The Challenge of Chemotherapy: Past, Present, Future Mary B. Uhlenhopp, RN, MS, MPH The field of oncology is advancing at a rapid pace, and oncology nurses are challenged to keep abreast of new therapies, technologies, and innovations. Available resources to assist nurses with change are increasing exponentially, and can be both helpful and overwhelming. While learning about new therapies is crucial, relearning essentials such as interpreting laboratory data is of equal benefit. With improved cure rates of some cancers, longer treatment phases, and more dose-intense regimens, the recognition and management of late effects of therapies take on greater significance as well. At the 26th Congress of the Oncology Nursing Society (ONS) in San Diego, California, nurses from around the world shared their experiences and expertise for the purposes of education, enrichment, and collaboration. Compiled here are the highlights of several sessions on chemotherapy, biotherapy, and their related side effects. These sessions focused on the past (late effects of therapy), the present (clinical application of laboratory data), and the future (new treatments). The Past: Late Effects of Therapy As the incidence of childhood cancers has increased, so too have cure rates. Long-term survivors of cancer therapies are known to have a greater risk of multiple long-term effects as well as secondary cancers. Patsy McGuire-Cullen, RN, MSEd, CPNP, CPON, a Pediatric Nurse Practitioner from Childhood Hematology-Oncology Associates in Denver, Colorado, presented a review of second or subsequent neoplasms.[1] Isolating prior cancer therapy as the cause of subsequent malignancies is difficult if not impossible. The causes of most cancers remain multifactorial, follow-up for most late-effects studies is too short, and treatment regimens frequently change, making conclusions difficult. However, ongoing studies are attempting to clarify some of the late effects of therapy. From prior studies and clinical data, it is known that bone and soft tissue sarcomas are more likely to develop in radiation fields. Female survivors of Hodgkin's disease have a 35-fold greater risk of developing breast cancer than the general population. Head and neck cancer patients who have had radiation to the neck region have an increased risk for thyroid cancer. Patients treated with cranial radiation have a greater propensity to develop central nervous system tumors.[1] Treatment with alkylating agents and anthracyclines carries a low but significant risk of late effects such as leukemia. With more and more high-dose, dose-intense therapies and larger numbers of patients receiving bone marrow transplantation, one could surmise that the number of patients with second malignancies will also grow. Our role as nurses is to counsel patients to minimize lifestyle and environmental exposures. Patients should avoid the sun, stop smoking, eat a low-fat, high-fiber diet, and exercise. Children of patients who received thoracic radiation should be advised to begin breast self-exam during puberty. The Present: The Clinical Application of Laboratory Data Oncology nurses use laboratory data daily; however, we could all benefit from a review of the clinical applications of these data. In a session at the ONS Congress,[2] nurses were re-educated about how laboratory data can be used not only to assess but to anticipate treatment response. Kimberly Luebbers, RN, BSN, OCNŽ, an Ambulatory Oncology Nurse from Fletcher Allen Health Care in Burlington, Vermont, is both a medical technologist and a nurse. Her valuable presentation shed light on the often dry topic of hematologic laboratory values. The causes of neutropenia are varied (Table 1). Medical oncology nurses calculate the absolute neutrophil count (ANC) every day (ANC = total white blood cell count [WBC] x % of neutrophils [segments and bands]). Recent studies recommend using this calculation and first cycle nadir WBCs (the lowest peripheral blood count after chemotherapy) after the first chemotherapy cycle to predict a person's risk for neutropenic episodes (neutrophil count less than 2500/mm3) and the need for supportive growth factors during the entire course of treatment. Table 1. Causes of Neutropenia Treatment-Related * Chemotherapy * Radiation therapy * Surgery * Corticosteroids Viral Disease Lymphocytic, Monocytic Leukemias, Anemia Marrow Invasion Drug Induced * Antibiotics * Immunosuppressive drugs Hypersplenism Congenital Causes New models to assess first cycle nadir counts are being tested to predict the probability of subsequent events and determine the need for supportive growth factors early in the course of treatment.[3-5] The concept behind this model is to predict the requirement of growth factors, administer the therapy on time, and minimize or potentially eliminate the need to reduce chemotherapy dose. Achieving these targets would maximize the potential of therapy. Optimal dosing and timely administration of chemotherapy is critical. The use of risk models such as the Silber model validated by Savvides and colleagues[4] is used to assess risk of nadir events and determine the need for supportive growth factors, and can offer new and effective means to improve quality of care. Laboratory Values Relating to Anemia Ms. Luebbers also reviewed the use of mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), reticulocyte count, and erythropoietin levels as values that can be useful in the prediction, assessment, and treatment of anemia. MCV indicates the size of the red blood cell (RBC). Microcytic, normocytic, and macrocytic are terms used to identify cell size. MCHC measures the hemoglobin concentration per unit of RBC volume. MCV and MCHC are used to help identify the type of anemia (Table 2). Table 2. MCV in Anemia Increased MCV Decreased MCV Folic acid deficiency Iron deficiency B12 deficiency Thalassemia Sideroblastic anemia Anemia of chronic disease Rheumatoid disease Cancer-related anemia Severe chronic infection MCV, mean corpuscular volume RDW denotes the size difference among RBCs. This value is useful in predicting anemias early, before changes occur in the MCV and before signs and symptoms of anemia occur. Reticulocyte count is an indicator of bone marrow activity. The reticulocyte count will be elevated due to hemolysis or hemorrhage, during treatment for leukemia-related or pregnancy-related anemia, or during treatment with B12 iron or folic acid. This value is decreased in anemia related to radiation therapy, adrenal cortical hyperfunction, and alcohol consumption. Erythropoietin is a hormone that is produced primarily by the kidneys. Baseline levels are helpful to determine possible response to epoetin alfa trials for anemia. In general, patients with lower baseline erythropoietin levels respond better to exogenous epoetin alfa than those with higher baseline levels. Although there is no specific level above which patients will not respond to epoetin alfa, it is generally suggested that patients with erythropoietin levels greater than 200 mU/mL should not be treated with epoetin alfa.[6] In summary, the picture of anemia may present as follows: * Normal WBC * Hemoglobin and hematocrit decreased * MCV decreased * MCHC decreased * RDW decreased * Platelets increased * Serum ferritin level decreased * Serum iron level decreased * Iron binding capacity increased The Future: New Therapies With antiangiogenesis inhibitors, epidermal growth factor receptor inhibitors, enzyme inhibitors, gene therapy, photosensitizers, and other new biotherapeutic agents flooding the field, oncology nurses are challenged to understand the therapeutic mechanisms and know the names or abbreviations of therapies being evaluated. Over the years, the volume of research devoted to chemotherapies and biotherapies has increased significantly. Searching cancer trials on the Internet via the National Cancer Institute (NCI) Physician Data Query system at http://cancertrials.nci.nih.gov reveals that, including the NCI and other cooperative groups worldwide, there are: * 736 biologic response modifier trials * 414 cytokine therapy trials (76 of which are anticytokine studies) * 71 antiangiogenesis trials * 23 gene therapy trials * 17 kinase inhibitor trials The Pharmaceuticals Research and Manufacturers of America recently reported that there are 402 cancer medications in the pipeline, compared with 215 medications 6 years ago.[7] At the ONS Congress, several speakers clarified the actions and uses of many of the newer therapies. A few key therapies are presented here. Major advances in the understanding and identification of genes, cell characteristics, cell proteins, and receptors have paved the way toward new, more targeted therapies. Deborah Rust, RN, MSN, CRNP, AOCNŽ, Coordinator of the Oncology Nurse Practitioner Program at the University of Pittsburgh, Pennsylvania, and Kristi Kay Orbaugh, RN, MSN, RNP, AOCNŽ, of Indiana Oncology Hematology Consultants, Indianapolis, Indiana, provided a comprehensive overview of new molecular targeted therapies, updated new therapies, and thoughtfully reviewed the process of tumor growth.[8] The proliferation of tumors is a result of either the activation of an oncogene or the deactivation of tumor suppressor genes.[9] These processes lead to the development of abnormal or excessive proteins. Protein products initiate coordinated signals on the cell surface, such as the binding of growth factors to receptors on the cell surface. The binding activates enzymes that communicate within the cell to activate signal transduction. The overexpression of proteins on the cell surface leads to structural alterations of the cell or alteration of the signal transducers. The result of this series of alterations is the development of malignant cell characteristics: uncontrolled cell proliferation, loss of contact inhibition, and the development of resistance to therapy. Biotherapy/Chemotherapy Update Tyrosine kinase inhibitors. Tyrosine kinase inhibitors inhibit signal transduction and cell growth. The overexpression of epithelial growth factor receptors has been associated with several types of cancer. Therapies that target these and other such receptors are examples of tyrosine kinase inhibitors and signal transduction inhibitors. Trastuzumab (Herceptin) interferes with an epidermal growth factor receptor binding to receptor and inhibits proliferation. Other tyrosine kinase inhibitors under evaluation are IMC C225, ZD 1839 (Iressa), CCI 779, and SU 101.[10-13] Of special note is the unusually rapid US Food and Drug Administration (FDA) approval of imatinib mesylate (Gleevec) on May 10, 2001. Imatinib mesylate is the first approved drug to directly turn off the signal of a protein known to cause cancer.[13] Other molecular-targeting drugs interfere with proteins associated with cancer but not with proteins that directly cause the disease. Imatinib mesylate was initially developed to treat chronic myelogenous leukemia; however, it now appears to work in a rare type of cancer called gastrointestinal stromal tumor. It is also being evaluated in clinical trials for glioblastoma and leukemia. Imatinib mesylate is administered orally and its side effects include swelling, cramps, nausea, and, in some cases, severe anemia. Long-term effects are unknown at this time. IMC C225, like trastuzumab, is a monoclonal antibody that prevents tyrosine kinase activity. It is an antiepidermal growth factor receptor and inhibits proliferation.[10] IMC C225 is not yet FDA-approved, and it is being evaluated for colorectal cancer as a single agent and in combination with chemotherapy agents. ZD-1839 is another investigational oral epidermal growth factor tyrosine kinase inhibitor that has been tested alone and in combination with various cytotoxic agents in ovarian, breast, and colon cancer.[14] It is being evaluated in lung and prostate cancers as well. In combination with chemotherapy, apoptosis (cell suicide) was markedly increased. Alemtuzumab (Campath IH) was also recently approved by the FDA and is a monoclonal antibody that binds to CD52 on T and B cells in prolymphocytic or chronic lymphocytic leukemia that has become refractory.[15] Major side effects include allergic reactions and possible severe leukopenia and/or prolonged protracted pancytopenia. Consequently, patients are treated prophylactically with antibiotics, antifungals, and antivirals during therapy and for 3 months after the completion of therapy. Antiangiogenesis Agents The field of antiangiogenesis agents is a vital area of research. It has taken years of investigation to learn how to decipher and interrupt the genetic control of tumors since Dr. Judah Folkman introduced the concept of angiogenesis in 1971.[16] Ms. Rust reviewed the concept of angiogenesis and described how tumors cannot grow beyond 1 mm to 3 mm without developing new vasculature. A collection of tumor cells requires the nourishment of oxygen for growth. The further the tumor is from major blood vessels, the lower the rate of cell replication; and the denser the blood vessel formation, the higher the rate of tumor formation and the greater the metastatic potential. Carol Hill, RN, OCNŽ from Emory University in Atlanta, Georgia, reported on carboxyamidotriazole (CAI).[17] CAI is an oral angiogenesis inhibitor that was first developed to treat parasites in chickens. It was found to inhibit a broad spectrum of tumor cells such as melanoma, lymphoma, prostate, colon, renal, and brain tumor cells. It was then chosen for development because of antiproliferative and antimetastatic activity against several human tumor cells in vitro and in vivo. It appears to cut off blood supply to cancer cells by inhibiting certain proteins involved in signal transduction by inhibiting calcium influx.[12] Other antiangiogenesis agents under investigation include marimastat, neovastat, endostatin, thalidomide (being investigated for "off-label" activity), SU5416, SU6668, interferon alfa, suramin, and others (Tables 3-6). Table 3. Angiogenesis Inhibitors Under Investigation That Block Matrix Breakdown Drug Trial Mechanism Marimastat Phase 3 small-cell lung, breast cancers Synthetic inhibitor of MMPs COL-3 Phase 1/2 brain cancer Synthetic MMP inhibitor, tetracycline derivative Neovastat Phase 3 renal cell (kidney) cancer. Phase 3 nonsmall-cell lung cancer Naturally occurring MMP inhibitor BMS-275291 Advanced or metastatic nonsmall-cell lung cancer Synthetic MMP Adapted from http://cancertrials.nci.nih.gov/news/angio/table.html. MMP, matrix metalloproteinase Table 4. Angiogenesis Inhibitors Under Investigation That Inhibit Endothelial Cells Directly Drug Trial Mechanism Thalidomide Phase 1/2 for advanced melanoma. Phase 2 ovarian cancer, metastatic prostate cancer, and Kaposi's sarcoma. Phase 2 with chemotherapy against solid tumors; adjuvant study in recurrent or metastatic colorectal cancer. Phase 2 gynecologic sarcomas, liver cancer, multiple myeloma, chronic lymphocytic leukemia. Phase 3 nonsmall-cell lung cancer, nonmetastatic prostate cancer, refractory multiple myeloma, renal cancer. Inhibits cell proliferation Endostatin Phase 1 solid tumor studies Inhibition of endothelial cells Adapted from http://cancertrials.nci.nih.gov/news/angio/table.html Table 5. Angiogenesis Inhibitors Under Investigation That Block Activators of Angiogenesis Drug Trial Mechanism SU 5416 Phase 1 recurrent head and neck cancer, advanced solid tumors, stage IIIB or IV breast cancer. Phase 1 advanced malignancies. Recurrent or progressive brain cancer (pediatric). Phase 1 with chemotherapy against solid tumors. Phase 1/2 acute myeloid leukemia, advanced malignancies, advanced colorectal cancer, recurrent brain cancer. Phase 2 von Hippel-Lindau disease, advanced soft tissue cancer. Phase 2 prostate cancer, metastatic melanoma, multiple myeloma, malignant mesothelioma, metastatic renal cancer, advanced or recurrent head and neck cancer. Phase 3 metastatic colorectal cancer. Blocks VEGF receptor signaling SU 6668 Phase 1 against advanced tumors Blocks VEGF, FGF, and PDGF receptor signaling Interferon-alfa Phase 2/3 renal cancer, myeloid leukemias, melanoma, myeloma, prostate cancer, lymphoma, meningioma. Inhibition of bFGF and VEGF production Anti-VEGF antibody Phase 1 refractory solid tumors. Phase 2 metastatic renal cell cancer. Phase 2 with chemotherapy in untreated advanced colorectal cancer, metastatic breast cancer. Phase 3 with chemotherapy in untreated metastatic colorectal cancer. Monoclonal antibody to VEGF Adapted from http://cancertrials.nci.nih.gov/news/angio/table.html. VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; bFGF, basic fibroblast growth factor Table 6. Angiogenesis Inhibitors Under Investigation With Nonspecific Mechanisms of Action Carboxyamidetriazole Phase 1 studies in combination against solid tumors. Phase 2 ovarian cancer, metastatic renal cell cancer. Inhibitor of calcium influx Interleukin 12 Phase 1/2 Kaposi's sarcoma Upregulation of interferon gamma and IP-10 IM 862 Phase 1 recurrent ovarian cancer. Phase 2 for untreated metastatic cancers of the colon and rectum; Phase 3 Kaposi's sarcoma Unknown mechanism Adapted from http://cancertrials.nci.nih.gov/news/angio/table.html In summary, oncology nurses can provide higher quality care to patients when they are knowledgeable and up-to-date about new therapies, new assessment and monitoring techniques, and other topics important in the care of the patient with cancer. References 1. McGuire-Cullen P, Ruccioni K, Ruble K. The long and short of it: assessment and management of late effects. Program and abstracts of the 26th Congress of the Oncology Nursing Society; May 17-20, 2001; San Diego, California. Instructional Session 27. 2. Ireland AM, Luebbers KP, Singer M. Fitting the pieces together: clinical application of laboratory data. Program and abstracts of the 26th Congress of the Oncology Nursing Society: May 17-20, 2001; San Diego, California. Instructional Session 2. 3. Thomas ES, Rivera E, Erder H, Fridman M, Frye D, Hortobagyi GN. Using first cycle nadir absolute neutrophil count (FCNANC) as a risk factor for neutropenic events: a validation study. Program and abstracts of the 37th Annual Meeting of the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, California. Abstract 144. 4. Savvides P, Terrin N, Erban J, Selker HP. Development and validation of a patient-specific predictive instrument for the need for dose-reduction in chemotherapy for breast cancer: a potential decision aid for the use of myeloid growth factors. Program and abstracts of the 37th Annual Meeting of the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, California. Abstract 972. 5. More T, Shiftan TA, Knight CA, et al. A prospective trial assessing a risk model for filgrastim use on chemotherapy (CT) dose intensity (DI) in the adjuvant treatment of stage I-II breast cancer patients. Program and abstracts of the 37th Annual Meeting of the American Society of Clinical Oncology; May 12-15, 2001; San Francisco, California. Abstract 1778. 6. Medscape DrugInfo. Epoetin alfa injection: uses & dosage. Available at: http://promini.medscape.com/drugdb/drug_uses_dosage.asp?DrugCode=2%2D4553&Dr ugName=EPOETIN+ALFA+INJECTION&DrugType=1 <http://promini.medscape.com/drugdb/drug_uses_dosage.asp?DrugCode=2%2D4553&D rugName=EPOETIN+ALFA+INJECTION&DrugType=1> . Accessed June 8, 2001. 7. Pharmaceutical Research and Manufacturers of America. PhRMA survey finds 402 medicines in the pipeline for cancer. March 29, 2001. Available at: http://www.phrma.org/press/newsreleases//2001-03-29.203.phtml. Accessed May 28, 2001. 8. Orbaugh KK, Anton ML, Rust DM, Binnie C. Hot topics -- clinical. Program and abstracts of the 26th Congress of the Oncology Nursing Society; May 17-20, 2001; San Diego, California. Instructional Session 17. 9. DeVita T Jr, Hellman S, Rosenberg SA, eds. Principles & Practices of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven; 1997: 3087-3092. 10. Waksal HW. Role of an anti-epidermal growth factor receptor in treating cancer. Cancer Metastasis Rev. 1999;18:427-436. 11. Ciardiello F, Caputo R, Bianco R, et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res. 2000;6:2053-2063. 12. Strawn LM, Kabbinavar F, Schwartz DP, et al. Effects of SU101 in combination with cytotoxic agents on the growth of subcutaneous tumor xenografts. Clin Cancer Res. 2000;6:2931-2940. 13. Cancer Trials, National Cancer Institute. Digest page: STI571 (GleevecTM). Available at: http://cancertrials.nci.nih.gov/types/leuk/sti571/index.html. Accessed May 27, 2001. 14. Pitot HC, Golberg RM. Future directions in adjuvant therapy for stage III colon carcinoma. Oncology. 2001;15(suppl 5):31-36. 15. Weiss MA. Novel treatment strategies in chronic lymphocytic leukemia. Curr Oncol Rep. 2001;3:217-222. 16. Brem S. Angiogenesis and cancer control: from concept to therapeutic trial. Available at: http://www.moffitt.usf.edu/pubs/ccj/v6n5/article2.htm. Accessed May 27, 2001. 17. Hill C. Carboxyamidotriazole (CAI), an oral antiangiogenic agent: nursing implication of phase II clinical trials. Program and abstracts of the 26th Congress of the Oncology Nursing Society; May 17-20, 2001; San Diego, California. Abstract 8. Edward E. Rylander, M.D. Diplomat American Board of Family Practice. Diplomat American Board of Palliative Medicine.