active

  • Adoptive

Active immune therapy (mediated by active immunity) aims to provoke or amplify an anticancer immune response in a patient with cancer. This can be done, for example, using a cancer cell vaccine alone or combined with an adjuvant, which boosts the desired immune response. An example is sipuleucel-T, which is a dendritic cell vaccine used to treat prostate cancer. Another strategy is to remove T cells from a patient with cancer, modify them genetically to recognize a cancer-related antigen, and return them to the patient. The most common example of this strategy is termed chimeric antigen receptor (CAR)-T-cells. CAR-T-cells are an effective therapy in patients with acute lymphoblastic leukemia, B-cell lymphomas, and multiple myeloma. They are not yet proved effective in solid cancers. Another active strategy is to give monoclonal antibodies against the programmed death-1 (PD-1) or PD-1-ligand (PD-1L) to release a patient's immune system response, which is presumably suppressed by the cancer in a PD-1 or PD-1L–mediated mechanism. PD-1 and PD-1L antibodies are now widely used to treat solid cancers but not blood and bone marrow cancers. Another example of active immune therapy is instilling bacille Calmette–Guérin (BCG) in the bladder of patients with bladder cancer.

Adoptive immune therapy (mediated by passive immunity) involves giving anticancer antibodies or cells to a patient with cancer . Often these are monoclonal antibodies produced in the laboratory. Typically, the target of these antibodies is not cancer specific but directed against lineage-specific antigens. These antibodies may be linked to a toxin or radionuclide to increase efficacy. The most widely used example is rituximab, which is used in patients with lymphomas. Some antibodies are bi-specific with one receptor directed to a cancer-related antigen and another to an antigen on T cells. The goal is to bring T cells to the cancer to eradicate it. Another adoptive immune therapy approach is to give T cells or natural-killer (NK) cells from a healthy person to someone with cancer. Sometimes these cells are genetically modified by inserting an anticancer 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.

Differentiating drugs

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 hypomethylating 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.

Anti-angiogenesis drugs

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.

Targeted therapies

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 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 ruxolitinib and fedratinib used to treat myeloproliferative neoplasms and selinexor, which inhibits transport of proteins from the nucleus to cytoplasm and 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, includung trametinib, cobimetinib, and binimetinib.

Monoclonal antibodies

Monoclonal antibodies are widely used to treat some cancers. Monoclonal antibodies can be directed against antigens that are cancer-specific or over-expressed on cancer cells. They can also be directed toward lineage-specific antigens also present on normal cells. Some monoclonal antibodies are given directly; others are linked to a radionuclide or toxin. These linked antibodies are referred to as antibody-drug conjugates (ADCs).

Trastuzumab, an antibody directed against a protein called ERBB2, is active in breast cancers that express this antigen. Antibodies to CD19 and CD20 on normal B cells are used to treat lymphomas (rituximab), anti-CD30 antibodies are used to treat Hodgkin lymphoma (brentuximab vedotin), and anti-CD33 antibodies are used to treat acute myeloid leukemia (gemtuzumab ozogamicin).

Several monoclonal antibodies activate anticancer immunity (active immune therapy) by binding immune checkpoint inhibitors such as PD1 (nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab) or PD-1L (ipilimumab, tremelimumab). These drugs are being widely used to treat diverse solid cancers, alone or combined with chemotherapy.

Most recently, anticancer monoclonal antibodies that target 2 or 3 antigens have been developed. These monoclonal antibodies typically target cancer-related antigens and T-cell antigens to enhance T-cell killing of cancer cells. Blinatumomab, which targets CD19 on acute lymphoblastic leukemia cells and CD3 on T cells, is an example.

Vaccines

Vaccines designed to trigger or enhance immune system response to cancer cells have been extensively studied and have typically provided little benefit. However, recently, sipuleucel-T, an autologous dendritic cell–derived vaccine is available for prostate cancer.

More important are vaccines designed to prevent virus-related cancer. Examples include vaccines to human papillomavirus (HPV), which can prevent cervical and anal cancers (and possibly and head and neck and tonsil cancers) and vaccines to hepatitis B virus (HBV), which can prevent liver cancer.

Gene therapy

Gene therapy of cancer has not been successful so far except for the development of CAR-T-cells. There is hope that CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 (CRISPR-associated protein 9) gene editing may be useful in some cancers alone or combined with other anticancer therapies. An example in synthetic biology is altering antigen expression on normal cells such that they are not killed by CAR-T-cell or bi-specfic monoclonal antibodies.

Targeted therapy refers to therapies directed against a specific gene or gene product thought to be important in the cause or progression of a cancer rather than the anatomic site (eg, breast) or even cell type. For example, patients with a BRAF mutation might receive a BRAF inhibitor regardless of whether they have a melanoma or leukemia. Therapy targets are typically identified by genetic analysis of a patient’s cancer. An example of targeted therapy is the use of tyrosine kinase inhibitors (eg, imatinib, dasatinib, nilotinib) in chronic myeloid leukemia, a cancer caused by one mutation (BCRABL1). However, most cancers are caused by 10s or even 100s of mutations, making the approach considerably more complex.

Recently, drugs directed against the FLT3 mutation (midostaurin) and the isocitrate dehydrogenase-2 (IDH2) mutation (enasidenib) became available to treat some forms of acute myeloid leukemia and systemic mastocytosis (midostaurin). Other drugs that target receptors for VEGF and EGFR are mostly small molecule kinase inhibitors (eg, sorafenib, erlotinib, gefitinib, sunitinib, regorafenib).

In some hematologic conditions, such as polycythemia vera and myeloproliferative neoplasm–associated myelofibrosis, JAK2-inhibitors (ruxolitinib, fedratinib, pacritinib) are used.

Drugs directed against poly ADP ribose polymerase (PARP) are available for BRCA-mutated ovarian cancer, fallopian tube cancer, and peritoneal cancer. These drugs include olaparib, rucaparib, and niraparib. Adverse effects include bone marrow toxicity (eg, infection, bleeding), fatigue, diarrhea, headaches, dizziness, and liver and kidney abnormalities.

The most advanced form of gene therapy involves genetically modifying a cancer patient's T cells by inserting a receptor for an antigen onto their cancer cells. For example, CD19 or CD20 antigens coupled with a stimulatory signal to promote T-cell proliferation are used in patients with acute lymphoblastic leukemia or lymphoma. These modified T cells are designated chimeric antigen receptor or CAR-T-cells. These cells can produce remissions in patients with advanced disease. Recently, two CAR-T-cell therapies, tisagenlecleucel for young patients with advanced acute lymphoblastic leukemia and axicabtagene ciloleucel for advanced lymphomas, became available.

Oncolytic viruses

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.

Adjuvant and Neoadjuvant Therapies

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 neoadjuvant 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.

More Information

The following is an English-language resource that 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

Click here for Patient Education
NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

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