Treatment

Principles of Therapy

In treating cancer it is assumed that all malignant cells should be destroyed, removed, or neutralized to achieve cure, since experimentally the control of tumors requires eradication of the last neoplastic cell. It is not known at present whether successful treatment must eradicate all neoplastic cells or merely reduce the cell number to a level that the host's own defenses can control. Three modalities of therapy exist today: surgery, radiotherapy and chemotherapy (including hormonal treatment). Immunotherapy has experienced a resurgence of interest in the 1980's within a broader context of biologic therapies. Because cancer is not one but 100 or more different diseases, many therapeutic strategies are needed. For some tumors a specific therapy may exist; for others there may be several satisfactory alternatives. Thus, optimal therapy depends not only on the nature and extent of the disease but also on the experience of the treating physician and the treatment facilities available. Each patient requires a proper histological diagnosis of cancer including as appropriate, biochemical and immunological subtyping. Adequate staging to determine the extent of disease allows an appropriate treatment plan to be formulated, the prognosis to be determined, and morbidity and complications to be minimized.

For solid tumors, surgery and radiotherapy are traditionally chosen first to deal with the early locoregional presentation of the disease. Once the disease has disseminated, a systemic therapy such as chemotherapy is needed for secondary or tertiary treatment. Hematologic malignancies are frequently disseminated from the start, so chemotherapy may be the treatment of choice initially.

The multiplicity of diseases and therapies requires a multidisciplinary input from surgical oncologists, radiation oncologists, medical oncologists, and pathologists. The pediatric oncologist has demonstrated the value of a multimodal therapeutic attack on cancer, as shown by advances in the treatment of Wilms' tumor, embryonal rhabdomyosarcoma, and Ewing's sarcoma. More recently, adult oncologists have appreciated the combined modality approach in adult solid tumor therapy. The primary physician works in the prevention and early detection of cancer, and participates in follow-up, supportive and palliative care.

Many tumors that are apparently localized at the time of diagnosis are in fact microscopically dissemi-nated, as subsequent recurrences after attempts at curative locoregional therapy prove. Groups of pa-tients in whom dissemination can be assumed to have occurred at diagnosis in a large percentage of in-stances include breast cancer with positive axillary lymph nodes, colon cancer with penetration through the entire bowel wall or involving regional lymph nodes, and all gastric, pancreatic, and lung cancers after "curative" resection. Current diagnostic tools fail to identify these patients. Thus, a systemic ther-apy, such as chemotherapy in the case of breast or colorectal cancers, is added as an adjuvant to local therapy to reduce recurrences and prolong survival. In this case, "cure" means a life expectancy the same as "normal" life expectancy of a matched cohort in the general population. Neoadjuvant therapy refers to the use of chemotherapy before surgery to allow for more conservative local therapy.

Experimentally, chemotherapy is more effective with smaller tumor cell burdens, since drugs kill by first order kinetics (each dose kills a fixed percentage rather than a fixed number of cells). Thus, adequate cell kill can be achieved with a small tumor burden using a reasonable number of repetitive doses. With a large tumor cell burden the same doses would still leave residual cells, resulting in regrowth of resistant cell populations. For adjuvant regimens, drugs are chosen that can give objective regressions (greater than 50 per cent tumor shrinkage) frequently in advanced disease. It is then assumed that they will achieve total cell kill of the microscopic residual disease remaining after surgical removal of the great mass of tumor bulk. Recent results in the adjuvant therapy of breast cancer and osteogenic sarcoma suggest that this assumption is valid. New chemotherapeutic agents, often with novel mechanisms of action, are entering clinical trials. The first differentiating agent that can be used to treat cancer has recently come into clinical use.

The use of immunotherapy as an adjuvant to surgery and radiotherapy has a similar rationale. However, the modality kills a fixed number of cells per application of treatment and is able to control only small cell numbers. Therefore, regression of advanced disease cannot be used to predict success, and there is no correlation yet established between tumor cell control and the various tests of immune function. The lack of effective monitoring and the empirical approach necessary for design of therapy still make immunotherapy an experimental modality at present. Tumor vaccines and gene transfer strategies are beginning to enter early clinical trials.

The rapid technologic developments in the deliv-ery of these various modalities have made the bulk of cancer therapy deliverable in the outpatient and office setting. This is a significant development for patients who must cope, often for months or years, with their cancer therapy in addition to their normal daily activities.

Implementation of Treatment Programs

Implementation for treatment requires several steps:

• Treatment policies need to be adapted to the predominant patterns of malignant disease in the country and to available resources in a flexible way that responds readily to changes, especially in resources.
• Establish clear referral policies to triage patients appropriately.
• Integrate treatment with early detection programs.
• Identify groups of patients who are suitable for curative, maintenance or palliative therapy.
• Put in place a national committee to formulate treatment guidelines specific to cancer site and stage.
• An information system will also be needed to allow for monitoring and evaluation of the program.

The basic model of education, legislation and national leadership is modified for treatment as follows:

• Provide for the availability of the major modalities of cancer treatment: surgery, radiotherapy and chemotherapy.
• Provide potentially curative treatment for localized, early disease that is integrated with screening.
• For locally extensive disease provide curative or palliative therapy appropriate to tumor type and available resources.
• Provide palliative treatment and care for disseminated, advanced disease.

Process, impact and outcome measures are used to monitor and evaluate treatment programs. Examples might include (WHO,1995):

DeVita VT Jr, Hellman S and Rosenberg SA Eds (1997) Cancer. Principles and Practice of Oncology. Ed 5. Lippincott-Raven, Philadelphia.
DeVita VT Jr, Hellman S and Rosenberg SA Eds (1995) Biological Therapy of Cancer. Ed 2. Lippincott-Raven, Philadelphia.
Jamison DT, Mosley WH, Measham AR and Bobadilla JL Eds (1993) Disease Control Priorities in Developing Countries. Oxford Medical Publications, New York.
MacDonald JS, Haller DG & Mayer RJ (1995) Manual of Oncologic Therapeutics. Ed 3. JB Lippincott Co.,Philadelphia.
Perez CA & Brady LW (Eds) Principles and Practice of Radiation Oncology. Ed 3, Lippincott-Raven, Hagerstown MD, 1998.
Pizzo PA & Poplack DG. Principles and Practice of Pediatric Oncology. Ed 3, Lippincott-Raven, Hagerstown MD, 1997.
WHO (1995) National Cancer Control Programmes. Policies and Managerial Guidelines. World Health Organization, Geneva.
Winchester DP (Ed). Tumor Board Case Management. Lippincott-Raven, Hagerstown MD, 1997.

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