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Chapter 11

FUTURE DEVELOPMENTS IN TREATMENT METHODS OTHER THAN RADIOTHERAPY


Summary Increasingly more cancer patients are being diagnosed at an early stage in the disease. Consequently, more patients receive curative treatment. Milder methods and better care even make curative treatment an alternative for medically frail patients. As knowledge advances, primary curative treatment is becoming more complicated and embraces more forms of treatment. The local treatment methods, surgery and radiotherapy, will continue to play at least as large, or perhaps a larger, role in the outcome of cancer. Even for patients who cannot be cured, meaningful treatment is successively improving and resulting in longer and better lives for patients. This, coupled with the expected increase in the number of cancer patients discussed in Chapter 5, will result in an increasing and rapid overall need for cancer treatment. Surgery is expected to continue developing toward becoming increasingly mild and organconserving. Endoscopic methods will continue to expand. Chemotherapy will advance further, mainly through increased knowledge about active mechanisms and possibilities of combination therapy. This will lead to a successive, gradual improvement in results, and chemotherapy will become a meaningful approach for treating more cancers. Bone marrow transplantation, both allogeneic and autologous, and stem cell transplantation, is expected to continue. Hormonal treatment will continue. Through the introduction of new agents and applications for more diagnoses, the use of this method may expand, perhaps mainly in adjuvant situations. Biologic therapy is at an early stage in development. It has become an established treatment approach for certain types of cancer. Continued, intensive research can be expected. The practical potential for improving treatment results is, however, expected to be somewhat limited in the foreseeable future. With most cancers, primary treatment has the potential to cure the patient, but cure becomes less attainable on relapse. The greatest progress in recent decades has not involved curing more patients, but improving the care of those who cannot be cured. This trend will continue, which will place greater demands mainly on nursing care and palliative treatment. Nothing suggests that the development of other treatment methods will reduce the need for radiotherapy. However, much suggests that local treatment methods will gain increased importance, particularly if the trend continues toward early detection of more cancers.

Introduction Recent decades have witnessed rapid development in cancer treatment. It appears that this trend will continue. Roughly about half of the cancer patients can be cured today. In the late 1980s, an EU study estimated that approximately 45% were cured. Twenty-two percent were cured by surgery alone, 12% by radiotherapy, 6% by a combination of surgery and radiotherapy, and 5% by medical therapy alone, mainly chemotherapy. Improvement in survival has been shown, eg, by figures from the Oncology Center in Stockholm and Gotland where survival in each 5-year cohort of major tumor groups has successively increased since 1960. The trend has been toward more complex treatment, mainly combination therapy. Surgery, radiotherapy, or chemotherapy alone are considered less often, whereas it has become more common to use several methods either simultaneously or in succession. Developments in combination therapy are most obvious for curative treatment, but may even apply to palliative situations. Another important advancement has been the potential to offer more meaningful treatment to patients who cannot be cured. Patients with incurable cancer live increasingly longer and better. These patients are subjected to various treatments during the different phases of disease. It is not unusual for patients with prolonged, chronic cancers, which may extend over many years, to receive multiple forms of treatment, perhaps on several occasions. Individual forms of treatment are also becoming increasingly complex. The introduction of various supportive therapies allow cancer treatment to be intensified, which increases the demand for specialized knowledge and resources. Many new treatment methods have been introduced. Initially, people usually place high expectations on new technology, and assume that the new method will replace other cancer treatment methods. Later, it becomes

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85 clear that the new therapy falls short of these expectations. Rather, it finds its place in combination with, or as a complement to, established methods. The 1970s and 1980s were characterized by high expectations on the development of systemic treatment methods such as chemotherapy and hormonal treatment. What we can achieve, in reality, with these treatments has now become rather clear. During the 1990s, there has been increasing interest in locally active treatment methods, surgery and radiotherapy for both curative and palliative purposes. This was confirmed, eg, during ECCO 7 (the 7th European Conference on Clinical Oncology and Cancer Nursing) where broad reviews were presented to show the major importance that local tumor control has for the opportunity to cure patients, and for patients survival and quality of life.
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Surgery Most cancer patients are cured with the help of surgery. Most patients receive surgery at some time during the course of their disease-either diagnostic, curative, or palliative. During the first half of this century, it was thought that more patients could be cured by radical surgery. Many patients were subjected to major, mutilating interventions that did not improve survival. These insights have led surgical trends in the opposite direction, toward milder less mutilating interventions. Major emphasis is now given to preserving organs and functions to offer patients a better quality of life (1). Surgical techniques for certain types of tumors, mainly concerning the head and neck region and the breast, are becoming milder. Milder surgery often increases the need for combination therapy, usually radiotherapy. One example is breast cancer. Until the first half of the 1980s, most surgery involved removal of the entire breast. The current practice is to resect only a part of the breast. This requires, as discussed in Chapter 6 , followup radiotherapy. Surgery is also advancing in other areas, eg, stomach cancer and rectal cancer, toward more extensive local intervention, eg, increased lymph node evacuation. Concerning liver surgery, for example, advancements are being made toward smaller and milder interventions for certain types of tumors, and toward more extensive resection of others. Only in exceptional cases has surgery been replaced by other treatment modalities, eg, by chemotherapy and radiotherapy for lymphoma and by radiotherapy for early laryngeal cancer. Experiences in recent years with laparoscopic surgery and endoscopic procedures show promise even in tumor surgery. A combination of laparoscopic surgery and conventional surgery is being developed which is much easier on the body, yet achieves the same surgical results in, eg, esophageal cancer and colon cancer (2). Advancements in

microsurgery, with the opportunity to suture even the smallest vessels and nerves, provides improved opportunities for reconstruction following cancer surgery, eg, in the head and neck. Photodynamic treatment is being developed, mainly for surface tumors and those accessible by endoscopy. Endoscopic laser methods will expand the opportunities for palliative treatment of stenosed tumors. Thanks to milder methods, more patients can benefit from surgical treatment, both curative and palliative. Important advancements have been made in the field of anesthesia, both in anesthetic methods and related treatment. These advancements enable surgery in more frail patients. Patients who earlier were judged to be incurable because of poor general health status may be operated on and even cured today. This trend is expected to continue. It is expected that increasingly more patients can be offered both curative and palliative surgical treatment. Furthermore, the functional and cosmetic results of surgery will improve, benefiting quality of life. Surgery will probably not be replaced by other treatment methods, nor will other treatment methods be replaced by surgery to any great extent.

Chemotherapy The first successful chemotherapy treatment was given in December of 1941 using nitrogen mustard. It had an obvious, although very temporary effect. It would take nearly 20 years before chemotherapy alone could be shown to cure a cancer patient. Success was first achieved in a trophoblastic tumor. The best results were achieved in hematological malignancies such as lymphomas and leukemias. Earlier, children with acute leukemia died almost without exception. Today, 60% to 80% can be cured. The success with childhood tumors probably depends both on biologic factors and cancer characteristics, but also that younger individuals tolerate chemotherapy better. Treatment of nonseminoma testicular cancer improved dramatically in the late 1970s with the introduction of a new chemotherapy combination. Long-term survival increased from a few percent to approximately 60%, and later to approximately 90%. Other tumor groups have experienced less improvement. One example is small cell lung cancer, where high expectations were initially placed on chemotherapy. They were never realized. Outcomes have successively improved, and today approximately 14% of patients with confined disease can be cured by combination chemotherapy and radiotherapy. In some situations, survival can be increased and symptoms alleviated by chemotherapy, eg, breast cancer and myeloma. For years, there has been a resigned attitude toward chemotherapy for cancer in the gastrointestinal tract. Since the mid1980s, however, increased interest has been shown in this type of cancer. Many studies are investigating different combinations involving chemotherapy, eg, in colorectal

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cancer substantial tumor shrinkage can be achieved in 30% to 40% of the patients with metastatic disease. Adjuvant chemotherapy is an interesting area of application, and is addressed later in this chapter. Forty different anticancer drugs are registered in Sweden, some under multiple synonyms. Modern chemotherapy is delivered, almost without exception, in a combination of several agents, sometimes even with noncytostatic agents. Many cases have shown that the order in which the agents are delivered is of importance. Furthermore, the method of administration-injection, short-term infusion, or long-term infusion can be of decisive importance. It may be possible that even the time of day when treatment is delivered plays a role. Consequently, a nearly infinite number of combinations are possible (3). Future technology may enable practitioners to direct anticancer drugs at specific tissues. This, in turn, permits the delivery of higher tumor doses with fewer side effects. A limiting factor concerning the use of anticancer drugs is the development of multidrug resistance, whereby the cancer simultaneously loses its sensitivity to different anticancer drugs. Trials are under way to develop methods to circumvent this problem, which is decisive to the applicability of anticancer drugs (4, 5). A yet unproved theory is that increased drug doses can improve the rate of cure. The most important dose-limiting side effect of chemotherapy is its impact on bone marrow. Hematopoietic growth factors (colony stimulating factors) have been available for several years. These naturally occurring substances stimulate bone marrow to recover more quickly following chemotherapy. The use of hematopoietic growth factors permits the delivery of higher drug doses. Even other supportive treatment with antinausea, antifungal, and antiviral agents make it possible to increase the drug dosage. One alternative is the simultaneous delivery of chemotherapy and radiotherapy. The idea here is that the presence of anticancer drugs enhances the effects of radiotherapy, and that this effect is most pronounced in tumor cells. Trials thus far have yielded discouraging results, and use is limited to a few unusual cancer types, such as penile cancer and anaplastic thyroid cancer. Renewed interest in, eg, gastrointestinal cancer has emerged and will probably continue to develop. Sensitivity to anticancer drugs varies widely among different diseases and from patient to patient. The proportion of sensitive tumors in some types of cancer, eg, leukemia, is very high and for others, eg, pancreatic cancer, it is low. Attempts are under way to determine anticancer drug sensitivity in the laboratory. Success has been limited, but new methods are being developed. Several basic questions remain unanswered after 50 years of chemotherapy practice and research. Gains should be possible through a better understanding of how to use existing agents. Presumably, major leaps forward are the exception rather than the rule. Most likely, irnprovements will be slow with regard to the number of patients cured and the percentage benefiting from treatment. Adding a few percent with each step, however, leads to meaningful change in the long term. Hence, it is expected that chemotherapy will become increasingly important in treating cancer diseases, whereas its use is limited today. All things considered, better results from chemotherapy will do little to reduce the need for other types of treatment. A serious problem concerns the overutilization of anticancer drugs. One reason is that such agents, in contrast to radiotherapy and surgery, are accessible to any physician. Therefore, these toxic agents can be given when physicians have difficulty managing situations where no effective cancer treatment is available.

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Bone marrow and stem cell transplantation Two principally different approaches, autologous or allogeneic, may be used in bone marrow transplantation. In both, the initial strategy is to reduce the number of cancer cells in the patient, eg, by using conventional chemotherapy. Thereafter, a final and very powerful treatment is delivered either by chemotherapy alone or in combination with whole-body irradiation. The treatment doses are so strong that the patients own bone marrow is destroyed, and a patients survival depends on the transplantation of new bone marrow. Autologous transplantation involves transplanting the patients own stem cells. Prior to receiving chemotherapy, some of the patients bone marrow is removed and frozen. The method has been simplified by increased use of the blood-forming stem cells from the peripheral blood. The method involves the extraction of stem cells from the patients peripheral blood after chemotherapy and after hemdtopoietic growth factors have been supplied. Today, the procedure for harvesting peripheral stem cells is usually performed on an outpatient basis (6). In allogeneic transplantation, the patient receives bone marrow from another individual. This method has the advantage of being able to create a graft-versus-tumor reaction, ie, the new bone marrow is able to keep any residual tumor cells under control. Earlier, only close relatives were considered as donors. Advancements and the establishment of international donor registers make it increasingly possible to use unrelated donors, thereby increasing the number of potential patients (7). Bone marrow transplantation has been practiced for approximately 15 years, first for hematologic malignancies, but is now being tested for solid tumors, eg, breast cancer. The value of the method is discussed more fully in Chapter 6, but we can assume that the use of bone marrow transplantation will increase.

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Hormone therapy

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The most important applications for endocrine therapy concern two of the most common cancers, breast cancer and prostate cancer. However, it also plays a role for other types of cancer. Approximately 35% of breast cancers and approximately 70% of prostate cancers are hormone sensitive. The possibility of treating breast cancer hormonally was described already in the late 1800s. It was later applied through ablative therapy, ie, resection of hormone-forming organs such as the ovaries, adrenal and pituitary glands. Several hormonal strategies for treating cancer are available today. It is possible to supply drugs that block hormone formation and/or hormonal effects, supply other hormones, eg, female sex hormones to males with prostate cancer, and male sex hormones to women with breast cancer. Endocrine therapy is used mainly for palliative treatment. In breast cancer, large studies have shown that endocrine therapy is also an effective adjuvant strategy to avoid recurrence. Furthermore, antiestrogens have been found to protect against the formation of new primary breast cancers. Against this background, studies in prevention have been started in England and in the United States. Antiestrogens are delivered to healthy women at major risk for developing breast cancer, thereby hopefully preventing cancer from developing. Cancer in the body of the uterus may also be hormone sensitive. Progesterone therapy can potentially achieve long-term tumor shrinkage. In isolated cases it may also have a curative effect. Some types of thyroid cancer can also be treated hormonally. In the future, we can expect the introduction of new agents with better specificity and fewer side effects. We can also expect an increased use of adjuvant strategies. These developments, however, can hardly be expected to radically change the use of other methods of cancer treatment.
Biologic treatment

multiple myeloma, osteosarcoma, and endocrinal gastrointestinal cancers. An interesting observation is that interferon alone has no effect on colorectal cancer. Combined with an anticancer agent, it greatly potentiates the 5-fluorouracil effect (8). Monoclonal antibodies, which more or less have the ability to specifically bind themselves to cancer cells, have been used according to two principles. The first is conjugated, ie, where a substance such as a radionuclide binds to the antibody, which in turn delivers it to the cancer. This method delivers local radiotherapy of tumor cells themselves. Small, and yet preliminary, studies suggest that approximately 20% to 30% of the patients respond to this treatment, a few of whom remain cancer-free for prolonged periods. There is less experience with antibodies that are conjugated with toxins or pharmaceuticals. The relatively few reports on the subject suggest that the effects are similar in magnitude (9). The second principle involves the unconjugated use of the antibodies. The antibodies bind themselves to the tumor cells and can induce the immune system to kill them. The antibodies can also have a directly lethal effect, through a physiological mechanism called programmed cell death. Several thousand patients are being treated according to this principle. Many different antibodies have been used for several cancer diseases. Even here, 20% to 30% of the patients in whom tumors had spread showed tumor shrinkage, isolated cases were cancer-free for many years. Monoclonal antibodies are also being tested as adjuvant treatment. A randomized study of colorectal cancer found a significant reduction in relapse and better survival in the treatment group (10). As early as the 1960s. attempts were made to vaccinate patients against cancer to prevent relapse. Nearly all of these studies were negative. Knowledge has expanded, and we now have a better understanding of the structures that should be tested for immunization. Reported studies, yet with limited data, have yielded encouraging results
(1 1).

Humans have an exceptionally effective immunologic protection system. It has long been debated whether the immune system protects against cancer. The scientific evidence now convincingly shows it does. One form of biologic therapy is immune therapy. It is based on using the immune systems own effector functions, and the substances normally found in the system. Through modern gene technology, a series of substances within the immune system itself have become accessible in large quantities for therapeutic use. Hematopoietic growth factors are one example. In addition to stimulating bone marrow, they can also be used directly in cancer therapy. Interferons were the first substances to become available. They are used, often experimentally, for several cancers such as chronic lymphatic leukemia, hairy-cell leukemia,

Biologic treatment methods are still at an early stage of development and have not yet found their place. Experience thus far suggests that immunotherapy shows potential and will probably play a role in the future, perhaps mainly in adjuvant situations. Major studies are under way to test the prerequisites for genetic therapy. It is yet too early to judge their clinical potential (12).
Adjuvant treatment

Some patients are at greater risk for relapse from their cancer after, eg, surgery has succeeded in removing all visible cancer. Adjuvant treatment involves providing further therapy at this point to reduce the risk for relapse, ie, treatment of potential but not proven disease.

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In principle, all treatment methods may be considered. Of those discussed above, the most commonly used are chemotherapy and endocrine therapy, but also radiotherapy for, eg, breast cancer. In many ways, the adjuvant situation is ideal from a treatment perspective. Patients are often in good condition and not affected by their disease. They have few cancer cells. This should provide the best conditions for curing these patients. The disadvantage of adjuvant therapy is that a substantial proportion of individuals will be treated without benefit, either because they are already cured or because treatment will not be successful and they will relapse in any case. Large randomized studies have shown that, for several types of cancer, adjuvant therapy can reduce the risk for relapse and increase the potential for definitive cure. The same treatment, however, does not cure clinically observable relapse when the number of cancer cells is much higher. There is substantial interest in adjuvant treatment. The trend has been a successive increase in the use of adjuvant therapy. As soon as a therapy is shown to be effective in patients with diffused disease, it is logical to test its adjuvant applications. We have reason to believe this trend will continue (13).

General nursing care


A n important development in recent decades concerns the improvement in care for terminally ill patients. Earlier, health services focused heavily on cure, and patients with incurable disease were more or less abandoned. Now, symptom-relieving treatment, mainly pain therapy, is available. These developments represent substantial gains in the quality of life for this group of patients. Further advancements in this direction can be expected.

REFERENCES
I . Stephens FO, Marsden FW, Storey DW, et al. Developments in surgical oncology-past, present and future trends. Med J Aust 1991; 155: 803-7. 2. Greene FL. Laparoscopic surgery in cancer treatment. Important Adv Oncol 1993; 4: 157-66. 3. Newell DR. Can pharmacokinetic and pharmacodynamic studies improve cancer chemotherapy. Ann Oncol 1994; 5 (Suppl 4): 9-14. 4. Mansouri A, Henle KJ, Nagle WA. Tumor drug-resistance: A challange to therapists and biologists. Am J Med Sci 1994; 307: 438-44. 5 . Gottesman MM. How cancer cells evade chemotherapy: Sixteenth Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 1993; 53: 747-54. 6. Antman KH, Souhami RL. High-dose chemotherapy im solid turnours. 1993; Ann Oncol 4 (Suppl 1): 29-44. 7. Hurd DD. Bone marrow transplantation for cancer: An overview. Recent Results. Cancer Res 1993; 132: 1-14. 8. Einhorn S, Strander H. Interferon treatment of human malignancies- A short review. Med Oncol Tumor Pharmacother 1993; 10: 25-9. 9. Kummer U, Staerz UD. Concepts of antibody-mediated cancer therapy. Cancer Invest 1993; 11: 174-84. 10. Mellstedt H. Unconjugated monoclonal antibodies in cancer treatment-the story so far. Oncology Today 1994; 9: 9-13. 11. Dagleish AG. Cancer vaccines. Eur J Cancer 1994; 30A: 1029-35. 12. Schmidt-Wolf G, Schmidt-Wolf IGH. Human cancer and gene therapy. Ann Hematol 1994; 69: 273-9. 13. Trimble EL, Ungerleider RS, Abrams JA, et al. Neoadjuvant therapy in cancer treatment. Cancer 1993; 72 (Suppl 11): 3515-24.

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Importance of screening and early diagnosis


The main explanation for improved treatment outcomes is that cancer diseases are diagnosed earlier in their course. This has different effects on the utility of various treatment methods, but mainly it means that more patients can be candidates for more complex and resource-demanding curative treatment. Furthermore, many of the patients who cannot be cured will live longer and become candidates for more comprehensive treatment. Patients previously diagnosed at an advanced stage, where the opportunities for active treatment of cancer were limited, have been largely replaced by patients at earlier disease stages where several meaningful strategies for treating cancer might be attempted.