Biomedicine and Health: Cancer and Oncology

Introduction

Cancer refers to uncontrolled cell growth (or proliferation), little or no cellular differentiation, invasion of tissue around the point of origin, and migration to other parts of the body (metastasis).

Cancer is not one specific disease, but a class of diseases that can develop anywhere in the body at any age. In the twenty-first century, most cancers are potentially curable at an early stage when discovered through routine self-examination or diagnostic screening. Nevertheless, cancer remains the United States's second-most common cause of death, after cardiovascular disease.

Historical Background and Scientific Foundations

People justifiably dread receiving a cancer diagnosis; in the past it was often tantamount to a death sentence. This view has gradually shifted as health care practitioners have acquired early detection and secondary prevention (prevention of recurrence after initial treatment) techniques and effective treatments.

Anyone can develop cancer, but the risk increases with age; the majority of cancer victims are middle-aged and older, with 77% of all cancers diagnosed in persons 55 and older. American men have a 50% lifetime risk of developing some kind of cancer, while women have a little higher than one chance in three. Certain factors strongly affect the risk of developing specific types of cancer: Male smokers, for example, are about 23 times more likely to develop cancer than nonsmokers, while women who have a first-degree relative (mother, sister, or daughter) with a history of breast cancer have about twice the risk of developing breast cancer compared to women without a family history.

The American Cancer Society (ACS) estimates that 168,000 cancer deaths annually are attributable to tobacco use, while another 200,000 deaths are linked to obesity, physical inactivity, and poor nutrition, all of which can be prevented. Many more deaths could be prevented through screening and early detection.

Early History of Cancer Treatment

Cancer or tumors have always afflicted humans and animals. Physicians in ancient societies wrote about cancer, and evidence of cancer has been found in fossilized bone tumors and ancient Egyptian mummies. The oldest description of cancer is found in the Edwin Smith papyrus, an Egyptian medical manuscript that dates from around 1600 BC, which describes cases of breast tumors that were cauterized with a tool called “the fire drill.” However, this treatment was evidently unsuccessful, since the writing said that the disease was untreatable.

The word “cancer” is attributed to the Greek physician Hippocrates of Cos (460–375 BC), who used the terms karkinos and karkinoma to describe cancer. Both are based on the Greek word for “crab,” because of the blood vessels that projected like arms from the central tumor.

Starting in the fifteenth century, Italian scientists began to apply the scientific method to treating disease. Giovanni Morgagni (1682–1771) performed the first autopsies in 1761 that linked illness to pathologic findings. When some autopsies revealed extensive tumors, his investigations set the foundation for scientific oncology, the study of cancer.

Scottish surgeon John Hunter (1728–1793) discovered that some cancers were operable. If the tumor were solid, he wrote, and did not appear to have invaded adjacent tissue and was “moveable,” it could be removed surgically. Within 100 years, with the development of anesthesia, surgical procedures such as radical mastectomy had been developed to treat cancer.

In the nineteenth century Rudolf Virchow (1821–1902), the founder of cellular pathology, correlated microscopic pathology findings to the course of various diseases, including cancer. In studying the pathology of cancer cells, he discovered the tissue and organ damage that cancer causes and helped improve the effectiveness of cancer surgery. By examining tissues from the patient's body before and after surgery, doctors could use Virchow's findings to make better diagnoses, or determine whether the tumor has been completely removed.

Cancer Causation

Since cancer was first recognized as a disease, physicians have wondered about its causes. The Egyptians believed that it was a punishment meted out by the gods. Hippocrates, who developed the theory of the four humors—blood, phlegm, yellow bile, and black bile—believed that cancer was caused by an excess of black bile in various parts of the body. This theory, accepted by Galen of Pergamum (AD c.129–c.216) and the Romans, became medical dogma during the Middle Ages. Although autopsies might have proven this false, such procedures were forbidden for religious reasons.

In the seventeenth century, humoral theory was replaced by the theory that cancer was composed of degenerating lymph. John Hunter believed that tumors develop from lymph constantly excreted by the blood. In 1838, however, pathologist Johannes Müller (1801–1858) demonstrated that cancer is comprised of cells rather than lymph. Müller believed that cancer cells arose from budding entities (blastema) that grew between normal tissues. Finally Virchow determined that cancer cells, like normal tissue, originate from other cells. He also suggested that chronic irritation caused cancer, a theory that has recently regained adherents, who point to chronic inflammation as carcinogenic (i.e., cancer causing). Somewhat later, the surgeon Karl Thiersch (1822–1895) showed that cancer can metastasize as malignant cells that break off from the primary tumor spread through circulating blood and lymph.

Over the centuries, various causes of cancer were discovered and scientifically documented. Nasal cancer was first identified as a result of snuff (smokeless tobacco) use by the English botanist John Hill (1714–1775), who cautioned that “No man should venture upon snuff who is not sure that he is not liable to cancer, and no man can be sure of that.” In 1911 American pathologist and future Nobel laureate Peyton Rous (1879–1970) described a sarcoma in chickens that was caused by a virus. In 1915 cancer was induced by applying coal tar to rabbit skin. Today many substances are known to be carcinogens, including coal tar, benzene, certain hydrocarbons, and asbestos. Radiation from the sun and radioactive sources can also cause cancer. Several viruses have been implicated in causing cancer, including Epstein-Barr (the cause of mononucleosis, known to cause non-Hodgkin's lymphoma), human immunodeficiency virus (HIV, known as a factor in Kaposi's sarcoma and non-Hodgkin's lymphoma), human papilloma virus (HPV, the cause of cancers of the cervix, vulva, and penis) and hepatitis B (liver cancer).

Modes of Cancer Treatment

Contemporary methods of cancer treatment, including surgery, radiation, and chemotherapy, have relatively deep historical roots; many of the techniques used today began to take shape in the nineteenth century.

Surgical Oncology

Even in ancient times physicians and surgeons realized that cancer usually returned after it was surgically removed. The Roman physician Aulus Cornelius Celsus (fl. 1st century AD) observed that cancer returned after excision. For this reason Galen and other physicians considered cancer incurable. This pessimistic view has persisted somewhat into the twenty-first century, increasing patients' fear of the diagnosis; it even dissuades some from consulting a doctor until the cancer has progressed beyond a curable stage.

Although ancient doctors recognized that there was no effective treatment once a cancer had spread, Galen did describe some surgical cures for breast cancer if the tumor could be excised early in tumor development. Not until the nineteenth century, however, with the advent of anesthesia and sterile techniques did surgical cancer treatment, now called surgical oncology, begin to make great strides. Surgeons in Germany, England, and the United States began to perform operations that attempted to remove the entire tumor, along with the lymph nodes near the tumor's location.

Working from the theory that cancer invades the body from a central point, British surgeons W. Sampson Handley (1872–1962) and William Stewart Halsted (1852–1922) developed the surgical technique of radical mastectomy (complete removal of the breast) for breast cancer in the 1890s. Halsted believed that complete excision of the primary tumor would cure the cancer; any recurrences, he believed, were new primary tumors. A century later, clinical trials established that in many cases, removal of the primary tumor only (lumpectomy) often followed by radiation therapy and chemotherapy, is often as effective as radical mastectomy, with less disruption to the patient and a shorter recovery time.

In contrast to his mentor Halstead, Stephen Paget (1855–1926) believed that one cancerous tumor could spread its cells through the bloodstream, but meta-static (secondary) tumors would only develop in certain organs. Paget suggested that circulating cancer cells required tissue that was somehow physiologically compatible to take root and grow. This hypothesis has been confirmed by modern cellular and molecular biology and became a key to recognizing the limitations of cancer surgery. It helped doctors develop systemic treatments such as chemotherapy to destroy cells that had spread throughout the body. It also paved the way to less invasive surgical techniques

Hormone Therapy

In the late nineteenth century the scientist Thomas Beatson (1848–1933) investigated the relationship of the ovaries to milk production in the breasts. He discovered that rabbits stopped milk production after the ovaries were removed. Because the breast was controlled by the ovaries in this way, Beatson tested the removal of the ovaries in advanced breast cancer cases and found that the procedure often helped the patient improve. He thus discovered the stimulating effect of estrogen on breast cancer, even though that hormone had not yet been identified. This research laid the foundation for modern hormone therapy, such as tamoxifen and aromatase inhibitors for treating and preventing breast cancer. Fifty years later urologist Charles Huggins (1901–1997) reported similar findings for men when he observed significant improvement of metastatic prostate cancer after removing the testes.

In recent decades, drugs that block the male hormone testosterone have been found to be effective against prostate cancer, and research is underway to see whether they can also prevent cancer of the prostate much as tamoxifen has been shown to prevent cancer in certain women at especially high risk for breast cancer.

Radiation Treatment

Near the end of the nineteenth century, German physicist Wilhelm Conrad Roentgen (1845–1923) discovered x rays, which he called an “unknown quantity.” After he demonstrated their ability to pass through solid objects and leave an impression on film, systems were developed to use x rays for disease diagnosis, and within several years of Roentgen's discovery, radiation had been harnessed to treat cancer. Early therapy used radium with relatively low-dose x-ray machines. Doctors soon discovered that daily radiation doses over several weeks dramatically improved therapeutic response. Current radiation treatment is so precise that it can destroy tumors with minimal harm to nearby normal tissue.

A few years after the therapeutic value of radiation treatment was discovered, scientists learned, paradoxically, that radiation could also cause cancer. Many early radiologists developed leukemia because they used the skin of their arms to test the radiation emitted from their radiotherapy machines, seeking a dose that would produce a sunburn-like reaction (erythema).

Technological advances led to conformal radiation treatment, which focuses only on the tissue that the cancer has invaded and avoids normal tissues as much as possible, increasing the treatment's effectiveness and reducing side effects. A similar technique uses proton beams, which scatter less radiation and produce less damage to adjacent normal tissues while destroying the cells to which they are targeted. Other radiotherapy techniques use linear particle accelerators to treat brain and inoperable cancers.

Current therapy for abdominal or pelvic cancers and those that tend to recur include intraoperative radiation therapy (IORT), which delivers radiation directly to the tumor site and adjacent tissues while the patient is still on the operating table. Normal tissue is moved aside and shielded, allowing more radiation to be targeted directly to the tumor.

Chemotherapy

While the basis for modern surgical and radiation treatment for cancer was already in place by the late

nineteenth century, the development of effective chemotherapeutic agents came much later. During the U.S. Army's World War II research into defenses against chemical warfare, particularly mustard gas, the nitrogen mustard drug mustine was found to be effective against lymphoma. This became first in a series of similar and increasingly effective alkylating agents that kill quickly dividing cancer cells (as well as other normal rapidly reproducing cells such as those found in hair follicles and mucous membranes) by disrupting their DNA during cell division.

Soon after the nitrogen mustard discovery, Boston pediatric pathologist Sidney Farber (1903–1973) showed that aminopterin, a chemical relative of folic acid (vitamin B₆), sent acute childhood leukemia into remission by blocking a key chemical reaction needed for DNA replication. Aminopterin was later replaced by the related drug methotrexate, as well as other drugs that interfered with various cellular growth and replication functions. Methotrexate was used in the first cure of a metastatic tumor (choriocarcinoma) in 1956.

Since then chemotherapy drugs have successfully treated many cancers, even after metastasis, including acute childhood leukemia, testicular cancer, and Hodgkin's lymphoma; they can also help control the spread of many other cancers for years or even decades. Research is underway to reduce chemotherapy's adverse side effects, which often include hair loss, nausea and vomiting, and immunosuppression, which makes patients vulnerable to infections. Efforts include 1.) less toxic agents and combinations of agents, 2.) new drug delivery methods, 3.) more specific targeting of cancer cells (e.g., monoclonal antibodies and liposomal therapy), 4.) colony stimulating factors G-CSF and GM-CSF to reduce the suppression of the immune system, and 5.) agents that overcome tumors' resistance to multiple drugs.

Liposomal therapy uses chemotherapy drugs enclosed within liposomes (synthetic fat globules). The fatty envelope helps them get inside the cancer cells more effectively and reduces drug side effects. Monoclonal antibodies target chemotherapy drugs exclusively to the tumor. They bind to tumor cell surface proteins (antigens) and destroy them by injecting chemotherapy drugs, radioisotopes, and other means.

Over the centuries, cancer treatment has progressed using a trio of methods against tumors, sardonically called “cut, burn, and poison.” Early treatments could only cure cancers that were small and accessible enough to be removed completely. Later, radiation was used to control tumors that surgery could not remove. Finally, chemotherapy was used to wipe out growths that had spread to distant parts of the body. This kind of chemotherapy, called adjuvant therapy, was first used effectively against breast cancer and later in colon and testicular cancers. Much contemporary chemotherapy combines several treatments, because clinical trials have shown that fast-growing cancers respond well to drug combinations that attack the tumor using a variety of biological modes. Clinical trials that compare new treatments to standard regimens have improved the effectiveness of drug combinations in use, resulting in many cures, and are essential to continued progress.

Biologic Therapy

Expanding knowledge of cancer cell biology has led to the development of biologic therapies that can regulate tumor growth. This treatment, also known as biologic therapy or immunotherapy, has been shown to be effective in clinical trials. Certain biologics that occur naturally can now be produced using recombinant gene technology. The most important of these are interferons, interleukins, and other cytokines (e.g., colony-stimulating factors that enhance the growth of immune cells). Biologics influence a patient's natural immune response by either directly inhibiting cancer cell growth or by stimulating immune cells. An increasingly effective therapy identifies protein targets called antigens on tumor cell surfaces and binds an antibody to these targets. Another type of biologic therapy, monoclonal

antibodies, help the immune system attack cancer cells and interrupt cellular communications that permit new growths. Vaccines designed to boost immune response to cancer cells are also being explored.

The Genetic Basis of Cancer

Cancer is now known to be the result of a series of mutations (changes or mistakes in genes) in somatic cells. As discussed above, scientists discovered in the nineteenth and twentieth centuries that cancer can be caused by chemicals, radiation, and viruses. It was also apparent that some cancers could run in families. Scientists have learned that DNA damaged by chemicals, radiation, or new genetic sequences introduced by viruses often led to carcinogenesis (development of cancer). They are now able to pinpoint specific gene mutations that have caused cancer in particular patients.

Ordinary body cells with damaged DNA die, but cancer cells with damaged DNA do not, and it is their unchecked replication that spreads cancer at the expense of normal tissue, ultimately resulting in tissue and organ failure. Medical researchers are gradually identifying the genes that, when damaged by chemicals or radiation or when inherited, can result in cancer. The recent discovery of two mutant genes that cause breast cancer in a small number of women, BRCA1 and BRCA2, has raised hopes that science will ultimately discover many of the aberrant genes that give rise to this deadly disease. Inherited cancer genes are estimated to cause only about 15% of all cancers, however. The rest appear to be caused by unfortunate accidents that occur to cells in growing bodies.

Modern Cancer Treatment

A growing arsenal of drugs is now available for cancer detection, diagnosis, and treatment. Because tumors need a blood supply to grow, some new drugs interfere with angiogenesis, the development of new blood vessels that allow tissue growth; these show significant promise in human clinical trials. Other new drugs interfere with the signaling process within tumor cells that causes them to grow, and one such drug, Gleevec (imatinib) has successfully treated a chronic form of leukemia and shows promise in treating other types of cancer.

Genetic therapy has also brought about successful new treatments. Herceptin (Trastuzumab) is a monoclonal antibody used for breast cancer patients who overexpress (i.e., have too many copies of) a gene called Her2/neu. Its success shows that specific mutations can be linked to individual kinds of cancer and,

in some cases, can be turned into highly effective and very precisely targeted treatments. A great deal of current research activity is dedicated to finding antibodies for other target gene mutations in different types of cancers.

Modern Cultural Connections

Knowledge of cancer biology and treatment has grown exponentially in the past decade and continues to accelerate. As the process of scientific discovery moves forward, cancer has been changed from a death sentence to a chronic illness for many patients. Some new treatments have even turned cancer into a potentially curable disease, however complex and difficult the cases. Perhaps the most significant change, brought about by basic biochemical research, is that much of the mystery of this deadly set of diseases is yielding to knowledge that more and more reliably effective interventions will be discovered. While cancer remains a formidable challenge to science and medicine, it is no longer intractable for a growing proportion of patients. This gradual resolution of an age-old struggle will not only transform thinking about these diseases, but more generally about human development and the nature of living organisms.

The discovery of the role of cancer stem cells in the growth and spread of various cancers, including leukemia, breast cancer, and small cell lung cancer, now appears to put medical researchers much closer to a possible cure for cancers of all types. Recent research is contributing toward a new paradigm of knowledge about the origins and growth of cancerous tumors.

Until recently, cancer treatments focused on reducing the size and distribution of tumors. Reducing the size of tumors has often been viewed as an “intermediate endpoint” in clinical research that indicates that a treatment could be promising in extending life. However, such treatment effects have often proved to be temporary and have not significantly extended survival. Even worse, some researchers have found evidence that disruption of the original tumor appears to promote the spread of distant metastases in some cases. On the other hand, de-bulking of the original tumor in prostate cancer, for example, does not confer additional survival benefit.

Some lines of important cancer research are built upon stem cell studies that are, in some segments of society, controversial. Recent advances on leukemia stem cell research, built upon basic research in blood stem cells that began in the 1940s, may have identified the key to the mystery of why eradicating and decimating primary tumors does not seem to halt the progression of deadly cancers. On one study, for example, the origin of leukemia was linked to mutated blood stem cells that generate progeny that are both leukemia stem cells and ordinary leukemia cells. When injected into mice, the leukemia stem cells give rise to cancerous growths, while the ordinary tumor cells had no effect and died off. Even though the huge growth of ordinary tumor cells proliferating throughout vital body organs ultimately kills the patient, these cells would be easy to eliminate were it not for the presence of the leukemia stem cells.

Work has also concentrated on the differences between leukemia stem cells and ordinary leukemia cells to determine what characteristics produce this outcome. Essentially, the stem cells were thought “immortal,” a property that earlier scientists had ascribed to all cancer cells. It turns out that ordinary tumor cells, while they multiply much more rapidly than tumor stem cells, are subject to “apoptosis”—i.e., they die off after a number of replications. Only a small minority of tumor cells are stem cells. Thus the treatments that kill masses of ordinary tumor cells along with some of the tumor stem cells might leave enough of the stem cells alive to give cancer a new lease on life.

If the theories of other cancer researchers that certain primary tumors may send out biochemical signals that partially (but not completely) suppress the establishment of distant metastases are correct, then eradicating the primary tumor might actually accelerate the replication of tumor stem cells that could be dormant in body organs distant from the original tumor site.

Many researchers argue that the key to curative cancer therapy is in being able to target the cancer stem cells, which should exhibit certain proteins on the cell wall. Treatments could then attack the tumor stem cells based on an affinity to the identified proteins and eliminate the relatively small population of stem cells, leaving the ordinary tumor cells to die off naturally. Such treatments could perhaps be far less disruptive to normal patient functioning than present day chemotherapy or biological therapy, because these contemporary treatments also kill normal tissue cells, which leads to hair loss, sensory loss, and other more devastating side-effects.

Treatments directed at stem cells may spur cancer therapy beyond the current model of treatment, in which doctors “slash, burn, and poison” the cancer. Hopefully future cancer patients will not have to experience the difficult struggles that many current patients now endure as they progress toward a more certain and beneficial treatment outcome.

Cancer Vaccines

Certain cancers, including liver cancer, some types of lymphoma and leukemia, Kaposi's sarcoma, and cervical cancer have long been known to be caused by chronic viral infection of a particular organ or organ system. For example, chronic liver infection with the hepatitis C virus leads to liver cancer in 1–5% of cases, usually appearing about 20–30 years after infection. Chronic viral infection can lead to tumor development because the prolonged inflammation of organ tissues caused by the infection appears to produce mutations in some affected cells, which can give rise to the uncontrolled cellular growth that characterizes cancer.

Recent research on chronic cervical infection by the papilloma virus in animals shows that the virus is able to “turn off” signals from the infected tissue that would alert the immune system to the presence of the virus. Consequently the virus, which inserts itself into the cellular DNA and replicates relatively freely, can promote abnormal tissue development and precancerous tissue growth within two years of infection.

Scientists have considered the link between chronic infection with the human papilloma virus (HPV), a sexually transmitted virus, and tumor genesis in cervical cancer to be particularly direct. Screening to prevent cervical cancer (the “PAP test”) for cervical tissue damage and dysplasia, a precancerous condition, is now widespread in Western countries. This prevention program has been so successful that cervical cancer, which is the most prevalent and deadly cancer among women in countries that do not have systematic HPV testing, is largely preventable. About 3,700 women die from cervical cancer annually in the United States, a much lower rate than in countries without screening programs.

Although many HPV infections go away without treatment, a significant number result in genital warts and cervical dysplasia, which are treated with surgical and radiological procedures. HPV also causes large numbers of abnormal PAP smears, which result in extensive and prolonged medical follow-up to monitor for dysplasia and cervical cancer that is stressful for patients and expensive for the health care system.

Development of a vaccine for preventing HPV infection is considered a promising means to prevent diseases of the cervix and cervical cancer, and major pharmaceutical companies have sponsored large-scale clinical trials conducted in the United States and 33 other countries that showed highly promising results. One set of pivotal trials showed that an experimental vaccine prevented nearly 100% of precancerous growths in 12,000 women that were virus free at the outset of the study over a 17 month to 2-year observation period. Two HPV vaccines are now currently on the market: Gardasil and Cervarix; these are preventative for women between 9 and 25 years old who do not already have HPV.

The most common side-effect of the vaccine detected so far is discomfort at the injection site, a decidedly small risk in comparison to the projected benefit.

As mentioned above, PAP smears have greatly reduced the U.S. cervical cancer death rate, but cervical cancer is still one of the leading cancers affecting women in this country. The prospect that the vaccine might be 100% effective makes it likely that vaccination of young women prior to initiating sexual activity will considerably reduce the need for screening and treatment of cervical disorders within that age group.

This raises questions regarding the possible application of a vaccine approach to the 20 million men and women currently infected with the HPV virus in America. Might people with pre-existing HPV infection benefit from a vaccine similar to that which has shown promise in clinical trials? This approach would be similar to that being pursued by many of the researchers attempting to develop a vaccine for HIV, the virus that causes AIDS. In order to be effective when HPV is already present, the vaccine might need to stimulate a more potent immune response. Such a vaccine might show partial effectiveness (i.e., a percentage reduction in death rate) rather than the virtually total efficacy demonstrated in the recent HPV vaccine trials among uninfected women.

The efficacy of one of the new experimental HPV vaccines or of a new vaccine for currently infected people will need to be demonstrated in additional clinical trials, which will require a follow-up period of several years.

Even though the application of the recently tested vaccines is limited to women without current HPV infection, the techniques gained in creating a vaccine for a cancer-causing virus are likely to find wider application over the years to come.

See Also Biology: Genetics; Biomedicine and Health: Immunity and the Immune System; Biomedicine and Health: Surgery.

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Kenneth T. LaPensee