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Systemic Antineoplastic Therapy


Robert Peter Gale

, MD, PhD, Imperial College London

Last full review/revision Jul 2018| Content last modified Jul 2018
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Systemic antineoplastic therapy includes traditional chemotherapy with cytotoxic drugs as well as newer techniques including hormonal drugs and immunotherapy (including targeted therapies—see also Overview of Cancer Therapy). The number of antineoplastic drugs is increasing rapidly, particularly as research leads to development of immunotherapies for cancer. 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 and destroy only cancer 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 agents. Common antineoplastic drugs and their adverse effects are described.

The most common routes of administration are IV for cytotoxic drugs and oral for targeted drugs. Frequent dosing for extended periods may necessitate subcutaneously implanted venous access devices (central or peripheral), multi-lumen external catheters, or peripherally inserted central catheters.

Drug resistance can occur to chemotherapy. Mechanisms include

  • Over-expression of target genes

  • Mutation of target genes

  • Development of alternative pathways

  • Drug inactivation by tumor cells

  • Defective apoptosis in tumor cells

  • Loss of receptors for hormonal drugs

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


Traditional cytotoxic chemotherapy damages cell DNA and kills many normal cells in addition to 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, producing more tumor killing as well as more toxicity at higher doses. At their highest doses, DNA cross-linkers may cause bone marrow aplasia, necessitating hematopoietic cell transplantation to restore bone marrow function.

Single-drug chemotherapy 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, Hodgkin lymphoma, non-Hodgkin lymphoma, and, less commonly, solid tumors such as small cell lung cancer and nasopharyngeal cancer). 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 tissue. Continuous infusion may increase cell kill with some cell cycle–specific drugs (eg, fluorouracil).

For each patient, the probability of significant toxicities should be weighed against the likelihood of benefit. End-organ function should be assessed before chemotherapy drugs with organ-specific toxicities are used (eg, echocardiography before doxorubicin use). Dose modification or exclusion of certain drugs may be necessary in patients with chronic lung disease (eg, bleomycin), renal failure (eg, methotrexate), or hepatic dysfunction (eg, taxanes).

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 GI epithelium.

Imaging (eg, CT, MRI, PET) is frequently done after 2 to 3 cycles of therapy to evaluate response. Therapy continues if there is a clear response. If the tumor progresses despite therapy, the regimen is often changed or stopped. If the disease remains stable with treatment and the patient can tolerate therapy, then a decision to continue is reasonable with the understanding that the disease will eventually progress.

Hormonal Therapy

Hormonal therapy uses hormone agonists or antagonists to influence the course of cancer. It may be used alone or in combination with other treatment modalities.

Hormonal therapy is particularly useful in prostate cancer, which grows in response to androgens. Other cancers with hormone receptors on their cells (eg, breast, endometrium) can often be palliated by hormone antagonist therapy or hormone ablation. Hormonal agents may block the secretion of pituitary hormones (luteinizing hormone–releasing hormone agonists), block the androgen (bicalutamide, enzalutamide) or estrogen receptor (tamoxifen), suppress the conversion of androgens to estrogens by aromatase (letrozole), or inhibit the synthesis of adrenal androgens (abiraterone).

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

Use of prednisone, a glucocorticosteroid, is also considered hormonal therapy. It is frequently used to treat tumors derived from the immune system (lymphomas, lymphocytic leukemias, multiple myeloma).


Immunotherapy is the most recently developed area of anticancer therapy.

Interferons are agents that have a long history in cancer therapy. Interferons are proteins synthesized by cells of the immune system as a physiologic immune protective response to foreign antigens (viruses, bacteria, other foreign cells). In pharmacologic amounts, they can palliate some cancers, including hairy cell leukemia, chronic myeloid leukemia, locally advanced melanoma, metastatic renal cell cancer, and Kaposi sarcoma. Significant toxic effects of interferon include fatigue, depression, nausea, leukopenia, chills and fever, myalgias, hepatotoxicity, hypothyroidism, and atrial fibrillation.

Interleukins, primarily the lymphokine IL-2 produced by activated T cells are active in metastatic melanomas and can provide modest palliation in renal cell cancer.

Other types of immune therapy include differentiating drugs, anti-angiogenesis drugs, signal transduction inhibitors, and various monoclonal antibodies.

Considerable data suggest an important role for immune surveillance in preventing cancers in normal individuals. These data include an increased cancer incidence in people with immune suppression such as those receiving drugs to prevent rejection of a transplant. There are several recently approved monoclonal antibodies that facilitate this anti-cancer immunity.

Differentiating drugs

These drugs induce differentiation of cancer cells. All-trans-retinoic acid is effective in acute promyelocytic leukemia. Other drugs in this class include arsenic compounds and the hypomethylating agents azacytidine and deoxyazacytidine. When used alone, these drugs have only transient effects, but their role in prevention and in combination with cytotoxic drugs is promising.

Anti-angiogenesis drugs

Solid tumors produce growth factors that form new blood vessels necessary to support ongoing tumor growth. Several drugs that inhibit this process are available. Thalidomide is antiangiogenic, among other effects. 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 renal cancer, hepatocellular cancers, and other tumors.

Signal transduction inhibitors

Many epithelial tumors possess mutations that activate signaling pathways that cause their continuous proliferation and failure to differentiate. These mutated pathways include growth factor receptors and the downstream proteins that transmit messages to the nucleus from growth factor receptors on the cell surface. Examples include erlotinib and gefitinib, which inhibit the epidermal growth factor receptor (EGFR) signaling pathway.

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 HER-2 (or ErbB-2), plus chemotherapy has shown benefit in metastatic breast cancer that expressed HER-2. 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 that take advantage of anticancer immunity include those to CTLA-4 (ipilimumab) and to so-called immune checkpoint inhibitors such as PD1 and PD-L1 (nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab). Pembrolizumab can be used for any advanced cancer with a DNA-repair defect independent of anatomic site of the cancer. These drugs are sometimes given alone or combined with other anticancer drugs.

Most recently, anticancer monoclonal antibodies that target 2 or even 3 antigens have been developed. These monoclonal antibodies target a cancer-related antigen and a normal antigen on T cells with the objective of enhancing T-cell killing of cancer cells. Blinatumomab, which targets CD19 on acute lymphoblastic leukemia cells and CD3 on T cells, is an example of an engineered bi-specific anticancer monoclonal antibody.


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 immunotherapy, has shown modest prolongation of life in metastatic prostate cancer.

More important are vaccines designed to prevent cancer. Examples include vaccines to human papillomavirus (HPV), which causes cervix, head and neck, and other cancers, and vaccines to hepatitis B virus, which causes liver cancer.

Gene Therapy

Genetic modulation is under intense investigation. Strategies include the use of anti-sense therapy, systemic viral vector transfection, DNA injection into tumors, genetic modulation of resected tumor cells to increase their immunogenicity, and alteration of immune cells to enhance their anti-tumor response.

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 individual 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 FLT3mutation (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.

Adjuvant and Neoadjuvant Therapy

In some tumors with a high likelihood of relapse after surgery and/or radiation therapy, the risk of relapse may be reduced by giving chemotherapy after completing initial therapy even when there is no evidence of residual cancer cells. This practice is referred to as adjuvant chemotherapy. Radiation therapy can also be given and is referred to as adjuvant radiation therapy. Sometimes, both are given.

Adjuvant therapy

Adjuvant therapy is systemic chemotherapy or radiation therapy given to eradicate undetected tumor after initial surgery. Patients who have a high risk of recurrence may benefit from its use. General criteria are based on degree of local extension of the primary tumor, presence of cancer in lymph nodes, and certain histologic or biologic characteristics of the cancer. Adjuvant therapy has increased disease-free survival and cure rate in breast and colorectal cancers.

Neoadjuvant therapy

Neoadjuvant therapy is chemotherapy, radiation therapy, or both given before surgery. This treatment may enhance resectability and preserve local organ function. For example, when neoadjuvant therapy is used in head and neck, esophageal, or rectal cancer, a smaller subsequent resection may be possible.

Another advantage of neoadjuvant therapy is in assessing response to treatment; if the primary tumor does not respond, micrometastases are unlikely to be eradicated, and an alternate regimen should be considered. Neoadjuvant therapy may obscure the true pathologic stage of the cancer by altering tumor size and margins and converting histologically positive nodes to negative, complicating clinical staging. The use of neoadjuvant therapy has improved survival in inflammatory and locally advanced breast, stage IIIA lung, nasopharyngeal, and bladder cancers.

More Information

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

Drugs Mentioned In This Article

Drug Name Select Trade
Axicabtagene ciloleucel
No US brand name
Brentuximab vedotin
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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