CHAPTER 13
Cancer
Recent Developments
Biologic therapies continue to play a major role in the treatment of cancer. Advances in stem cell biology may alter therapeutic strategies for cancer.
Genetic profiling of tumors and patients can contribute significantly to treatment and identify patients at risk for cancer.
More precise molecular targets for cancer increase the effectiveness and reduce the toxicity of systemic therapies.
Introduction
Cancer is the second-leading cause of death in the United States, with approximately 23% of all US deaths due to cancer. In 2014, 1.6 million new cases were diagnosed in the United States, and some 580,000 deaths occurred. Currently, more than 13 million Americans have a history of cancer, and cancer will develop in 1 in 4 Americans during their lifetime. Worldwide, in 2012, there were 14 million new cases and 8.2 million deaths due to cancer. Developing countries are disproportionately affected, with 60% of all cases and 70% of all deaths due to cancer.
Cancer is actually many different diseases; questions of etiology, cancer prevention, and cancer cure must therefore address the specific types of tumors. Nonmelanotic skin cancers are the most common tumors, but these cancers are rarely a cause of death. After skin cancer, the most common forms of cancer in adult Americans (in decreasing order of incidence) are lung, breast, prostate, and colorectal. Approximately 80% of adult cancers arise from the epithelial tissues.
Cancer is the leading cause of death by disease in children younger than 15 years in the United States. Nevertheless, death rates have dropped and survival rates have risen sharply. The 5-year survival rate for all childhood cancers combined has improved in the United States, from approximately 51% in 1973 to over 90% today.
Etiology
Cancer is caused by mutations in genes that control cell division. Some of these genes, called oncogenes, stimulate cell division; others, called tumor suppressor genes, slow this process. In the normal state, both types of genes work together, enabling the body to replace dead cells and repair damaged ones. Mutations in these genes cause cells to proliferate out of control. Such mutations can be inherited or acquired through environmental insults. Cancer causes, therefore, are explained on the basis of chemical, radiation-related, or viral conditions that occur in a complex milieu, including host genetic composition and immunobiologic status.
Epidemiologic data suggest that as much as 80% of human cancer may be due to exogenous chemical exposure. If these chemicals could be properly identified, a major proportion of human
cancers could be prevented by reducing host exposure or by protecting the host. Science is looking at a number of issues that need to be resolved before causation is established.
Cancer arises from genetic mutations that cause a cell to grow and divide without regard for cell death. The cell cycle is regulated biochemically, with 2 important groups of enzymes involved in this process, cyclin-dependent kinases (CDKs) and cyclin-dependent phosphatases. An example of CDK function involves the p53 tumor suppressor gene, which upregulates the p21 inhibitor of CDK function.
The general population is exposed to both naturally occurring ionizing radiation and man-made ionizing radiation. Man-made sources deliver an average of 106 millirems per year to each person. These sources include medical diagnostic equipment and technologically altered natural sources (such as phosphate fertilizers and building materials containing small amounts of radioactivity). The carcinogenic effects of radiation exposure result from molecular lesions caused by random interactions of radiation with atoms and molecules. Most molecular lesions induced in this way are of little consequence to the affected cell. However, DNA is not repaired with 100% efficiency, and mutations and chromosomal aberrations accrue with increasing radiation doses. Parameters that influence the response of the target tissue include the total radiation dose, the dose rate, the quality of the radiation source, the characteristics of certain internal emitters (such as radioiodine), and individual host factors.
The role of viruses in the etiology of cancer has been studied extensively. For example, researchers have inoculated laboratory animals with specific viruses to see whether tumor development is induced. Several human cancers show a definite correlation with viral infection and the presence and retention of specific virus nucleic acid sequences and virus proteins in the tumor cells (Burkitt lymphoma, nasopharyngeal carcinoma, carcinoma of the cervix, and hepatocellular carcinoma).
All of the DNA virus groups except the parvovirus family have been associated with cancer. This is notable because all the DNA viruses associated with cancer contain double-stranded DNA, whereas the parvoviruses contain only single-stranded DNA. There are 9 RNA virus groups, but only 1, the retrovirus group, is associated with oncogenicity. The papillomavirus of the papovavirus group has been associated with squamous cell carcinoma, cervical cancer, and laryngeal papilloma in humans. A vaccine against human papillomavirus (HPV) is now available. Immunization against HPV may prevent most cases of cervical cancer in women; see Chapter 12 for additional discussion. Infection with the hepatitis B virus has been associated with primary hepatocellular carcinoma in humans.
The Epstein-Barr virus, also known as human herpesvirus 4, causes infectious mononucleosis and has been associated with Burkitt lymphoma and nasopharyngeal carcinoma. Herpes simplex virus type 1, which causes gingivostomatitis, encephalitis, keratoconjunctivitis, neuralgia, and labialis, has been associated with carcinoma of the lip and oropharynx. Herpes simplex virus type 2, which causes genital herpes, disseminated neonatal herpes, encephalitis, and neuralgia, has been associated with cancer of the uterine cervix, vulva, kidneys, and nasopharynx. The cytomegalovirus, which causes cytomegalovirus disease, transfusion mononucleosis, interstitial pneumonia, and congenital defects, has been associated with prostate cancer, Kaposi sarcoma, and carcinoma of the bladder and uterine cervix. The varicella-zoster virus, which causes chickenpox, shingles, and varicella pneumonia, is to date unassociated with any specific human cancers.
Finally, cancers may aggregate in a nonrandom manner in certain families. These cancers may be of the same type or dissimilar. Such cancer-cluster families may have several children with soft tissue sarcoma and relatives with a variety of cancers, especially of the breast in young women. Multiple endocrine neoplasia types 1 and 2 are yet other examples of hereditary cancer syndromes. The recognition of familial cancer syndromes permits early detection that may be life-saving.
Radiation Therapy
For many patients with cancer, radiation therapy, which uses ionizing radiation to kill cancer cells and shrink tumors, is part of the treatment plan. Ionizing radiation interacts with tissues by an energy transfer and a chemical reaction, with the release of free radicals and the decomposition of water into hydrogen, hydroxyl, and perhydroxyl ionic forms. These ionic forms probably react with DNA and RNA in vital enzymes, producing biologic injury. The injuries noted to date include mitotic-linked death and chromosomal aberrations such as breakage, sticking, and cross-bridging. Consequent cell death occurs in both normal tissue and malignant lesions. In radiotherapy, biochemical recovery and biologic repair occur in the normal host, maintaining the integrity of vital systems.
The poorly differentiated lymphoid cells, intestinal epithelium, and reproductive cells are more readily damaged and recover more quickly than the highly differentiated cells of the body. Lymphocytes are damaged by 1 gray (Gy) of radiation and central nervous system tissue by 50 Gy. Surface irradiation of approximately 10 Gy produces skin erythema. The most serious damage is the late development of postradiation malignant changes, manifesting as squamous cell carcinoma and basal cell carcinoma. Radiation absorption in bone can produce osteogenic sarcomas and fibrosarcomas as well.
Radiation can be delivered through external beam radiotherapy (EBRT; most common) or internal placement (brachytherapy); radiation can also be administered systemically (eg, radioactive substance bound to a monoclonal antibody). In EBRT, high-energy X-ray beams generated either by linear accelerators, which produce photons or electrons, or by cobalt machines, which use radioactive decay of an element such as cobalt 60, are aimed at the tumor site. Planning for EBRT involves not only localizing the tumor, but also determining the proper dose, one that will kill the malignant cells while minimizing damage to the surrounding noncancerous tissue. There are many other methods of EBRT, including particle therapy and stereotactic radiosurgery.
In brachytherapy (also called internal radiation therapy), radioactive material is implanted within or adjacent to the tumor, delivering radiation while minimizing damage to the surrounding normal tissue. The term brachytherapy refers to various types of procedures, one example of which is seed implantation, used in the treatment of prostate cancer and some uveal melanomas.
For some conditions, monoclonal antibodies are available as a vector to deliver radiation directly to the target tissue; these antibodies are discussed later in this chapter.
Guerrero Urbano MT, Nutting CM. Clinical use of intensity-modulated radiotherapy: part I. Br J Radiol. 2004;77(914):88–96.
Ophthalmic considerations Ocular manifestations of fetal irradiation in the first trimester include microphthalmos, congenital cataracts, and retinal dysplasia. A 0.5-Gy dose of radiation may cause congenital anomalies in a fetus. Fetal exposure to approximately 0.30–0.80 Gy doubles the incidence of congenital defects; 5 Gy (the median lethal dose [LD50] for a human
fetus) generally induces an abortion.
The ocular effects of irradiation depend not only on total dose, fractionation, and treatment portal size but also on associated systemic diseases such as diabetes mellitus and hypertension. Concomitant chemotherapy has an additive effect.
The lens is the most radiosensitive structure in the eye, followed by the cornea, the retina, and the optic nerve. The orbit is completely included in the treatment portal in diseases such as large retinoblastomas; it is partially included in tumors of adjacent structures, such as the maxillary antrum, nasopharynx, ethmoid sinus, and nasal cavity. Usual doses range from 20 to 100 Gy. The total dose is usually fractionated during the treatment. In brachytherapy, a low-energy isotope such as radioactive iodine delivers a high dose of radiation within a few millimeters of the tumor but does not penetrate deep into it. This allows for radioactive episcleral implants to deliver a dose of 100 Gy to the apex of a tumor but much less to the rest of the eye. The sclera can tolerate doses up to 400–800 Gy.
Doses to the lens as low as 2 Gy in 1 fraction may cause cataract formation. However, cataracts caused by low doses may be asymptomatic and may not progress. Cataracts due to higher doses (7–8 Gy) may continue to progress, resulting in considerable vision loss. The average latent period for the development of radiation-induced cataracts is 2–3 years.
The clinical picture of radiation retinopathy resembles that of diabetic retinopathy. Development of radiation retinopathy is very rare with a fractionated dose of less than 50 Gy over 5–6 weeks. At higher fractionated doses (70–80 Gy), however, radiation retinopathy develops in most patients. The usual interval between radiation therapy and the development of radiation-induced retinopathy is 2–3 years. Radiation retinopathy may develop earlier in patients with diabetes or those undergoing chemotherapy. The earliest clinical manifestation of radiation retinopathy is usually cotton-wool spots. After several months, these spots fade away, leaving areas of capillary nonperfusion. Telangiectatic vessels grow from the retina into these areas. Microaneurysms may also develop. These ischemic changes may cause rubeosis iridis, which in turn may lead to neovascular glaucoma. The capillary endothelial cell is the first type of cell to be damaged, followed closely by the pericytes and then the endothelial cells of the larger vessels. The new intraretinal telangiectatic vessels have thick collagenous walls. There may be spotty occlusion of the choriocapillaris.
Doses to the optic nerve in the range of 60–70 Gy cause some injury in a small number of patients. Damage to the optic nerve is called radiation optic neuropathy. Clinically, these patients have disc pallor with splinter hemorrhages. Injury to the more proximal part of the optic nerve resembles retrobulbar optic neuropathy. Affected patients may report unilateral headaches and ocular pain; the disc may not reveal edema or hemorrhage. With doses of 60–70 Gy, a dry eye syndrome sometimes develops. This syndrome usually develops within a year and occasionally progresses to corneal ulceration and severe pain.
Chemotherapy
The goal of cancer chemotherapy is to damage or destroy cancer cells without killing normal cells. The first candidate drugs to selectively target rapidly dividing cells were sulfur and nitrogen mustards that were noted to suppress bone marrow when used in warfare. These compounds bound
covalently to DNA, and therefore DNA was the first molecular target of chemotherapy. In the 1950s, attention was directed to the precursors of DNA, and drugs such as methotrexate were found effective. The recognition that some tumors were hormonally dependent led to hormonal therapy or suppression as a treatment for cancer. Since the 1970s, many drugs have been developed that inhibit mitotic spindle formation.
Natural Products
Natural products, either naturally occurring or synthetically modified, have played a significant role in cancer chemotherapy and include a variety of agents, the most common of which are vinca alkaloids, podophyllin derivatives, paclitaxel, antitumor antibiotics, and related drugs (Table 13-1). Vinca alkaloids are derived from the periwinkle plant; they include vincristine, vinblastine, and several investigational agents. These agents block incorporation of orotic acid and thymidine into DNA and cause arrest and inhibition of mitosis.
Table 13-1
Podophyllin derivatives and semisynthetic plant derivatives arrest cells in the G2 phase. Etoposide and teniposide are gaining acceptance in many treatment protocols.
Paclitaxel is a compound originally isolated from the bark of the Pacific yew tree. It was approved by the US Food and Drug Administration (FDA) to treat breast, ovarian, and lung cancers as well as AIDS-related Kaposi sarcoma. Paclitaxel stops microtubules from breaking down. In normal cell growth, microtubules are formed when a cell starts dividing. Once the cell stops dividing, the microtubules are broken down or destroyed. With paclitaxel, cancer cells become clogged with microtubules and cannot grow and divide.
Antitumor antibiotics are compounds produced by species of Streptomyces in culture. These agents interfere with the synthesis of nucleic acid. They include
anthracyclines (doxorubicin and derivatives), which interfere with template function of DNA bleomycin, which causes DNA-strand scission
actinomycin D (dactinomycin), which inhibits DNA-directed RNA synthesis mitomycin, which impairs replication by causing cross-linking between DNA strands
A unique adverse effect of anthracyclines is cardiac muscle degeneration that leads to cardiomyopathy. The major dose-limiting toxicity of mitomycin is myelosuppression. Mitomycin has also been implicated as a cause of the hemolytic uremic syndrome.
Angiogenesis Inhibitors
Angiogenesis is important to the growth and spread of cancers, as new blood vessels are critical to the formation of tumors. In animal studies, angiogenesis inhibitors have successfully stopped the formation of new blood vessels, causing tumors to shrink and die. Various angiogenesis inhibitors have been evaluated in human clinical trials. These studies include patients with cancers of the breast, prostate, brain, pancreas, lung, stomach, ovary, and cervix; patients with certain leukemias and lymphomas; and those with AIDS-related Kaposi sarcoma.
Antibodies against vascular endothelial growth factor (VEGF), which promotes vascular proliferation, have proven effective in cancer therapy. Bevacizumab, a humanized monoclonal antibody directed against VEGF-A, was the first angiogenesis inhibitor approved for the treatment of cancer in the United States. It has demonstrated clinical efficacy in the treatment of colorectal and other solid tumors and, on an off-label basis, in the treatment of neovascular (“wet”) age-related macular degeneration (AMD). Bevacizumab is also effective in the treatment of optic nerve gliomas in children. Tyrosine kinase inhibitors (TKIs), including pazopanib, have also shown promising antitumor activity. Aflibercept is a recombinant fusion protein that functions as a decoy receptor for VEGF. This agent inactivates VEGF-A, VEGF-B, and placental growth factor and is effective in the treatment of colorectal cancer and wet AMD.
Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab. JAMA Ophthalmol. 2014;132(1):111–114.
Biologic Therapies
Biologic therapies (sometimes called immunotherapy, biotherapy, or biologic response modifier therapy) use the immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments. Further, cancer may develop when the immune system breaks down or is not functioning adequately. Biologic therapies are designed to repair, stimulate, or enhance the immune system’s responses.
Cells in the immune system secrete 2 types of proteins: antibodies and cytokines. Cytokines are nonantibody proteins produced by some immune system cells to communicate with other cells. Types of cytokines include lymphokines, interferons, interleukins, and colony-stimulating factors. Some antibodies and cytokines, called biologic response modifiers, can be used in the treatment of cancer. Other biologic response modifiers include monoclonal antibodies, which can also be used to treat cancer, and vaccines.
Interleukins occur naturally in the body and can be made in the laboratory. Many interleukins have been identified; interleukin-2 has been the most widely studied in cancer treatment. Interleukin-2 stimulates the growth and activity of many immune cells, such as lymphocytes, that can destroy cancer cells. The FDA has approved interleukin-2 for the treatment of metastatic kidney cancer and metastatic melanoma.
Colony-stimulating factors (sometimes called hematopoietic growth factors) usually do not directly affect tumor cells but instead stimulate bone marrow production. Colony-stimulating factors allow doses of anticancer drugs to be increased without increasing the risk of infection or need for transfusion.
Monoclonal antibodies (mAbs) are produced by a single type of cell and are specific for a particular antigen. Researchers continue to examine ways to create mAbs that are specific for the antigens found on the surface of cancer cells being treated. Some examples of mAbs currently used in cancer treatment are rituximab and trastuzumab.
Therapeutic mAbs are made by injecting human cancer cells into mice, which stimulates an antibody response. The cells producing antibodies are then removed and fused with laboratory-grown cells to create hybrid cells called hybridomas. Hybridomas can produce large quantities of these mAbs indefinitely.
Monoclonal antibodies have many potential uses in cancer treatment, such as linking them to anticancer drugs, radioisotopes, other biologic response modifiers, or other toxins. When the antibodies attach to cancer cells, they can deliver these poisons directly to the cells. For example, ado-trastuzumab emtansine uses trastuzumab to deliver a cytotoxic microtubule inhibitor. Another example is tositumomab radioconjugate, which delivers specifically targeted radiotherapy to tumors. Monoclonal antibodies carrying radioisotopes may also prove useful in diagnosing certain cancers, such as colorectal, ovarian, and prostate cancer.
Cancer vaccines are being developed to help the immune system recognize cancer cells. These vaccines are designed to be injected after the disease is diagnosed rather than before it develops. They may help the body reject tumors and prevent cancer from recurring. Vaccines are being studied in the treatment of melanomas, lymphomas, and cancers of the kidney, breast, ovaries, prostate, colon, and rectum.
Other biologic approaches to cancer therapy include genetic profiling of certain tumors. Current management of lung cancer and melanoma is based on such profiling. Further, genetic profiling may prove more helpful and effective than classifying tumors by their organ of origin. An example of this is the differentiation between those tumors with a normal and those with an abnormal tumor suppressor gene p53. Tumor cells with normal p53 genes are far more sensitive to chemotherapy than those with mutant p53.
Vose JM, Wahl RL, Saleh M, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol. 2000;18(6):1316–1323.
Ophthalmic considerations The eye and its adnexa are frequently involved in systemic malignancies as well as in extraocular malignancies that extend into ocular structures (including local malignancies of skin, bone, and sinuses). Breast and lung cancers frequently metastasize to the eye and are the most common intraocular tumors in adults. Acute myelogenous and lymphocytic leukemias often have uveal and posterior choroidal infiltrates as part of their generalized disease. In children, these manifestations are often signs of central nervous system involvement and suggest a poor prognosis. Although malignant lymphomas do not usually involve the uveal tract, histiocytic lymphoma is one type that often involves the vitreous and presents as uveitis. The retina and choroid may also be involved.
Tumors of the eye and adnexa are discussed in several other BCSC volumes, including Section 4, Ophthalmic Pathology and Intraocular Tumors; Section 6, Pediatric Ophthalmology and Strabismus; Section 7, Orbit, Eyelids, and Lacrimal System; and Section 8, External Disease and Cornea.
American Cancer Society website; www.cancer.org.
European Society for Medical Oncology website; www.esmo.org. UpToDate; www.uptodate.com.