Cancer

To many people, the word cancer is synonymous with death; however, that is not the reality. In industrialized countries cancer mortality rates have slowly and progressively declined between 1950 and 2000. In 2000 overall cure rates reached approximately 50 percent. Nevertheless, cancer remains the second leading cause of death in industrialized countries and a rapidly increasing cause of death in developing countries.

The scope of the problem in the United States is large. Some 1.2 million people were diagnosed with potentially fatal cancer in the year 2000. Of these, 59 percent were expected to live for at least five years (in some, the cancer may be continuously present for more than five years) with or without evidence of cancer. People of all ages, from birth to advanced age, can manifest cancer, making it the second-leading cause of death in the United States. In children cancer is unusual, but it has consistently been the leading cause of death from disease. As mortality rates from cardiovascular disease decline, the proportion of cancer deaths increases. It is anticipated that the mortality rate from cancer will surpass that from heart disease by the year 2050. Direct and indirect financial costs of cancer in the United States for the year 2000 were $178 billion.

Developing countries represented 80 percent of the world's approximately 6 billion people in the year 2000. In these countries, cancer has grown from a minor public health issue in the early 1990s to a rapidly expanding problem by the beginning of the twenty-first century. The emergence of a middle class, with attendant changes in lifestyle, increased longevity and exposure to potential carcinogens, and expectations of improved medical delivery systems have fueled the growing impact of cancer in the third world. The financial resources and socio-medical infrastructure needed to diagnose and treat, much less screen and prevent these cancers, are lacking in the developing world.

A controversial issue in the United States is whether there has been progress in the "War on Cancer" declared by Congress in 1971. Since then a large flow of tax dollars has been directed to basic and clinical research with the goal of eliminating cancer. Mortality rates from all forms of cancer have declined slightly from 1990 through 2000, but with large variations among different types of cancer. Optimistic explanations include significant improvements in treatment and prevention. More pessimistic analyses suggest that some of the more common cancers can be diagnosed earlier so that benchmark five-year mortality rates have diminished, but that the actual course of the disease is unaffected because treatments are not really more effective.

Biology

Cancer is a disease whereby the genes regulating individual cell behavior and interactions with other cells malfunction. It is therefore a "genetic" disease, although not necessarily "inherited." Cancers clearly traced to inherited susceptibility are unusual, accounting for fewer than 10 percent of cases. Rather, the majority of cancers seem to result from complicated interactions between the environment and "normal" cells.

The routine operations of cell growth, division, cell-to-cell communication, and programmed cell death (apoptosis) are complex and must be tightly controlled to preserve the integrity of the organism. Chromosomes, which contain DNA molecules organized into genes, control these regulatory processes. Similar mechanisms are present in all animals and plants, are highly conserved through evolution, and so must provide significant survival benefit. The phenomenon of cancer is infrequent in wild animals and has only come to prominence in human beings since 1900. These statistics suggest that interactions of environmental agents with the genes result in fixed alterations that eventually manifest themselves as cancer. Public health measures have increased longevity so that the progressive, possibly inherent deterioration of regulatory functions accompanying aging allows less effective repair of chronic genetic damage.

Although no single cause has been or is likely to explain all of cancer, research has demonstrated that environmental factors predominate in the development of most cancer. Proven causes of DNA damage leading to malignant change include viruses, radiation, and chemicals. Viruses such as Epstein-Barr, HIV, and papilloma can contribute to cancer development (carcinogenesis). Both therapeutic and normal environmental exposure to radiation increase the risk of cancer. Multiple chemicals have been linked to cancer, of which the best examples are the constituents of tobacco. How these and other unknown environmental factors, particularly dietary and airborne, interact with human genes to cause irreversible, malignant transformation is the subject of intensive research.

Malignant cells can multiply and divide in the tissue of origin and can travel through the circulatory system and create secondary deposits (metastases) in vital organs. These capabilities underlie the phenomena of invasive lumps (tumors) and the potential for the dissemination of cancer. Most cancer cells, whether at the primary or secondary site, divide at about the same rate as their cells of origin. Malignant cells, however, do not typically undergo normal programmed cell death (apoptosis) and consequently accumulate. Most often, the cause of death in cancer is a poorly understood wasting process (cachexia).

Prevention and Screening

Prevention of cancer, or the reduction of risk for a person who has never experienced the disease, is a desirable goal. For those cancers resulting from known environmental exposures, such an approach has been most successful. Avoidance of tobacco products is no doubt the best proven means of preventing cancer. In industrialized countries, regulatory agencies monitor chemical and radiation exposure. Dietary habits are felt to influence the risk of developing certain cancers, but there is very little evidence that dietary manipulations lead to significant risk reduction.

Screening is the attempt to diagnose an established cancer as early as possible, usually before the onset of symptoms, in order to optimize the outcome. A screening technique is designed to simply, safely, and cheaply identify those patients who may have a certain type of cancer. If screening-test result is positive, further testing is always necessary to rule the diagnosis in or out. There is considerable controversy in this field. It cannot be assumed that early detection is always in the patient's best interest, and the overall financial costs in screening a population must be weighed against the actual benefits. Screening may be counterproductive under the following conditions:

1. Treatment is not more effective with early detection.
2. The patient will die of an unrelated condition before the diagnosed cancer could be troublesome or fatal.
3. The screening examination can be harmful.
4. The screening examination is falsely "negative" and thus falsely reassuring.
5. The treatment causes complications or death in a patient in whom the cancer itself would not have led to problems.

In spite of these limitations, there have been successes. Good evidence exists that not only early detection but also improved survival can be achieved in breast, cervical, and colorectal cancers. With minimal danger and cost, appropriate populations screened for these diseases benefit from reduced mortality. Prostate cancer, however, is more problematic. Measurement of prostate-specific antigen (PSA), a substance made by both normal prostate as well as malignant prostate cells, can identify a patient with prostate cancer before any other manifestations. But because of the relatively elderly population (often with unrelated potentially serious conditions) at risk, it has been difficult to prove that treatment confers a quantitative or qualitative benefit. Continued efforts will be made to create screening techniques that truly allow more effective treatment for cancers detected earlier.

Diagnosis and Treatment

Once a malignancy is suspected, tests (usually imaging techniques, such as X rays, ultrasounds, nuclear medicine scans, CAT scans, and MRIs) are performed for confirmation. Ultimately a biopsy, or removal of a piece of tissue for microscopic examination, is necessary for determination of the presence and type of cancer. Staging tests reveal whether the disease has spread beyond its site of origin. Because of the inability of current techniques to detect microscopic deposits of cancer, a cancer may frequently appear to be localized but nevertheless exist elsewhere in the body below the threshold of clinical detection.

The diagnostic and staging process should permit the optimal clarification of the goals of treatment. Curative treatment intends permanent elimination of cancer, whereas palliative treatment intends to relieve symptoms and possibly prolong life. In every cancer situation there are known probabilities of cure. For example, a specific patient with "localized" breast cancer may have a 50–60 percent chance of cure based on predictive factors present at the time of diagnosis. Follow-up "negative" tests, however, do not yield the certainty that there is no cancer, whereas the documented presence of recurrent cancer has clear significance. Cancer, indeed, is the most curable of all chronic diseases, but only the uneventful passage of time allows a patient to become more confident of his or her status.

Surgery is the oldest and overall most effective cancer treatment, particularly when tumors appear to be localized and cure is the goal. It is a preferred modality for breast, prostate, skin, lung, colon, testicular, uterine, brain, stomach, pancreas, and thyroid tumors. The aims of cancer surgery include elimination of as much cancer as possible, preservation of organ function, and minimal risk and suffering for the patient. Occasionally surgery is intentionally palliative, particularly when other treatment modalities are added in an effort to improve symptoms.

Radiation therapy has been a mainstay of cancer treatment since the 1940s, when doctors first began to understand its potential benefits and short and long-term risks. Therapeutic ionizing radiation is generated by a linear accelerator and delivered externally to a well-defined area. It thus shares with surgery an advantage for localized tumors. The inherent differences in radiation sensitivity between malignant tissues and the surrounding normal tissues permits the exploitation of radiation for therapeutic benefit. When the cancerous tissue is less sensitive to radiation than the normal tissues, radiation can cause more harm than good. Radiation has been a useful primary treatment modality in tumors of the head and neck, lung, cervix, brain, pancreas, and prostate. For tumors that have metastasized to tissues such as bone and brain, radiation has been very useful for palliative purposes.

Systemic treatments, either by themselves or in concert with surgery and/or radiation, offer the most rational options for a disease, which so often has spread before diagnosis. The ideal treatment would be a substance that travels throughout the body, neutralizes every cancer cell, but causes no harm to any normal cell. Research has not yet yielded such a completely specific and non-toxic substance.

The 1950s saw the advent of anticancer drugs that came to be known as "chemotherapy." By the year 2001 approximately sixty chemotherapy drugs became commercially available. In general these drugs cause irreversible cell damage and death. They tend to be more destructive to rapidly dividing cells and so take their heaviest toll on relatively few malignancies as well as predictability on normal tissues (mucous membranes, hair follicles, and bone marrow). For some very sensitive disseminated cancers such as testicular, lymphomas, and leukemias, chemotherapy can be curative. For many others, such as advanced breast, ovarian, lung, colon cancers, chemotherapy may offer palliative benefits. Since the 1980s chemotherapy has played an important role in the multimodality treatment of localized breast, colon, lung, and bladder tumors. Except for curable and highly chemosensitive malignancies, chemotherapy kills at most 99.99999 percent of cells, but with a burden of trillions of cancer cells, millions of resistant cells remain. Even using high-dose chemotherapy, it appears that by the year 2001 chemotherapy may have reached a plateau of effectiveness.

Insights into the basic genetic, molecular, and regulatory abnormalities of malignant cells have opened up entirely new systemic approaches. "Natural" substances such as interferons and inter-leukins have therapeutically modulated cell proliferation and led to regression of some tumors. Antiangiogenesis agents interfere with the malignant cell's need for accessing new blood vessels. Chemicals designed to inhibit the inappropriate production of growth factors by malignant cells have been synthesized and show promise. Monoclonal antibodies aimed at proteins concentrated on the malignant cell's surface have achieved tumor shrinkage. By the year 2000 the thrust in basic cancer research had focused on manipulation of the fundamental processes that allow malignancies to grow and spread.

The Internet has allowed patients, families, and medical providers rapid access to information previously obtainable only through libraries or physicians. Such information, however, may be unfiltered, unsubstantiated, and misleading. Even when the information is correct, consumers may be unable to process it properly because of fears concerning their condition. All observers agree, however, that this form of communication will rapidly affect cancer research and treatment.

"Complementary" or "alternative" modalities have existed for many years and represent nonscientific means of attempting to cure or palliate cancer. The multitude of available products and techniques is enormous: herbal extracts, vitamins, magnetic therapies, acupuncture, synthetic chemicals, modified diets, and enemas. The vast majority of these have never been evaluated in a rigorously controlled scientific way that would allow more definitive and precise evaluation of their benefits and risks. Nevertheless, evidence has shown that as many as 50 percent of all cancer patients, irrespective of treatability by conventional methods, try at least one form of complementary medicine. Some proponents feel that these treatments should serve as adjuncts to conventional ones, while others feel that all conventional treatments are toxic and should be replaced by alternative ones. To investigate the potential of these approaches, the National Institutes of Health established the Institute of Alternative Medicine in 1996.

End-of-Life Care

Because approximately 50 percent of cancer patients will die from their cancer, management of their dying takes on great importance. In the 1980s and 1990s multiple studies demonstrated that such basic concerns as pain and symptom control, respect for the right of the individual to forego life-prolonging measures, and spiritual distress have been mismanaged or ignored by many health care providers. In spite of the emergence of the modern hospice movement and improvements in techniques of symptom alleviation, most cancer patients die in hospitals or in nursing homes while receiving inadequate palliative care. The American Society of Clinical Oncology (ASCO) in 1998 mandated that part of fellowship training for oncologists include the basics of palliative care in order to rectify these problems.

See also: Causes OF Death ; Pain AND Pain Management ; Symptoms AND Symptom Management

Bibliography

Ambinder, Edward P. "Oncology Informatics 2000." Cancer Investigation 19, supp. 1 (2001):30–33.

Burns, Edith A., and Elaine A. Leventhal. "Aging, Immunity, and Cancer," Cancer Control 7, no. 6 (2000):513–521.

Chu, Edward, and Vincent T. DeVita Jr. "Principles of Cancer Management: Chemotherapy." In Vincent DeVita, Jr., Samuel Hellman, and Steven A. Rosenberg eds., Cancer: Principles and Practice of Oncology, 6th edition. Philadelphia: Lippincott, Williams & Wilkins, 2001.

DeVita Jr., Vincent T. and Ghassan K. Abou-Alfa. "Therapeutic Implications of the New Biology." The Cancer Journal 6, supp. 2 (2000):S113–S121.

Groopman, Jerome. "The Thirty-Years War." The New Yorker, 4 June 2001, 52–63.

Hong, Waun Ki, Margaret R. Spitz, and Scott M. Lippman. "Cancer Chemoprevention in the 21st Century: Genetics, Risk Modeling, and Molecular Targets." Journal of Clinical Oncology 18, Nov. 1 supp. (2000):9s–18s.

Ishibe, Naoko, and Andrew Freedman. "Understanding the Interaction between Environmental Exposures and Molecular Events in Colorectal Carcinogenesis." Cancer Investigation 19, no. 5 (2000):524–539.

Lichter, Allen S. and Theodore S. Lawrence. "Recent Advances in Radiation Oncology." New England Journal of Medicine 332, no 6 (1995):371–379.

Plesnicar, Stojan, and Andrej Plesnicar. "Cancer: A Reality in the Emerging World." Seminars in Oncology 28, no. 2 (2000):210–216.

Rosenberg, Steven A. "Principles of Cancer Management: Surgical Oncology." In Vincent DeVita, Jr., Samuel Hellman, and Steven A. Rosenberg eds., Cancer: Principles and Practice of Oncology, 6th edition. Philadelphia: Lippincott, Williams & Wilkins, 2001.

Task Force on Cancer Care at the End of Life. "Cancer Care during the Last Phase of Life." Journal of Clinical Oncology 16, no. 5 (1998):1986–1996.

Walter, Louise C., and Kenneth E. Covinsky. "Cancer Screening in Elderly Patients." Journal of the American Medical Association 285, no. 21 (2001):2750–2778.

Wein, Simon. "Cancer, Unproven Therapies, and Magic," Oncology 14, no. 9 (2000):1345–1359.

Internet Resources

American Cancer Society. "Statistics." Available from www.cancer.org .

JAMES BRANDMAN