Adjuvant Antineoplastic Drugs

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Chapter 55 Adjuvant Antineoplastic Drugs

Abbreviations
ADCC Antibody-dependent cell-mediated cytotoxicity
ATP Adenosine triphosphate
EGFR Epidermal growth factor receptor
HPV Human papilloma virus
IFN-α Interferon alpha
IL-2 Interleukin-2
IV Intravenous
mRNA Messenger ribonucleic acid
NK Natural killer (cell)
PDGFR Platelet-derived growth factor receptor
VEGFR Vascular endothelial growth factor receptor

Therapeutic Overview

Immunotherapy, vaccines, drugs affecting angiogenesis, specific tumor growth factor receptor antagonists, and other forms of biological therapies are becoming more common in the treatment of neoplastic disease. Traditional chemotherapy, as discussed in Chapter 54, is aimed at destruction of rapidly dividing tumor cells. However, newer approaches involve drugs that are aimed at more specific cellular targets on the cancer cells with reduced effects on normal cells. Thus these agents typically have fewer side effects than the traditional chemotherapeutic agents. In addition to being administered alone for the treatment of certain cancers, many of these compounds are also used in combination with traditional chemotherapeutic regimens.

The cell targets and agents directed towards these targets are summarized in the Therapeutic Overview Box.

Mechanisms of Action

Hormonal Agents

Steroids act by passing through the plasma membrane and binding to cytoplasmic receptors, which then enter the

Therapeutic Overview
Targets
The immune system
Growth factors and their receptors
Intracellular signaling molecules
Angiogenesis
Agents
Hormones and antihormones
Cytokines
Monoclonal antibodies
Vaccines
Small molecules

nucleus and interact with specific hormone-responsive elements on chromatin to induce synthesis of specific messenger ribonucleic acids (mRNAs). Translation of these mRNA species leads to formation of new proteins that alter physiological or biochemical reactions in a beneficial manner. Most of the proteins involved, however, have not yet been identified and characterized.

Antihormonal drug treatment strategies for breast cancer include:

Approximately 70% of all postmenopausal patients whose breast tumors show the presence of estrogen receptors respond favorably to antiestrogen therapy, as opposed to only approximately 10% of those whose tumors do not express receptors. Tamoxifen is the main antiestrogen used clinically, and it acts by binding to estrogen receptors and blocking estrogen-dependent transcription of cells in the G1 phase. By blocking the binding of estrogens, tamoxifen (see Chapter 40) may decrease estrogen stimulation of the production of transforming growth factor-α and secretion of associated proteins. Toremifene, closely related to tamoxifen, is a newer estrogen receptor antagonist that is also used to treat estrogen receptor-positive breast cancer, or when estrogen sensitivity is unknown. It is indicated in postmenopausal women whose cancer has metastasized. Fulvestrant has also been recently approved for the treatment of estrogen receptor-positive breast cancer in postmenopausal women. However, in contrast to tamoxifen and toremifene, instead of blocking estrogen receptors, fulvestrant destroys them.

Although postmenopausal women have very low levels of estrogen, small amounts are produced through the conversion of androstenedione, secreted by the adrenal glands, to estrogen via an aromatase enzyme (see Fig 38-1). Even these low levels can stimulate estrogen-sensitive breast cancer. The aromatase inhibitors letrozole, anastrazole, and exemestane effectively block the production of estrogen from the adrenals and are alternatives to the estrogen receptor antagonists in postmenopausal women. These drugs do not affect ovarian secretion of estrogen and for this reason are not used in the treatment of breast cancer in premenopausal women.

In metastatic prostate cancer, as in breast cancer, hormonal manipulations can produce objective responses. For prostate cancer this involves either orchiectomy or pharmacological castration. Testosterone concentrations can be reduced by the estrogen diethylstilbestrol or by suppression of the pituitary gonadotropic axis. Leuprolide and goserelin are analogs of gonadotropic-releasing hormones that inhibit release of gonadotropins and result in reduced testosterone concentrations. The two agents are available in depot form and can be given monthly. Both are agonists and antagonists of luteinizing hormone-releasing hormone. They produce an initial rise in gonadotropin concentrations, followed by a decline in 2 to 3 weeks.

Flutamide is an antiandrogen that inhibits androgen binding to receptors in the nucleus. Unlike other agents discussed, it increases concentrations of testosterone; however, the testosterone is ineffective because flutamide blocks its action. There has been recent interest in achieving total androgen blockade (both testis and adrenal) through concurrent use of flutamide and luteinizing hormone-releasing hormone analogs.

Biological Therapy

Harnessing intrinsic biological systems for treatment of disease is an appealing concept, because theoretically it could be highly targeted and of limited toxicity. “Biological therapy” attempts to use our native host defense system and its humoral and cellular components as weapons to fight cancer (see Chapter 6). Many of these weapons are intended to stimulate the immune system for destruction of malignant cells. The immune system involves the action of many different cell types acting in concert, particularly lymphocytes, which can be classified as B, T, or null cells. These cells can secrete proteins, including antibodies, which possess unique affinity for their conjugate antigens and impart specificity to the immune system. They also secrete cytokines, which have wide-ranging cellular influences. Use of these systems may introduce remarkable therapeutic target specificity at the risk of induction of autoimmunity and unique toxicities. Agents currently in use include cytokines, monoclonal antibodies, and vaccines.

Interleukin 2 (IL-2) is one of a family of soluble glycoproteins that is involved in direct communication between leukocytes. IL-2 is produced by activated T lymphocytes and is a growth factor for T cells. Recombinant IL-2 therapy as a single agent has activity in treatment of melanoma and renal cell carcinoma, producing durable resolution of all disease in 6% to 7% of patients with metastatic disease. IL-2 is also being investigated as an adjunct with chemotherapy, monoclonal antibodies, and vaccines.

Interferon-alpha (IFN-α) is one of a family of glycoproteins, the interferons, which are synthesized by macrophages and lymphocytes that have been stimulated by mitogens, antigens, RNA, or infected by a virus. Interferons also express a wide variety of biologic activities, often making it difficult to determine which ones might be operant in a particular context. They modulate immune responses, augmenting T-cell and natural killer (NK) cell-mediated cytotoxicity; participate in the regulation of cellular differentiation and antigenic expression; and possess antiviral activity. Thus, they are useful clinically for the treatment of viral hepatitis and as anti-tumor agents due to their antiangiogenic and antiproliferative effects. IFN-α has clinical activity in the treatment of hairy cell leukemia, chronic myelogenous leukemia, indolent lymphoma, multiple myeloma, Kaposi’s sarcoma, superficial bladder carcinoma, renal cell carcinoma, and melanoma. Benefit from adjuvant therapy with high-dose IFN-α after resection of high-risk cutaneous melanoma remains controversial.

Antibodies are products of B cells produced as a result of exposure to specific stimulating agents or antigens. Technological advances, including development of hybridoma methodologies, have allowed production of large quantities of pure antibodies specific for individual epitopes. These can be used as an informer, identifying malignant cells as targets for attack by antibody-dependent cell-mediated cytotoxicity (ADCC). Bi-specific antibodies simultaneously and specifically target a tumor cell antigen and “trigger” molecules on neighboring effector cells, inducing cytotoxicity. Antibodies have been constructed to target and then block selected growth factor receptors and affect cellular growth. Cetuximab is an example of an antibody directed against the epidermal growth factor receptor (EGFR). Antibodies may also be used as the missile of biological “smart bombs” carrying a radiopharmaceutical or biologic toxin warhead to a specific target.

Rituximab is a chimeric immunoglobulin G1-κ monoclonal antibody raised against the CD20 antigen, constructed with a murine light and heavy-chain variable region and a human constant region sequence. CD20 is a transmembrane protein expressed by most B cells at various stages of development and by malignant B lymphocytes. It is found on more than 90% of B cell non-Hodgkin’s lymphomas, but importantly, is not expressed by hematopoietic stem cells or other normal tissues. Rituximab binds to B lymphocytes after intravenous (IV) administration; therefore serum concentrations vary inversely with tumor burden. Complement-dependent cytotoxicity and ADCC are both mechanisms through which this agent may cause target cell lysis. Rituximab is used in the treatment of indolent low-grade non-Hodgkin’s lymphoma, where it may be used as monotherapy, and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy as treatment for CD20-positive diffuse large B-cell non-Hodgkin’s lymphoma. Rituximab is a component of a combination regimen using ibritumomab tiuxetan and is being evaluated in the treatment of chronic lymphocytic leukemia, thrombocytopenic purpura, and Waldenström’s macroglobulinemia.

I131-tositumomab is composed of the monoclonal murine anti-CD20 antibody tositumomab linked to I131, which is both a β and γ emitter. This drug may induce apoptosis, incite complement-dependent cytotoxicity or ADCC, and can cause cell death from radiation. Before administration, thyroprotection is provided with potassium iodide, and then unlabeled tositumomab is administered to saturate non-tumor sites. A test dose of I131-tositumomab is given to calculate the appropriate therapeutic dose based on the rate of clearance, terminal t1/2, and volume of distribution. In patients with a high tumor burden, splenomegaly, or bone marrow involvement, clearance is faster, and the volume of distribution is larger. I131 is excreted in the urine. This drug is not appropriate as initial therapy, because resultant cytopenias may eliminate other potential effective therapies. However, tositumomab is efficacious when administered as a single-course treatment in patients with relapsed, CD20-positive, follicular non-Hodgkin’s lymphoma, with or without transformation, who are refractory to rituximab. Radiotherapeutic dosimetry must be appropriately pursued or profound, and durable toxicity may result.

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