Biology of cancer: Current issues and future prospects

Biology of Cancer: Current

Issues and Future

Prospects

Jean Jenkins

HE CURE FOR cancer continues to be a challenging goal for the medical and the nursing profession. As more is learned about the body, the effects of lifestyle and environment, and the biology of cancer, the focus of health care shifts and expands. Because the interaction of these multiple variables is so complex, no single approach has produced a cure. Research continues to identify new agents that appear promising in cell lines and animal studies and later in clinical trials. This careful process of new therapy development requires time and resources but is essential for drug discovery. Each of the presently used chemotherapeutic and biological agents has successfully passed through this process. The National Cancer Institute (NCI) screens and tests new agents using an automated process. This enables evaluation of up to 20,000 natural and synthetic compounds each year.’ New materials are collected through a worldwide acquisition program. Many new agents are specifically designed based on active synthetic or natural compounds. The Developmental Therapeutics Program facilitates the NCI’s discovery of new anti-cancer agents.* Potential anti-cancer agents are tested in human tumor cell line assays. This process identifies agents that should progress to further testing in animals and humans. Most of the therapies described in this article are in the phase I stage of testing. Phase I is the first use of an investigational agent in humans to determine dose and toxicity and is performed in patients for whom no standard therapy is available. Toxicity is evaluated as doses are escalated until the maximally-tolerated dose and schedule are identified.3 Although the process is less specific and precise with biological agents, phase I testing also is used. Agents that appear to be safe and are potentially effective progress to phase II evaluation. This phase of research focuses on disease response and requires a greater number of patients (40 to 50) with specific forms of cancer. If the agent appears to be successful in treating those cancers, phase III trials are implemented to compare established cancer therapy with the new agent. Often, hundreds of participants are needed to answer the question of

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whether the new agent is better than standard theraw4 Better understanding of fundamental cell functions and the immune system have allowed new classes of agents to evolve. The ability to view the function of cells at the gene level will facilitate identification of persons at risk, detection of extent of disease, and treatment. A great deal of research will still be needed to identify doses, schedules, toxicities, and effectiveness of new chemotherapeutic and biological agents. NEW PRODUCTS UNDER DEVELOPMENT Oncogenes

Advances in molecular biology are creating new opportunities for treating cancer. Development of cancer appears to be a multistep process involving a number of genes. As more is learned about the specific effects of these oncogenes on cancer growth and spread, new targets for manipulation become available. As oncogenes are linked to specific cancers, it should be increasingly possible to identify highrisk individuals. Oncogenes, first discovered in the 1970s are the result of the inappropriate activation of genes that control cell growth.5 Activation of oncogenes may be caused by exposure to chemical carcinogens, radiation, virus insertion, familial genetic predisposition, or spontaneous mutations.6 It is now clear that tumor suppressor genes are involved in all common human cancers. Tumor suppressor genes act normally to control cell growth. Examples of tumor suppressor genes (antioncogenes) commonly involved in human cancers are p53 and retinoblastoma gene.7-9 A future strategy in cancer research will be to repair or replace the mutated or absent gene. From the Cancer Nursing Service, National Institutes of Health, Bethesda, MD. Address reprint requests to Jean Jenkins, MSN. RN, OCN, National Institutes of Health, Bldg 10, Room 7037, Bethesda, MD 20892. This is a US government work. There are no restrictions on its use. 0749-2081/92/0801-0008$5.OOlO

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Study of the malignant process provides more possibilities for interruption of the steps necessary for malignant growth. The protein products of these oncogenes may provide markers of tumor progression that will radically improve the detection of disease and therapy selection. Oncogene expression may be a “mark” for the metastatic potential of a variety of solid tumors. For example, the HER-2/neu oncogene, whose protein product is related to the epidermal growth factor receptor, is amplified in breast cancer metastases, whereas amplification of N-myc is associated with advanced disease and poor prognosis in patients with neuroblastoma. The NM-23 gene is associated with cancers of less malignant potential. Amplification of NM-23 in some way prevents tumor cell metastasis.” Thus, measurement of levels of genes or gene products may guide therapy in individual patients . Growth Factors Many of the critical stages in normal and malignant cell growth are mediated by peptide growth factors. Many oncogenes code for growth factors and several growth factors play a role in cellular transformation. l1 Future research will focus on ways to block or prevent interactions of growth factors with receptors. This might be accomplished by developing antibodies to growth factors or to their receptors or by developing growth factor antagonists. Potential applications exist with breast cancer where transforming growth factor alpha, epidermal growth factor, and fibroblast growth factor have been identified as important to cell growth. Some studies of this type have already been performed. Tamoxifen blocks the growth factor estradiol to suppress tumor growth. i* A study reported the testing of monoclonal antibodies against bombesin to evaluate effectiveness of blocking this growth factor in treatment of lung cancer. l3 Metastases Advances in molecular biology have led to the identification of biochemical and cellular factors that promote cancer metastases. Cancer metastasis is a complex process involving tumor cell invasion, attachment to and penetration of basement membranes, survival in the circulation, and avoid-

JEAN JENKINS

ance of immune surveillance. Thus, metastatic cells are a selected subpopulation with properties that allow them to spread from the primary tumor to other sites. Understanding the various steps required for metastasis not only will improve the ability to predict tumor aggressiveness but also may make it possible to interrupt the process at one or more points. Research efforts under development focus on cellular and biochemical properties that are augmented in metastatic cells.14 For example, the cell surface receptors for laminin may be altered. Antibodies to laminin receptors on cancer cells or treatment with laminin fragments is an approach that will enter clinical study soon. Future research will focus on treatment with inhibitors of the enzymes that promote metastasis. ’ 5 NEW STRATEGIES FOR CANCER TREATMENT

Gene Therapy New technologies may make it possible to correct genetic defects by genetic engineering in humans.16 Somatic cell gene therapy or the correction of a genetic defect in the somatic cells in the body is the only applied strategy so far. This type of therapy has just begun in patients with a severe immunodeficiency disease resulting from a missing enzyme, adenosine deaminase (ADA). Much preliminary work had to be completed before the actual administration of the treatment. Delivery of the gene had to be efficient, safe, and allow integration of the gene into the DNA. ” The use of the other three types of genetic engineering are still in the future. Technological, ethical, and social concerns will need to be addressed before implementation of these theories. Chemotherapy Therapeutic cancer research has focused on the development of new antineoplastic agents. The understanding of how the agents work in the body and the ability to enhance effectiveness by the use of biologicals to prevent toxicity, ie, colonystimulating factors, will extend effective cancer chemotherapy. The identification of potential active agents is facilitated by a program sponsored by the National Cancer Institute, the Compare Program. This program uses pattern recognition of drugs that appear to be similar to known active agents. Similar patterns imply similar biochemical

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actions and thus potentially active agents for further testing. An example is dolastatin, a drug identified to have a similar pattern to taxol and which will be evaluated for further clinical testing. Analogues are being developed which may be less toxic. ‘* Examples of analogues under clinical evaluation include idarubicin, epirubicin, piroxantrone, and 9-aminocamptothecin. Another way to increase effectiveness of chemotherapy agents is to protect the body from serious side effects. Use of cardioprotective agents such as ICRF-187 or myelosuppressive protective agents such as the colony-stimulating factors will allow greater doses of drugs to be administered. Chemoprevention Chemoprevention is the use of agents to interfere with the process of carcinogenesis in order to lower the rate of cancer incidence. l9 Several chemopreventive agents have been found to have protective effects against some animal cancers. These include vitamins A, C, E, and selenium. Clinical trials using chemoprevention require persons identified as “high risk” for development of cancer. For example, ongoing clinical trials focus on those at high risk for lung cancer to evaluate the use of beta-carotene or 13 cis-retinoic acid and their influence on cancer development.20‘22 Dietary manipulations are being evaluated to determine the effects of fiber and calcium on colon cancer development. A planned chemoprevention study will evaluate the use of tamoxifen to prevent breast cancer.23 The opportunities for chemoprevention continue to grow but these studies present several challenges. Such studies are long-term and the number of study subjects required is usually large. Yet prevention is preferable to treatment so the future of cancer research must continue to focus on preventive strategies. Vaccines The use of vaccines for prevention of cancer is complicated by the diversity of etiologic factors. More epidemiological and experimental studies are needed to determine which cancers are associated with viruses. Cervical cancer and liver cancer have been associated with virus infections. It is likely that vaccines could be developed to prevent the virus infection and therefore prevent the cancer. The development and testing of vaccines will re-

quire extensive use of animal models. Clinical trials in progress that are evaluating use of vaccines include autogenous papilloma vaccine for juvenile papilloma of the larynx and hepatitis B vaccine to prevent liver cancer. 24 Future clinical trials will evaluate the role of human papilloma viruses in cervical carcinoma and Epstein-Barr virus in several cancers. Work is being conducted to develop vaccines against nonviral tumor-associated antigens. In order for the immune response to be more effective against the tumor, the immune cells must be able to recognize the tumor cell and travel to sites where the cancer is located. There is a great deal not yet known as to how the cellular immune response to tumors occurs. As each piece of the puzzle is solved, greater opportunities for cancer treatment will evolve. Ongoing vaccine research efforts try to stimulate the immune system to recognize cancer cells. This research uses agents such as tumor-associated antigen prepared specifically from a patient’s tumor, monoclonal antibodies, and cytokines. Gene modification offers another possible method for vaccine research. Manipulations of genes to enhance production of markers on cancer cells to promote recognition and destruction of the cancer is another potential method of vaccine therapy.*s Advances in biological therapy have allowed this modality of cancer treatment to emerge as an exciting research focus. Biological Response Modifiers Biological response modifiers (BRMs) are substances that boost, direct, or restore the normal defenses of the body.26 Over the last century, technological developments have permitted the isolation, identification, and production of many substances found in the body. Clinical testing of these substances was delayed in the past due to a limited supply, impurities, and contaminants. Advances in recombinant DNA technology have now made it possible to expand the identification and testing of BRMs in patients with cancer. One difficulty with testing many of these unique substances is that it is difficult to measure the appropriate biological effects. Correlation of biological activity with the dose of the agent is necessary for an understanding of the agent’s role in the complex immune system. Research is currently focused on cytokines (Table l).*’ Cytokines are proteins that are found in

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all human cells and function to regulate cells involved in the immune reaction. Most research is still in animal and laboratory studies. Cytokines such as the interferons, interleukin 1 (IL-l) and IL-2, tumor necrosis factor, and the colonystimulating factors have reached clinical application in patients with cancer. Most of the BRMs produce fever, myalgias, fatigue, and other agentspecific side effects. For example, IL-2 produces severe side effects at high doses that require close monitoring. These include fluid shifts, hypotension, pulmonary symptoms, and pruritus.** Future research will be needed to expand the usefulness of each of the BRMs in the treatment of cancer. Clinical trials designed to combine the BRMs together or with chemotherapy, surgery, or radiation will expand. As more is learned about the biological role of each substance, more effective manipulation of the immune system will be possible. This knowledge can be expected to advance the management of cancer. ISSUES OF THERAPY DEVELOPMENT

Ethical Issues The development of new therapies can create many ethical dilemmas. The individual who has no other treatment options available may enter a clinical research study without full comprehension of the benefits and risks involved. This places conTable 1. Future

Biological

Therapies Effect

CVtokine IL-1

IL-2

IL-3 IL-4

IL-5 IL-6 IL-7 Tumor necrosis factor (alpha, beta) Interferon (alfa, beta, gamma) Adapted al.*’

and reprinted

Induces lymphokine (T-cell) release and is useful to promote bone marrow growth Induces T-cell activation, production, and activity to remove cancer cells Stimulates growth of platelets, neutrophils, and macrophages Growth factor for T cells, enhances B-cell growth and antibody production Induces differentiation of eosinophils Stimulates cytolytic effector cells, stimulates platelet production Early lymphoid cell growth factor Cytotoxic for selected cell lines

with permission

from

Rosenberg

et

siderable responsibility on the nurse and physician to insure that the patient has been adequately informed about the investigational nature of the study. Education about the side effects, treatment plan, and expected outcomes of the therapy is essential in obtaining an informed consent.29 The process of new therapy development can create ethical dilemmas for members of the health care community. Physicians may feel reluctant to refer a patient for therapy in a clinical trial setting. This reluctance might stem from a lack of understanding of the experimental therapy, fear of losing contact with the patient, and cost in both dollars and time.30 The health care industry must also assume the responsibility for assuring that every clinical trial has significance to the future health of our society. Safeguards have been developed to protect individuals who participate in clinical trials.3’ Each clinical trial must be reviewed by an institutional review board (IRB) to assure that the research is medically and ethically sound. Some of the new knowledge that will lead to improved therapies also creates ethical concerns for society. For example, the ability to view the structure and function of genes may allow identification of persons at risk, and although this is beneficial, it also creates a number of problems. Issues such as employment, insurance, and labeling of persons at “high risk” will emerge as increasing progress is made. As an example, consider a woman who is identified as being at high risk for breast cancer as the result of a genetic marker. She appears otherwise quite healthy. Preventive interventions might include lifestyle changes and medications. Questions of employment and insurance will arise. Decisions about the type, extent, frequency, and tolerance of such interventions will require education and support from health care professionals. The National Center for Human Genome Research at the National Institutes of Health is developing guidelines that will address such concems.32 The ability to identify gene defects also creates the opportunity for human gene therapy. The use of gene therapy has been closely monitored to assure the safety of the procedure of inserting a normal gene for the replacement of defective or missing protein in humans. Any federally funded gene therapy experiment involving recombinant DNA must be approved by the Recombinant DNA Ad-

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visory Committee as well as the IRB.33 The possibility of having the technical capability of genetic engineering creates many fears in society and thus will require protection against possible abuse. Cost Concerns The process of new therapy development creates economic problems. Obtaining active agents requires developmental costs such as identifying, purifying, and creating enough drug for testing. An active agent may be identified that is only available in limited quantities, such as taxol isolated from the yew tree. This creates additional costs to synthesize the drug. Technology may allow the development of drugs or biologics for which the cost may be prohibitive. Cost is often the reason patients are not entered into clinical trials. Although the research costs are borne by the sponsor of the trial, much of the cost for the required treatment and monitoring are not.34 If an agent has not been approved by the Food and Drug Administration (FDA), many insurers will not pay for the treatment.35’36 This practice impedes development of new therapies and limits access of patients to clinical trials. The reimbursement issue may result in delay of payments to hospitals and physicians producing a disincentive for participation in clinical trials. This will ultimately affect the outcomes of research and increase the already outrageous health care costs.30 The increasing cost of research means that priorities need to be set, especially because not all questions can or should be addressed in a clinical tria1.37 Current plans for epidemiological studies to determine the effects of dietary fat on the incidence of breast cancer will be expensive and difficult to perform.38 Financial considerations determine what studies are implemented. This will, no doubt, influence future availability of preventive and therapeutic modalities, but at present this seems unavoidable. Trial Design The most efficient way to reach conclusions about research questions will continue to evolve as new technologies develop. Complexities of research design, methodology, safety, numbers of subjects needed, schedule, and duration of interventions are only a few of the details investigators must address when designing a study. Chemoprevention studies that involve changes in lifestyle

and active involvement of the individual produce additional research complexities such as using healthy individuals to answer questions about cancer risks. Involvement of statisticians is important in the design of a study to assure credibility of clinical trial results.39 Political Components Political considerations have become a factor in research design. It has been claimed by some that women’s health issues have not been addressed as equitably as men’s and this is now a factor that will need to be considered in the design of clinical trials. Studies designed to include this biological perspective will be coordinated by the National Institutes of Health (NIH) Office of Research on Women’s Health.40 Research funding is legislatively driven. The level of funding has remained flat over the past years thus freezing the availability of research grants and of progress. The health priorities of the nation guide public policy for financing the NIH budget which supports the majority of clinical trials in the nation. THE NURSE’S ROLE

The nurse plays an important role in cancer prevention, detection, and treatment. This role includes education of self and others about options available, risks and benefits, and the safe delivery of these new technologies. The nurse who specializes in oncology may practice in a variety of settings. These settings, whether at a research facility such as the NIH Clinical Center or in a community hospital, will allow the nurse to expand personal capabilities to promote the future health of the nation. It requires considerable energy, flexibility, and confidence in practice skills for a nurse to feel comfortable in a research setting. Clinical trial implementation demands that the nurse constantly be learning something new. Advances in the understanding and manipulation of the biological system offer new interventions previously unavailable. The nurse is the direct care provider, the supporter, the educator, and the monitor. It is often the nurse who notices trends in toxicities, who raises safety concerns or compliance issues, and who documents the outcomes. The community setting offers additional challenges for the nurse. Prevention trials may be of-

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fered to the public in a rural setting. Education of the public about the advances in cancer research is important. The nurse will need to know how to access written information and resources to learn the results of clinical trials and options available. Much of the challenge for oncology nurses is communication regarding what treatment is available, where to access care, and how to pay for it. The nurse in the community setting needs to be an advocate for patient reimbursement, an expert on access to the health care system, and a resource to identify those at high risk for targeted interventions.41 SUMMARY

The future of cancer treatment is limited only by the rate of progress made in understanding the biology of cancer. The future will present a considerable challenge to health care professionals to

learn new theories, understand new terms, and expect different toxicities. The explosion of information and technology is exciting, yet frightening. The willingness of scientists, health care professionals, and consumers to deal with the ethical, financial, and political issues generated by this progress is gratifying. Because science has created such advances, the effort to deal with the outcomes is worthwhile but still difficult. The challenge to rapidly facilitate the sharing of the scientific and clinical advances has been recognized by the nation. A legislative mandate to create a way to store and analyze the vast data related to molecular biology, biochemistry, and genetics resulted in the National Center for Biotechnology Information.42 The development of automated systems to analyze genetic, environmental, biological, and chemistry information can only enhance future progress in the management of cancer.

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