Hormonal Agents

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

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 t_1/2, 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.

Y⁹⁰-Ibritumomab tiuxetan is composed of ibritumomab, a murine anti-CD20 monoclonal antibody related to rituximab, linked to a moiety, tiuxetan, designed to chelate a radioisotope. Indium-111 is attached to the complex, creating an agent that can be used for imaging. If yttrium-90 is attached, an agent is created that can be used therapeutically. An initial rituximab infusion is given to clear peripheral B cells before treatment to permit more effective targeting, because Y⁹⁰-ibritumomab tiuxetan is cleared from plasma mainly by cellular or tumor binding with minimal urinary and no fecal excretion. Although there is no correlation between the pharmacokinetics of Y⁹⁰-ibritumomab tiuxetan and severity of hematologic toxicity, the extent of baseline bone marrow involvement and level of the platelet count accurately predict hematotoxicity and indicate necessary dose adjustments when taken into account with weight. This agent is used for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma, including patients with rituximab refractory follicular non-Hodgkin’s lymphoma. Further study, however, is needed to establish the role of this agent in various therapeutic regimens and to clarify its effectiveness relative to that of tositumomab.

Gemtuzumab ozogamicin is a recombinant humanized monoclonal antibody against CD33 designed to deliver calicheamicin, a chemotherapeutic agent, to the myeloid cell surface, where the chemotherapeutic agent can be internalized by the cell and cause cytotoxicity. Treatment with gemtuzumab ozogamicin is indicated for patients who are 60 years of age or older with no other alternatives for therapy who suffer from CD33-positive acute myeloid leukemia in first relapse.

Growth Factor Receptors: Anti-EGFR Therapy

The EGFR is present on a variety of solid tumors including non-small-cell lung cancer, head and neck cancer, and malignant gliomas. EGFR expression correlates with poor clinical outcome and resistance to cytotoxic agents. The EGFR consists of an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and an intracellular domain with tyrosine kinase activity. Upon stimulation by ligand, the EGFR dimerizes, which initiates an intracellular pro-survival signaling cascade, resulting in increased cell proliferation, metastasis, and decreased apoptosis (Fig. 55-1). The EGFR pathway can be inhibited by either blocking the extracellular domain with monoclonal antibodies or by small molecule tyrosine kinase inhibitors that block adenosine triphosphate (ATP)-binding and inhibit kinase activity.

FIGURE 55–1 The EGFR family is a group of structurally similar growth factor receptors with tyrosine kinase activity (K); these receptors play a critical role in regulating cell cycle progression and metastasis. Upon stimulation by ligands including EGF, transforming growth factor, and mitogenic signals, the receptor (R) dimerizes and the intracellular tyrosine kinase is activated, which transmits the pro-growth signal to the effector molecules as shown. The EGFR pathway can be inhibited either immunologically with the monoclonal antibody cetuximab or pharmacologically by inhibiting the tyrosine kinase ATP-binding site as shown with gefitinib. Overexpression of EGFR is frequent in non-small-cell lung cancers and in head and neck cancers.

Trastuzumab is a recombinant deoxyribonucleic acid-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human EGFR2 protein HER2. The HER2 (or C-ERBB2) protooncogene encodes a transmembrane receptor protein structurally related to the EGFR. Trastuzumab inhibits the proliferation of human tumor cells that overexpress HER2 and is approved for treatment of patients with metastatic breast cancer. As a single agent, it is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for metastatic disease. It is also indicated for administration in combination with paclitaxel for treatment of patients with metastatic breast cancer who are chemotherapy naive and whose tumors overexpress the HER2 protein. Cetuximab is the first monoclonal antibody directed against the EGFR to be approved for treatment of colorectal cancer, either alone or in combination with irinotecan. Cetuximab is a genetically engineered version of a mouse antibody that contains both human and mouse components targeting EGFRs.

Gefitinib, an orally available small-molecule tyrosine kinase inhibitor, was approved as third-line treatment for non-small-cell lung cancer. This was based on a 10% objective response rate and an improvement in quality of life. Several other small-molecule tyrosine kinase inhibitors and monoclonal antibodies directed against the EGFR are in late-stage clinical trials.

Vaccines

Vaccines for the prevention and treatment of cancer have been studied for many years, but advances in this area have been slow to develop. For the most part, vaccines are still primarily experimental treatments. The one notable exception is the approval of a recombinant quadrivalent human papillomavirus (HPV)-like particle vaccine to prevent diseases related to HPV types 6, 11, 16, and 18, including precancerous cervical lesions, cervical cancer, vaginal or vulvar lesions, and genital warts. HPV is sexually transmitted, but initial infections typically go undetected. However, the presence of the virus can lead to abnormalities in the cervical epithelium that may progress to cancer. The most appropriate use of this vaccine is to administer it to young girls before sexual activity; however, girls and women who are sexually active should also be vaccinated. The United States Advisory Committee on Immunization Practice recommends vaccination in all girls and women between 11 and 26 years of age.

Inhibitors of Intracellular Signaling