Chemotherapy

Cancer Chemotherapy
Cytotoxic drugs, hormones, antihormones, and biologic agents have become increasingly effective means of treating cancer. Many patients are treated on protocols to provide optimal therapy for refractory or poorly responsive malignancies. Treatment may be inadequate or ineffective because of drug resistance of the tumor cells. This has been attributed to spontaneous genetic mutations in subpopulations of cancer cells prior to exposure to chemotherapy. After chemotherapy has eliminated the sensitive cells, the resistant subpopulation grows to become the predominant cell type (Goldie-Coldman hypothesis). This has been the basis of alternating non-cross-resistant chemotherapy regimens.
Molecular mechanisms of drug resistance are now the subject of intense study. In many instances, specific drug resistance results from an amplification in the number of gene copies for an enzyme inhibited by a specific chemotherapeutic agent. A more general form of "multidrug resistance" (MDR) has been described in association with expression of a gene (MDR1) encoding a transmembrane glycoprotein of MW 170 (P-glycoprotein) on tumor cells. This protein is an energy-dependent transport pump that facilitates drug efflux from tumor cells and promotes resistance to a broad spectrum of unrelated cancer drugs. Acquired multidrug resistance in multiple myeloma and lymphoma has been reversed clinically by adding the calcium channel blocker verapamil to chemotherapy regimens. Unfortunately, the doses of verapamil required to overcome drug resistance are associated with cardiovascular side effects. High doses of cyclosporine appear to increase the cytotoxicity of etoposide both in vitro and in vivo, probably by inhibiting the function of P-glycoprotein. The use of cyclosporine to enhance the effect of etoposide in purging resistant tumor cells in vitro from autologous bone marrow is under investigation. Cyclosporine has also been shown to enhance the cytotoxic effect of multiagent chemotherapy against resistant multiple myeloma. Verapamil and cyclosporine increase the accumulation and cytotoxicity of daunorubicin in myeloid leukemia cells, enhancing cell kill. MDR modulators will need to be both less toxic and more potent to be clinically useful. An example is the cyclosporine analog PSC 833, with little of the immunosuppressive effects or renal toxicities of cyclosporine but with five- to tenfold greater MDR-modulating activity.
Chemotherapy is used to cure a small percentage of malignancies, as adjuvant therapy to decrease the rate of relapse or improve the disease-free interval, and to palliate symptoms in some patients with incurable malignancies. In addition, chemotherapy may play a role as preoperative or "neoadjuvant" therapy to reduce the size and extent of the primary tumor, thereby allowing complete excision at the time of surgery. Chemotherapy was first shown to be curative in the treatment of advanced stages of choriocarcinoma in women. It is also curative in Hodgkin's disease, diffuse large-cell and some high-grade lymphomas (including Burkitt's), carcinoma of the testis, some cases of acute leukemia, and embryonal rhabdomyosarcoma. When combined with initial surgery—and in some instances with irradiation—chemotherapy increases the cure rate in Wilms' tumor and increases the rate of long-term control and cure of breast cancer, colon cancer, rectal cancer, and osteogenic sarcomas. Combination chemotherapy provides palliation and prolongation of survival in adults with Hodgkin's disease, non-Hodgkin's lymphoma, mycosis fungoides, multiple myeloma and macroglobulinemia, acute and chronic leukemias, and breast, ovary, and small-cell lung carcinoma as well as carcinoid. Patients with incurable tumors who desire aggressive treatment should be referred for experimental protocol therapy. Tumor cell vaccines combined with immune adjuncts are under investigation as specific immunotherapy for chemotherapy-resistant tumors such as malignant melanoma.
High-dose chemotherapy followed by bone marrow transplantation is curative therapy for various types of leukemia, multiple myeloma, and high-risk lymphoma and testicular cancer. Allogeneic or autologous bone marrow or peripheral blood stem cells with or without ex vivo purging is used depending on the disease. The use of growth factors and blood stem cells has decreased the toxicity and cost of bone marrow transplantation. Autologous transplantation may now be used with low morbidity and mortality on selected patients up to age 70. In addition, dose-intense chemotherapy regimens with autologous bone marrow or peripheral blood progenitor cell rescue are currently being investigated in the high-risk adjuvant or early relapse setting for patients with carcinoma of the breast and ovaries. A small study suggests that intensive doses of chemotherapy followed by bone marrow or peripheral blood stem cell infusion in incurable diseases such as metastatic breast cancer may prolong survival. It is possible that this aggressive approach may be useful even when "cure" is not the objective.
While most anticancer drugs are used systemically, there are selected indications for local or regional administration. Regional administration involves direct infusion of active chemotherapeutic agents into the tumor site (eg, intravesical therapy, intraperitoneal therapy, hepatic artery infusion with or without embolization of the main blood supply of the tumor). These treatments can result in palliation and prolonged survival.
A summary of the types of cancer responsive to chemotherapy and the current treatments of choice is offered in Table 4–3. In some instances (eg, Hodgkin's disease), optimal therapy may require a combination of therapeutic resources, eg, radiation plus chemotherapy rather than either modality alone. Patients with stages I, II, and IIIA Hodgkin's disease are often treated with radiation alone, avoiding the potential toxicity of systemic chemotherapy. A small percentage of these patients may require chemotherapy later for disease recurrence.
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