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Innovative therapies in hematology and oncology
NEW CHALLENGES IN INTERNAL MEDICINE
0025-7125/92 $0.00 + .20
INNOVATIVE THERAPIES IN HEMATOLOGY AND ONCOLOGY David S. Hanson, MD, and Burke J. Brooks, Jr, MD
Over the last several years, there have been major advances in both prevention and treatment of many of the major cancers that afflict individuals in North America. In this article, we briefly review the major advances that have been made in both the prevention and treatment of lung, breast, and colon cancer, which currently are the most common, lethal cancers in North America in 1992. We also show how many of the advances in these therapies have been the result of large cooperative group trials that have involved the participation of many individuals from both the United States and Canada, and how the collaboration of various investigators from universities, group practices, and community-based practices have led the advances in the treatment and prevention of these malignancies. We also would like to show how the recent advances in biotechnology have led to the introduction into clinical practice of innovative growth factors, such as erythropoietin and the colony-stimulating factors. These exciting compounds will change the way clinical medicine is practiced, not only in hematology and oncology but in many other areas of medicine in the next several years. HEMATOPOIETIC GROWTH FACTORS
A vast array of glycoproteins stimulates the proliferation and differentiation of hematopoietic progenitor cells along multiple pathways (Fig. 1).17,58,62 Recently, four of these factors have been purified From the Department of Hematology and Oncology, Ochsner Clinic of Baton Rouge, Baton Rouge, Louisiana THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76' NUMBER 5' SEPTEMBER 1992
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Stem Cells
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~ ~ ~ -IL--3-+:::=- @; _ IL-6 ~ GM-CSF
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Figure 1. Schema of hematopoiesis. G-CSF = granulocyte colony-stimulating factor; GMCSF = granulocyte-macrophage colony-stimulating factor; M-CSF = monocyte colony-stimulating factor; EPO = erythropoietin; IL = interleukin; Mega-CSF = megakaryocyte colonystimulating factor. (From Champlin RE: Therapeutic use of hematopoietic growth factors for patients receiving high-dose chemotherapy and bone marrow transplantation. Cancer Bull 43:197-207, 1991; Copyright © 1991 by Medical Arts Publishing Foundation, Houston, Texas; with permission.)
and characterized biochemically in culture, and the human genes for these factors have been cloned, thus providing sufficient quantities of functional protein for clinical trials. 46, 47, 50, 66, 86-88 Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are both cytokines that stimulate the growth and differentiation of the pluripotential hematopoietic progenitor cells as well as more differentiated cells that are committed to myeloid, megakaryocytic, and even erythroid progeny, IL-3, also called multipotentialCSF, seems to act at an earlier stage in cell development than GM-CSF. The remaining two proteins cloned thus far are granulocyte colonystimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF). Both of these proteins exert their stimulatory effect in a much more lineage-specific fashion, stimulating maturation of granulocytes and monocytes respectively. 17, 58, 62 Over the past several years, the hematopoietic growth factors have been evaluated in both the laboratory and the clinic. G-CSF and GMCSF are both commercially available and are being investigated in phase II and phase III trials. IL-3 and M-CSF are undergoing phase I and phase II studies. Several areas of possible application of these growth factors include (1) stimulation of hematopoietic recovery after myelosuppressive chemotherapy, (2) enhancing bone marrow engraftment and recovery after marrow ablative therapy and bone marrow transplantation, (3) stimulation of the bone marrow in cytopenic states, such as myelodysplastic syndromes, aplastic anemia, lymphoproliferative disorders, congenital or cyclic neutropenia, and acquired immunodeficiency syndrome related cytopenias.
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G-CSF
G-CSF stimulates cells capable of differentiating into mature neutrophils. 17, 58, 62 G-CSF has been approved by the US Food and Drug Administration to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of neutropenia with fever. Phase I and 11 studies have shown that G-CSF can be administered safely to patients receiving myelosuppressive chemotherapy, and in all cases, a dose-dependent increase in white blood cell counts was found. In addition, administration of GCSF was shown to reduce the duration of absolute neutropenia as well as the incidence of febrile neutropenic episodes. 10, 34 GM-CSF
GM-CSF stimulates granulocyte/macrophage and eosinophil progenitor cell division and differentiation as well as possibly a number of effector functions. 17, 58, 62 GM-CSF has been approved by the US Food and Drug Administration for the acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). Several phase I and 11 studies have examined the effects of GM-CSF administration in patients undergoing chemotherapy for solid tumors as well as patients undergoing autologous bone marrow transplantation for solid tumors and non-Hodgkin's lymphoma.3, 9, 34, 37 Although these studies clearly demonstrate that both G-CSF and GM-CSF enhance white blood cell recovery after treatment with chemotherapy, further trials are required to evaluate the efficacy and toxicity of multiple cycles of chemotherapy with growth factor support and to define the optimal dose and schedule of drug administration. M-CSF
Laboratory studies have shown that monocyte colony-stimulating factor (M-CSF or CSF-I) can be cloned and that it stimulates both differentiation and proliferation of macrophages and growth stimulation of pluripotent stem cells. 86 Enhanced antibody mediated cellular cytotoxicity has been shown to be induced by M-CSF.64 In addition, M-CSF may also produce direct antitumor effects and is currently being evaluated in an experimental malignant melanoma model. 43 IL-3
Laboratory studies show that IL-3 is a hematopoietic growth factor that induces renewal of pluripotent stem cells and differentiation of
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these cells into committed myeloid, erythroid, and megakaryocytic progenitors. 79 Interleukin-3 also stimulates monocyte cytotoxicity and enhances histamine production by basophils. 11,82 Phase I clinical trials have shown that IL-3 can be safely administered to humans. Patients with adequate bone marrow generally responded to therapy with an increase in white blood cells, whereas in patients with bone marrow failure, hematologic responses were more sporadic. Toxicities observed included predictable fever and chills, headache, and bone pain at higher doses. IL-3 will likely be most useful in combination with other growth factors in attempts to more closely mimic in vivo hematopoiesis. 35 , 49
ERYTHROPOIETIN
One of the most exciting areas in the biotechnologic applications of growth factors to clinical medicine has been the introduction of erythropoietin. Erythropoietin was first found to be an erythropoietic factor in the 1950s. 23 , 73 The gene for erythropoietin was cloned by investigators from Amgen and Genetics Institute in 1985. 44 ,52 It was from 1986 to 1987, a period of only 2 years, during which the first clinical trials demonstrating the effectiveness of erythropoietin in dialysis patients occurred. 26, 69, 85 Since then, erythropoietin has been used in a number of experimental settings and is currently licensed by the US Food and Drug Administration for the treatment of anemia secondary to chronic renal failure in both dialysis and predialysis patients and for the treatment of anemia induced by zidovudine in AIDS patients. Erythropoietin is a glycoprotein produced by the kidney that has been found to have distinct effects on the erythropoietic progenitor cells. A number of investigators have shown that in anemia related to blood loss or iron deficiency, there is an inverse relationship with a marked increase in the level of erythropoietin with decreasing levels of hemoglobin (Fig. 2).24 A number of refractory anemias have been shown to be able to be corrected by the administration of erythropoietin. 74 In a number of disease states in which anemia develops, such as chronic inflammation, rheumatoid arthritis, or cancer, some individuals have an inadequate erythropoietin response to their degree of anemia. 24, 53, 60,71,72 It is in these individuals that erythropoietin is being investigated, and it is fair to say that in the years to come the use of erythropoietin for treatment of well-defined disease entities will become more frequent so that anemia of chronic disease will be segregated into those diseases that are erythropoietin responsive or nonresponsive. 7, 24, 25, 41, 71, 72 Erythropoietin has also been shown to increase preoperative blood collections. In a study by Goodnough et al, 39 the amount of blood able to be collected for patients undergoing elective joint replacement was shown to be markedly increased in the group receiving erythropoietin
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Figure 2. Normal inverse relationship between hematocrit and serum erythropoietin. (Adapted from Erslev AJ: Erythropoietin drug therapy. N Engl J Med 324:1340, 1991; with permission.)
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Hematocrit
at the time of preoperative blood collection. It is hoped that current studies are able to demonstrate the exact dose and schedule of erythropoietin necessary to augment autologous blood donation and perhaps this agent's use in the perioperative period to augment one's own blood. The major limiting factor in the use of erythropoietin now is its cost. Currently in the United States, the commercial cost of the drug is approximately $1.00 per 100 units. Usual doses are 50 u/kg two to three times per week. As one can see from this, the cost of treatment of a 70-kg individual at the dose of 50 U/kg three times a week can exceed $400 US dollars per month, thus making cost an important factor in the drug's use. In the well-defined disease states in which repeated blood transfusions are needed to maintain the patient's well-being, early studies have shown that this is a cost effective and safe way of maintaining the patient's hemoglobin. 27, 38, 41 The key in the future will be to better define which individuals in these various disease states could benefit from erythropoietin therapy. LUNG CANCER
In 1991 there will be over 160,000 new cases of lung cancer diagnosed in the United States. IS Of these, more than 90% of the patients will die of their cancer within 5 years. s New and innovative therapies in this malignancy are needed to offset this devastating toll. The number of cases of small cell lung carcinoma (SCLC) in the United States will be approximately 48,000 cases, more cases than all of Hodgkin's and non-Hodgkin's lymphoma combined. Approximately one third of these cases' of SCLC will be confined to the chest after extensive staging and are called limited stage SCLC. These patients have the best chance of cure, and many studies show a 3-year survival
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of 10% to 15%. 7H In SCLC, which has been traditionally treated with chemotherapy, there have been exciting advances in the use of combined modality therapy with chemotherapy and radiation therapy. Based on experimental studies done at the National Cancer Institute by Carney et al, 12 in vitro cell work has shown that SCLC cell lines are much more sensitive in vitro to the effects of radiation therapy when the radiation is given in smaller divided doses with an interval of approximately 4 hours between radiation treatments, thus allowing for repopulation of normal cells at the expense of continued killing of tumor cells. This experimental cell biology work has been taken to the bedside in a series of early trials that have demonstrated improvements in survival of patients given combination cis-platinum/etoposide (VP16) with twice daily radiation. 45. SI Several cooperative groups are currently enrolling patients in continuing trials comparing standard once daily radiation therapy plus cis-platinumIVP-16 versus twice a day radiation plus cis-platinumIVP-16 in the hopes of improving the longterm survival of patients with limited stage SCLC. Nonsmall cell lung carcinoma (NSCLC), which currently accounts for 75% of all lung cancer diagnosed in the United States, has had some new clinical information come to light. Next to prevention, the best treatment for early stage NSCLC (stage 1, II) is clearly surgical removal of the cancer and adjacent lymph nodes. In the treatment of stage II NSCLC, two studies are well worth noting. Patients who have had totally resected NSCLC have traditionally undergone external beam radiation therapy in hopes of preventing local recurrence of the cancer in the chest as well as preventing distant metastasis. A recently reported trial from the Lung Cancer Study Group,S3 however, demonstrated that in totally resected stage It III squamous carcinoma of the lung, external beam radiation therapy does not influence long-term survival and the subsequent development of distant metastasis. There is an improvement in prevention of tumor recurring in the chest; however, this has not been translated into a long-term survival advantage. It is hoped that patients who have had totally resected NSCLC treated with adjuvant chemotherapy would have improved long-term survival as has been seen in other cancers, such as breast and colon. The Lung Cancer Study Group 42 recently completed a trial using cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and cisplatinum chemotherapy in totally resected stage II and III adenocarcinoma of the lung in an adjuvant setting compared with a control group treated with BCG. This study has had some criticism in that the control group was not a true no treatment group; however, in this study, there was a survival advantage in terms of the treatment group receiving chemotherapy. To confirm this preliminary data exploring whether chemotherapy with or without irradiation added to total resection will lead to improved long-term survival in lung cancer, further trials are continuing. Stage II NSCLC has been reported by many to be very heterogeneous in origin. 65 Several single institution trials have shown an advantage to treating patients with combination chemotherapy followed either
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by surgery, radiation therapy, or both with the hope of improving long-term survival in these traditionally poor-risk patients. 4u The Cancer and Leukemia Group recently reported a prospective randomized cooperative group study using two cycles of combination chemotherapy consisting of cisplatinum and vinblastine prior to radiation therapy versus radiation therapy alone in the hopes of improving long-term survival. 19 This recently reported trial did show improvement in survival of the group receiving chemotherapy prior to radiation therapy as compared with the group receiving radiation therapy alone. Several studies are currently underway to confirm this exciting finding. From the previously mentioned studies, one can see that the integration of radiation therapy and chemotherapy in novel and innovative ways through cooperative group studies is leading to improvement in the care of patients with lung cancer. It is hoped that with the use of both cell and molecular biology in the study of both SCLC and NSCLC that new and innovative treatment options, such as twice a day irradiation, will be available to our patients in years to come. 4 BREAST CANCER
Breast cancer remains the most common life-threatening malignancy among women. In 1991, an estimated 175,000 women will be diagnosed with a new case of breast cancer and 44,500 women will succumb to this disease. 2 Fortunately, more women are being diagnosed with smaller primary tumors and without axillary node involvement. Although evidence from prospective, randomized clinical trials indicates that adjuvant chemotherapy and adjuvant endocrine manipulation can be of benefit to certain axillary node-negative (ANN) breast cancer patients, approximately 70% of such women will not experience recurrence after definitive local therapy (lumpectomy, axillary dissection followed by radiation therapy, or modified radical mastectomy).18,56 Therefore, considerable attention has been focused on the use of various prognostic variables that may help identify patients with axillary node negative breast cancer at increased risk of recurrence. Tumor size appears to be closely related to recurrence and survival. Data gathered by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute suggest a direct relationship of primary tumor size to the 92% 5-year survival rate in patients with a primary tumor smaller than 2 cm,13 Rosen et aF5 published a long-term follow-up study of 474 women with ANN breast cancer. The median duration of follow-up exceeded 18 years. The probability of recurrence calculated for women with tumors sized 1 cm or smaller was 14% and 31 % for women with tumors 1.1 to 2 cm. Because a significant number of women with ANN breast cancer present with tumors 2 cm in diameter or smaller, size is an important prognostic indicator.
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Estrogen receptor (ER) measurement in breast cancer tumor specimens has become commonplace. The National Surgical Adjuvant Bowel and Breast Project (NSABP) has reported a significant survival advantage for ANN patients whose tumors were found to contain estrogen receptors 29; however, the magnitude of difference in survival was only 8% (74% versus 66%). For this reason, some investigators have concluded that ER alone should not be used to make an adjuvant treatment decision. The role of histologic nuclear grading as a prognostic factor for patients with ANN breast cancer has recently been evaluated. 57 Nuclear grades 1 and 2 were grouped into a "good" category and grade 3 called "poor" based on disease-free survival of patients with ANN treated by surgery without systemic adjuvant therapy. Although there are problems with inter-observer variance, nuclear grade should be universally available for use as an adjunct in decision making. The increasing availability of flow cytometry is making the measurement of proliferative rate (%S phase) and ploidy more widely available. Clark et aP6 measured %S phase and ploidy in 345 ANN breast cancers. Patients with diploid tumors had a 12% probability of recurrence versus 26% probability of recurrence within 5 years (P = 0.02). If ploidy is associated with %S phase, however, the probability of recurrence in patients with diploid tumors and low %S phase was 10% versus 29% for those patients with diploid tumors and high S phase (P = 0.007). Patients with aneuploid tumors in this study could not be similarly segregated into groups with differing probabilities of relapse. Reproducible application of flow cytometry will be an increasingly important prognostic factor in selecting candidates for adjuvant therapy. Cathepsin D levels appear to be an important marker of risk of recurrence and death in patients with ANN breast cancer. Tandon et alSO examined cathepsin D levels in 199 patients with ANN breast cancer. Actuarial 5-year recurrence rates in women with aneuploid tumors and high cathepsin D levels were 60% versus 29% in women with aneuploid tumors and low cathepsin D levels, whereas the risk of recurrence in all diploid tumors was 22%. This study found cathepsin D level elevation to be associated with aneuploidy but not associated with patient age, tumor size, or estrogen or progesterone receptor status. Cathepsin D levels, in patients with ANN breast cancer, when generally available, will likely be an important predictor of highrecurrence risk. Decisions regarding adjuvant chemotherapy for patients with ANN breast cancer can be difficult. Evaluation of available prognostic factors can help to better estimate recurrence risk and assist in better analyzing the potential benefits and risks of adjuvant therapy. As more data from clinical trials become available, a better framework for decision making will evolve, allowing adjuvant therapy to be targeted at individuals who will benefit most from treatment.
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COLORECTAL CANCER
Colorectal cancer is the third most commonly diagnosed lifethreatening malignancy in the United States. 2 Approximately 157,500 citizens will be diagnosed with colorectal cancer in 1991, and an additional 60,500 persons will die as a result of these cancers. Because a large number of persons eventually die of recurrent colorectal cancer after undergoing potentially curative surgery and because the treatment of advanced metastatic disease is rarely curative, considerable resources have been devoted to developing effective adjuvant treatment strategies. A variety of adjuvant therapies have been applied in patients with resected colon cancer. Until 1989, there were no data from randomized, prospective studies that conclusively supported any form of adjuvant treatment; however, Laurie et al s1 performed a three-armed, randomized, prospective study that compared postoperative observation with surgery followed by levamisole or levamisole plus 5-fluorouracil in patients with Duke's B or C carcinoma. A statistically significant (P = 0.003) reduction in recurrence rate (31 %) was demonstrated for the treatment group receiving levamisole plus 5-fluorouracil. Subset analysis revealed the advantage for levamisole plus 5-fluorouracil to be significant only in patients classified as having Duke's C carcinoma. Because of these data, a national, intergroup study comparing observation to levamisole or levamisole plus 5-fluorouracil was conducted in patients with resected Duke's B2 and C colon cancer. Among those patients with Duke's C cancers, therapy with levamisole plus 5-fluorouracil reduced the risk of recurrence by 41 % (P
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In 1991, Krook et a1 48 reported the results from a North Central Cancer Treatment Group trial in which patients with stage II and III rectal cancer were grouped randomly (after resection with curative intent) to receive either combined modality therapy including methylCCNU, 5-fluorouracil, and radiation therapy or radiation therapy alone. Both a reduction in recurrence (P = 0.0016) and improved survival (P = 0.026) were demonstrated in patients who received combined modality therapy; however, because of the concern for long-term toxicity related to methyl-CCNU therapy, an intergroup trial tested combined modality therapy with and without methyl-CCNU in a manner identical to the aforementioned study.7o At an interim analysis performed after 50% of the predicted recurrences had occurred, a 1.2 times higher recurrence rate was noted in the group of patients who received methyl-CCNU, which statistically ruled out the possibility that methyl-CCNU conferred an advantage in disease control. No survival data were yet mature. These data led the National Cancer Institute to release a "clinical announcement" that concluded that "preliminary information suggests that substantial treatment benefits may be achieved (in rectal cancer) using irradiation and standard doses of 5fluorouracil."67 Currently, prospective, randomized trials are determining whether levamisole and leucovorin may contribute to the adjuvant therapy of rectal cancer, both in terms of relapse and recurrence rates. PREVENTION OF CANCER
The goal of all physicians is to prevent illness. In no disease is this more evident than in cancer. Clearly, the most single preventable cause of cancer in North America and emerging rapidly in the world is cigarette smoking. It is estimated in the United States that one third of all cancer-related deaths are a direct effect of tobacco. Five percent of all deaths in the United States are lung cancer alone. s Clearly, this single action would have major health effects in both the United States and around the world. Unfortunately, other actions in the prevention of lung cancer have not been so successful. Two large multicenter trials compared early intervention with either yearly chest radiographs, sputum cytologies, or both with control arms. 31 - 33 These studies have not revealed an increase in survival in patients screened more frequently. The development of newer more innovative means, such as the development of monoclonal staining of sputum cytologies, may change this and will be the subject of further trials in the next several years. 63 Breast Cancer
The increasing use of mammography to detect early breast cancer has changed the face of breast cancer in North America. 2o . 76 In most
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studies prior to the large-scale use of mammography, noninvasive breast cancer accounted for less than 2% of all breast cancer reported. Today, in many large series of patients undergoing mammography, noninvasive breast cancer accounts for more than 20% of all breast cancer. The changing face of breast cancer in the United States is largely a result of intensive mammographic screening. Despite this advance in early detection, a large number of women in the United States have misconceptions concerning breast cancer treatment and screening. Many women still believe that mastectomy is the only means to treat breast cancer despite large cooperative group trials, such as the National Surgical Adjuvant Breast Project (NSABP) studies, clearly demonstrating that in the vast majority of women with invasive breast cancer, segmental mastectomy and irradiation are equally effective in both local control and long-term survivaJ.28 The overwhelming majority of women who preserve their breast feel they have excellent cosmetic results. 77 It is hoped that with more open communication about breast cancer and its treatment more women will undergo breast cancer screening and have their cancer detected at earlier and more favorable stages. Colon Cancer
Colon cancer remains a very lethal but preventable cancer in the United States. Unfortunately, in a large population-based series, fecal blood testing has not resulted in an efficient way of screening patients for colon cancer. 1, 8 Several large groups have advocated the use of flexible sigmoidoscopy of the lower colon for detecting adenomatous polyps or early cancers. 22, 84 Many of these studies have demonstrated approximately a 5% incidence of either adenomatous polyps or cancer in patients older than age 50. There has been no study to show the advantage of long-term survival and colon cancer screening as has been shown with mammography in breast cancer. The exact cause for this may relate to the long natural history of the development of a polyp and its subsequent development into a cancer. Another cause for the lack of aggressive screening has been the high cost of endoscopic evaluation. At our institution, Maule 54 has studied having nurse endoscopists perform screening flexible sigmoidoscopy (SFS), thus increasing the number of patients able to undergo this test. 54 Maule has been able to demonstrate the ability of nurse endoscopists to perform SFS in an equally effective and efficient manner as physician endoscopists with widespread patient acceptance. 55 It is hoped that studies such as this will increase the availability of this modality to larger groups of patients in a more cost-effective way. Other Cancers
The use of cervical cytology in early detection of cervical cancer is clearly the goal that all screening tests should try to emulate. 21
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Other cancers that are actively undergoing cancer screening trials include those of the prostate and ovary. Prostate cancer is a major cause of morbidity and mortality in older men. 5 Early studies have shown that prostate-specific antigen, digital-rectal examination, and transrectal ultrasound may be useful in detecting early prostate cancers.14, 59 Before this information is taken into large scale public use, it should be understood that the clinical significance of many of the prostate cancers detected is unknown. 36 Many prostate cancers will remain clinically insignificant for years as has been seen in autopsy series. Being able to predict which prostate cancers are biologically important remains in question. As our population ages, this predictability will become a more common problem and one that requires further study. Ovarian cancer is the leading cause of gynecologic cancer mortality.s Questions about screening for ovarian cancer have become increasingly common. 6 The use of the serum assay of the glycoprotein CA-125 in the follow-up of resected ovarian cancer patients has been quite successful in predicting relapse; however, being able to incorporate this test along with pelvic and vaginal ultrasound use in the screening of high-risk individuals for ovarian carcinoma has not clearly been demonstrated. Trials are currently underway to establish its efficacy. SUMMARY
As one can see, there are a number of new and exciting advances in the prevention, detection, and treatment of various malignancies. We anxiously await the future to see the exact integration of the tremendous advances taking place in the cellular and molecular biopsy of disease and its application to the therapy of patients. ACKNOWLEDGMENT The authors acknowledge Janet Hirstius for her technical assistance with the manuscript.
References 1, Ahlquist D, Wieand H, Moertel C. et al: Fecal blood testing (FBT) for postoperative surveillance of colorectal center: Hemoccult (HO) versus hemaquant (HQT). Proc Am Soc Clin Onc 10:87, 1991 2. American Cancer Society: Cancer Facts and Figures. Atlanta, GA, ACS, 1991, 3. Antman KS, Griffin JD, Socinski MA, et al: Effects of recombinant human granulocytemacrophage colony-stimulating factor on chemotherapy induced myelosuppression, N Engl J Med 319:593-598, 1988 4. Beck LK, Kane MA, Bunn PA: Innovative and future approaches to small cell lung cancer treatment. Sem Oncol 15(3):300-314, 1988 5. Boring Cc. Squires TS, Tong T: Cancer statistics 1991, CA 41(1):19-39, 1991 6. Bourne T, Reynolds K, Campbell 5: Ovarian cancer screening. Eur J Cancer 27(5):655659, 1991
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7. Bowen DT, Culligan D, Jacobs A: The treatment of anemia in the myelodysplastic syndromes with recombinant human erythropoietin. Br J Haematol 77:419-423, 1991 8. Brandeau ML, Eddy DM: The work-up of the asymptomatic patient with a positive fecal occult blood test. Med Decis Making 7:32-46, 1987 9. Brandt SJ, Peters WJ, Atwater SK, et al: Effect of recombinant human granulocytemacrophage colony-stimulating factor on hematologic reconstitution after high dose chemotherapy and autologous bone marrow transplantation. N Engl J Med 318:869876, 1988 10. Bronchud MH, Scarffe TH, Thatcher N, et al: Phase IIII study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small-cell lung cancer. Br J Cancer 56:809-8l3, 1987 11. Cannistra S, Vellengre E, Groshek P, et al: Human granulocyte-monocyte colonystimulating factor and interleukin-3 stimulate monocyte cytotoxicity through a tumor necrosis factor dependent mechanism. Blood 71:672-676, 1988 12. Carney DN, Mitchell JB, Kinsella TJ: In Vitro radiation and chemotherapy sensitivity of established cell lines of human small cell lung cancer and its large cell morphological variants. Cancer Research June 43:2806-2811, 1983 13. Carter CL, AlIen e, Henson DE: Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63:181-187, 1989 14. Catalona WJ, Smith OS, Ratliff TL, et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324:1156-1161, 1991 15. Champlin RE: Therapeutic use of hematopoietic growth factors for patients receiving high-dose chemotherapy and bone marrow transplantation. Cancer Bull 43:197-207, 1991 16. CIark GM, DressIer LG, Owens MA, et al: Prediction of relapse or survival in patients with node negative breast cancer by DNA flow cytometry. N Engl J Med 320:627633, 1989 17. CIark Se, Kamen R: The human hematopoietic colon-stimulating factors. Science 236:1229-1237, 1987 18. OeVita VT: Breast cancer therapy: Exercising all our options. N Engl J Med 320:527529, 1989 19. OiIlman RO, Seagren SL, Pro pert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage 1II non-small-cell lung cancer. N Engl J Med 323:940-945, 1990 20. Eddy OM: Screening for breast cancer. Ann Int Med 111:389-399, 1989 21. Eddy DM: Screening for cervical cancer. Ann Int Med 1l3:214-226, 1990 22. Eddy DM: Screening for colorectal cancer. Ann Int Med 1l3:373-384, 1990 23. Erslev A: Humoral regulation of red cell production. Blood 8:349-357, 1953 24. Erslev AJ: Erythropoietin drug therapy. N Engl J Med 324:1339-1344, 1991 25. Erslev AJ, Caro J, Miller 0, et al: Plasma erythropoietin in health and disease. Ann CIin Lab Sci 10:250-257, 1980 26. Eschbach JW, Egrie Je, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a combined Phase I and II clinical trial. N Engl J Med 316:73-78, 1987 27. Evans RW, Rader B, Mannigen OL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. JAMA 263:825-830, 1990 28. Fisher B: A biological perspective of breast cancer: Contributions of the National Surgical Adjuvant Breast and Bowel Project clinical trials. CA 41(2):97-109, 1991 29. Fisher B, Redmond C, Fisher ER, et al: Relative worth of estrogen or progesterone receptor and pathologic characterization of differentiation as indicators of prognosis in node negative breast cancer patients: Findings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06. J CIin Oncol 6:1076-1087, ]988 30. Fisher B, Wolmark N, Rockette H, et al: Prospective adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01. J Natl Cancer Inst 80:21-29, 1988 31. Flehinger BL Kimmel M, Melamed MR: Natural history of adenocarcinoma-large cell carcinoma of the lung: Conclusions from screening programs in New York and Baltimore. J NatI Cancer Inst 80:337-344, 1988 32. Fontana RS: Early detection of lung cancer: The Mayo Lung Project. In Prorok rc,
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46. 47. 48. 49. 50. 51. 52. 53.
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Miller AB, (eds): Screening for cancer. I-general principles on evaluation of screening for cancer and screening for lung, bladder and oral cancer, vol 78. Geneva, International Union Against Cancer. UICC Technical Report Series, 1984, pp 107- 122 Fontana RS, Sanderson DR, Woolner LB, et al: Screening for lung cancer: A critique of the Mayo Lung Project. Cancer 67:1155-1164, 1991 Gabrilove JL, Jakubowski A, Sher M, et al: Effect of granulocyte-macrophage colonystimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of the urothelium. N Engl J Med 318:1414-1422, 1988 Ganser A, Lundeman A, Seipelt G, et al: Effect of recombinant human interleukin-3 (rh IL-3) in patients with bone marrow failure. A phase IIII trial. Blood 74(suppl):50a, 1989 Gerber GS, Chodak GW: Routine screening for cancer of the prostate. J Natl Cancer Inst 83:329-335, 1991 Gianni AM, Bregni M, Siena S, et al: Recombinant human granulocyte-macrophage colony-stimulating factor reduces hematologic toxicity and widens clinical applicability of high-dose cyclophosphamide treatment in breast cancer and non-Hodgkin's lymphoma. J Cl in Oncol 8:768-778, 1990 Gibilaro SD, Delano BG, Quinn R, et al: Improved quality of life while receiving recombinant erythropoietin (r-HuEPO) [abstract]. Kidney Int 35:247, 1989 Goodnough LT, Rudnick S, Price TH, et al: Increased preoperative collection of autologous blood with recombinant human erythropoietin therapy. N Engl J Med 321:1163-1168, 1989 Gralla RJ, Kris MG: Chemotherapy in non-small cell lung cancer: Results of recent trials. Semin Oncol 15(suppl 4):2, 1988 Henry D, Nelson R, Brooks B, et al: Prospective evaluation of transfusion (Tx) requirement for anemic cancer patients + / - chemorx [abstract]. Proceedings of the American Society of Clinical Oncology 10:340, 1991 Holmes EC, Gail M, Lung Cancer Study Group: Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large-cell undifferentiated carcinoma. J C1in OncoI4:710-715, 1986 Hume DA, Donahue RE, Fidler IJ: The therapeutic effect of human recombinant macrophage colony stimulating factor (CSF-l) in experimental murine metastatic melanoma. Lymphokine Res 8:69-77, 1989 Jacobs K, Shoemaker C, Rudersdorf R, et al: Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313:806-810, 1985 Johnson BE, Grayson J, Woods E, et al: Limited (LTD) stage small cell lung cancer (SCLC) treated with concurrent etoposide/cisplatin (VP/PLAT) plus BID chest radiotherapy (RT) [abstract]. Proceedings of the American Society of Clinical Oncology 8:228, 1989 Kaushansky K, O'Hara PJ, Berkner K, et al: Genomic cloning, characterization, and multilineage growth promoting activity of human granulocyte-macrophage stimulating factor. Proc Natl Acad Sci USA 83:3101-3105, 1986 Kawasaki ES, Ladner MB, Wang AM, et al: Molecular cloning of complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-l). Science 230:291-296, 1985 Krook JE, Moertel CG, Gunderson LI, et al: Effective surgical adjuvant therapy for high risk rectal carcinoma. N Engl J Med 324:705-715, 1991 Kurzrock R, Talpaz M, Estrov Z, et al: Phase I study of recombinant human interleukin-3 in patients with bone marrow failure. J C1in Oncol 9:1241-1250, 1991 Lee F, Yokota T, Otsuka T, et al: Isolation of cDNA for a human granulocytemacrophage colony-stimulating factor by functional expression in mammalian cells. Proc Natl Acad Sci USA 22:4360-4364, 1985 Laurie JA, Moertel CG, Fleming TR, et al: Surgical adjuvant therapy of large bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J C1in Oncol 7:1447-1456, 1989 Lin F-K, Suggs S, Lin C-H, et al: Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 82:7580-7584, 1985 Ludwig H, Fritz E, Kotzmann H, et al: Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 322:1693-1699, 1990
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54. Maule WF: Colon cancer screening by a nurse endoscopist (NE) with flexible sigmoidoscopy (FS): Results of 650 examinations [abstract]. Am J Gastro 84:1191, 1989 55. Maule WF: Patient evaluation of flexible sigmoidoscopy (FS) performed by a nurse endoscopist (NE) or a gastroenterologist (GE): Results in 334 patients screened for colonic neoplasms [abstract]. Am J Gastro 84:1191, 1989 56. McGuire WL: Adjuvant therapy of node negative breast cancer. N Engl J Med 320:525-527, 1989 57. McGuire WL: Estrogen receptor versus nuclear grade as prognostic factors in axillary node negative breast cancer. J Clin Oncol 6:lO71-1072, 1988 58. Metcalf 0: The granulocyte-macrophage colony stimulating factors. Science 229:1622, 1985 59. Mettlin C, Lee F, Drago I, et al: Findings on the detection of early prostate cancer in 2425 men. Cancer 67:2949-2958, 1991 60. Miller CB, Jones RI, Piantadosi S, et al: Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322:1689-1692, 1990 61. Moertel CG, Fleming TR, MacDonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352-358, 1990 62. Morstyn G, Burgess AW: Hematopoietic growth factors: A review. Cancer Res 48:5624-5637, 1988 63. Mulshine JL, Tockman MS, Smart CR: Consideration in development of lung cancer screening tools. J Natl Cancer Inst 81:900-906, 1989 64. Munn OH, Cheung N-K: Antibody dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. J Exp Med 170:511-526, 1989 65. Murren JR, Buzaid AC, Hait WN: Critical analysis of neoadjuvant therapy for stage IIIa non-small cell lung cancer. Am Rev Respir Dis 143:889-894, 1991 66. Nagata S, Tsucluya M, Asano S, et al: Molecular cloning and expression of cON A for human graunulocyte colony-stimulating factor. Nature 319:415-418, 1986 67. National Cancer Institute Clinical Announcement: Adjuvant Therapy of Rectal Cancer. March 14, 1991 68. NlH Consensus Conference: Adjuvant Therapy for Patients with Colon and Rectal Cancer. JAMA 264:1444-1450, 1990 69. Nimer SO: Molecular biology and hematology of erythropoietin. Ann Intern Med 114:402-407, 1991 70. O'Connell M, Wieand H, Krook I, et al: Lack of value for methyl-CCNU (MeCCNU) as a component of effective rectal cancer surgical adjuvant therapy: Analysis of intergroup protocol 86-47-51. Proceedings of the Ameican Society of Clinical Oncology 10:l34, 1991 71. Oster W, Herrmann F, Gamm H, et al: Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8:956-962, 1990 72. Pincus T, Olsen NI, Russell I, et al: Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 89:161-168, 1990 73. Reissmann KR: Studies on the mechanism of erythropoietic stimulation in parabiotic rats during hypoxia. Blood 5:372-380, 1950 74. Rose EH, Rudnick SA, Abels RI, et al: Efficacy and safety of recombinant human erythropoietin (r-HuEPO) in anemic patients with myelodysplastic syndromes [abstract]. Proceedings of the American Society of Clinical Oncology lO:306, 1991 75. Rosen PP, Groshen S, Saigo PE, et al: A long-term follow-up study of survival in Stage I (TjNoMul and Stage II (TjNjMo) breast carcinoma. J Clin Oncol 7:355-366, 1989 76. Schnitt SI, Silen W, Sadowsky NL, et al: Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med 318(14):898-902, 1988 77. Schover LR: The impact of breast cancer on sexuality, body image, and intimate relationships. CA 41(2):112-120, 1991 78. Seifter El, Ihde DC: Therapy of small cell lung cancer: A perspective on two decades of clinical research. Sem Oncol 15(3):278-299, 1988 79. Spivak JL, Smith RR, Ihle IN: Interleukin-3 promotes the in vitro proliferation of murine pluripotent hemopoietic stem cells. J Clin Invest 76:16l3-1625, 1985
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80. Tandon AK, Clark CM, Chamness Cc, et al: Cathepsin-D and prognosis in breast cancer. N Engl J Med 322:297-302, 1990 81. Turrisi A, Wagner H, Clover 0, et al: Limited small cell lung cancer (LSCLC): Concurrent BID thoracic radiotherapy (TRT) with platinum-eto-poside (PE): An ECOC study. Proceedings of the American Society of Clinical Oncology 9:230, 1990 82. Valent P, Schmidt C, Besemer j, et al: Interleukin-3 is a differentiation factor for human basophils. Blood 73:1763-1769, 1989 83. Weisenburger TH, Cail M, et al: Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. N Engl J Med 315:1377-1381, 1986 84. Winawer SJ, Schottenfeld 0, Fiehinger BJ: Colorectal cancer screening. J Natl Cancer Inst 83(4)243-253, 1991 85. Winearls CC, Oliver DO, Pippard MJ, et al: Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet ii:1175-1178, 1986 86. Wong CC, Temple PA, Leary AC, et al: Human C5F-l: Molecular cloning and expression of 4-KB cDNA encoding the human urinary protein. Science 235:15041509, 1987 87. Wong CC, Witek J5, Temple PA, et al: Human CM-CSF: Molecular cloning of the complementary DNA and purification of the natural and recombinant proteins. Science 228:810-815, 1985 88. Young y-c, Ciarletta AB, Temple PA, et al: Human IL-3 (multi-CSF): Identification of expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell 47:3-10, 1986
Address reprint requests to David S. Hanson, MD Ochsner Clinic of Baton Rouge 16777 Medical Center Drive Baton Rouge, LA 70816
0025-7125/92 $0.00 + .20
INNOVATIVE THERAPIES IN HEMATOLOGY AND ONCOLOGY David S. Hanson, MD, and Burke J. Brooks, Jr, MD
Over the last several years, there have been major advances in both prevention and treatment of many of the major cancers that afflict individuals in North America. In this article, we briefly review the major advances that have been made in both the prevention and treatment of lung, breast, and colon cancer, which currently are the most common, lethal cancers in North America in 1992. We also show how many of the advances in these therapies have been the result of large cooperative group trials that have involved the participation of many individuals from both the United States and Canada, and how the collaboration of various investigators from universities, group practices, and community-based practices have led the advances in the treatment and prevention of these malignancies. We also would like to show how the recent advances in biotechnology have led to the introduction into clinical practice of innovative growth factors, such as erythropoietin and the colony-stimulating factors. These exciting compounds will change the way clinical medicine is practiced, not only in hematology and oncology but in many other areas of medicine in the next several years. HEMATOPOIETIC GROWTH FACTORS
A vast array of glycoproteins stimulates the proliferation and differentiation of hematopoietic progenitor cells along multiple pathways (Fig. 1).17,58,62 Recently, four of these factors have been purified From the Department of Hematology and Oncology, Ochsner Clinic of Baton Rouge, Baton Rouge, Louisiana THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76' NUMBER 5' SEPTEMBER 1992
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Stem Cells
Differentiating
Li neage- Restricted G-CSF
~
~~
~-
~-~ 'eI ~ ~ ,~~~, (§ID
IL-S
~ ~ ~ -IL--3-+:::=- @; _ IL-6 ~ GM-CSF
~ IL-3
~~
~ Granulocytes
-@
M-CSF
(jji;\
~
Monocytes Eosinophils 8asophils
@; - W Erythrocytes Mega~ ~ ffiii.;\ Mega~EPO
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~ karyocytes
Figure 1. Schema of hematopoiesis. G-CSF = granulocyte colony-stimulating factor; GMCSF = granulocyte-macrophage colony-stimulating factor; M-CSF = monocyte colony-stimulating factor; EPO = erythropoietin; IL = interleukin; Mega-CSF = megakaryocyte colonystimulating factor. (From Champlin RE: Therapeutic use of hematopoietic growth factors for patients receiving high-dose chemotherapy and bone marrow transplantation. Cancer Bull 43:197-207, 1991; Copyright © 1991 by Medical Arts Publishing Foundation, Houston, Texas; with permission.)
and characterized biochemically in culture, and the human genes for these factors have been cloned, thus providing sufficient quantities of functional protein for clinical trials. 46, 47, 50, 66, 86-88 Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are both cytokines that stimulate the growth and differentiation of the pluripotential hematopoietic progenitor cells as well as more differentiated cells that are committed to myeloid, megakaryocytic, and even erythroid progeny, IL-3, also called multipotentialCSF, seems to act at an earlier stage in cell development than GM-CSF. The remaining two proteins cloned thus far are granulocyte colonystimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF). Both of these proteins exert their stimulatory effect in a much more lineage-specific fashion, stimulating maturation of granulocytes and monocytes respectively. 17, 58, 62 Over the past several years, the hematopoietic growth factors have been evaluated in both the laboratory and the clinic. G-CSF and GMCSF are both commercially available and are being investigated in phase II and phase III trials. IL-3 and M-CSF are undergoing phase I and phase II studies. Several areas of possible application of these growth factors include (1) stimulation of hematopoietic recovery after myelosuppressive chemotherapy, (2) enhancing bone marrow engraftment and recovery after marrow ablative therapy and bone marrow transplantation, (3) stimulation of the bone marrow in cytopenic states, such as myelodysplastic syndromes, aplastic anemia, lymphoproliferative disorders, congenital or cyclic neutropenia, and acquired immunodeficiency syndrome related cytopenias.
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G-CSF
G-CSF stimulates cells capable of differentiating into mature neutrophils. 17, 58, 62 G-CSF has been approved by the US Food and Drug Administration to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of neutropenia with fever. Phase I and 11 studies have shown that G-CSF can be administered safely to patients receiving myelosuppressive chemotherapy, and in all cases, a dose-dependent increase in white blood cell counts was found. In addition, administration of GCSF was shown to reduce the duration of absolute neutropenia as well as the incidence of febrile neutropenic episodes. 10, 34 GM-CSF
GM-CSF stimulates granulocyte/macrophage and eosinophil progenitor cell division and differentiation as well as possibly a number of effector functions. 17, 58, 62 GM-CSF has been approved by the US Food and Drug Administration for the acceleration of myeloid recovery in patients with non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), and Hodgkin's disease undergoing autologous bone marrow transplantation (BMT). Several phase I and 11 studies have examined the effects of GM-CSF administration in patients undergoing chemotherapy for solid tumors as well as patients undergoing autologous bone marrow transplantation for solid tumors and non-Hodgkin's lymphoma.3, 9, 34, 37 Although these studies clearly demonstrate that both G-CSF and GM-CSF enhance white blood cell recovery after treatment with chemotherapy, further trials are required to evaluate the efficacy and toxicity of multiple cycles of chemotherapy with growth factor support and to define the optimal dose and schedule of drug administration. M-CSF
Laboratory studies have shown that monocyte colony-stimulating factor (M-CSF or CSF-I) can be cloned and that it stimulates both differentiation and proliferation of macrophages and growth stimulation of pluripotent stem cells. 86 Enhanced antibody mediated cellular cytotoxicity has been shown to be induced by M-CSF.64 In addition, M-CSF may also produce direct antitumor effects and is currently being evaluated in an experimental malignant melanoma model. 43 IL-3
Laboratory studies show that IL-3 is a hematopoietic growth factor that induces renewal of pluripotent stem cells and differentiation of
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these cells into committed myeloid, erythroid, and megakaryocytic progenitors. 79 Interleukin-3 also stimulates monocyte cytotoxicity and enhances histamine production by basophils. 11,82 Phase I clinical trials have shown that IL-3 can be safely administered to humans. Patients with adequate bone marrow generally responded to therapy with an increase in white blood cells, whereas in patients with bone marrow failure, hematologic responses were more sporadic. Toxicities observed included predictable fever and chills, headache, and bone pain at higher doses. IL-3 will likely be most useful in combination with other growth factors in attempts to more closely mimic in vivo hematopoiesis. 35 , 49
ERYTHROPOIETIN
One of the most exciting areas in the biotechnologic applications of growth factors to clinical medicine has been the introduction of erythropoietin. Erythropoietin was first found to be an erythropoietic factor in the 1950s. 23 , 73 The gene for erythropoietin was cloned by investigators from Amgen and Genetics Institute in 1985. 44 ,52 It was from 1986 to 1987, a period of only 2 years, during which the first clinical trials demonstrating the effectiveness of erythropoietin in dialysis patients occurred. 26, 69, 85 Since then, erythropoietin has been used in a number of experimental settings and is currently licensed by the US Food and Drug Administration for the treatment of anemia secondary to chronic renal failure in both dialysis and predialysis patients and for the treatment of anemia induced by zidovudine in AIDS patients. Erythropoietin is a glycoprotein produced by the kidney that has been found to have distinct effects on the erythropoietic progenitor cells. A number of investigators have shown that in anemia related to blood loss or iron deficiency, there is an inverse relationship with a marked increase in the level of erythropoietin with decreasing levels of hemoglobin (Fig. 2).24 A number of refractory anemias have been shown to be able to be corrected by the administration of erythropoietin. 74 In a number of disease states in which anemia develops, such as chronic inflammation, rheumatoid arthritis, or cancer, some individuals have an inadequate erythropoietin response to their degree of anemia. 24, 53, 60,71,72 It is in these individuals that erythropoietin is being investigated, and it is fair to say that in the years to come the use of erythropoietin for treatment of well-defined disease entities will become more frequent so that anemia of chronic disease will be segregated into those diseases that are erythropoietin responsive or nonresponsive. 7, 24, 25, 41, 71, 72 Erythropoietin has also been shown to increase preoperative blood collections. In a study by Goodnough et al, 39 the amount of blood able to be collected for patients undergoing elective joint replacement was shown to be markedly increased in the group receiving erythropoietin
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• ••
Figure 2. Normal inverse relationship between hematocrit and serum erythropoietin. (Adapted from Erslev AJ: Erythropoietin drug therapy. N Engl J Med 324:1340, 1991; with permission.)
------------~----~
Hematocrit
at the time of preoperative blood collection. It is hoped that current studies are able to demonstrate the exact dose and schedule of erythropoietin necessary to augment autologous blood donation and perhaps this agent's use in the perioperative period to augment one's own blood. The major limiting factor in the use of erythropoietin now is its cost. Currently in the United States, the commercial cost of the drug is approximately $1.00 per 100 units. Usual doses are 50 u/kg two to three times per week. As one can see from this, the cost of treatment of a 70-kg individual at the dose of 50 U/kg three times a week can exceed $400 US dollars per month, thus making cost an important factor in the drug's use. In the well-defined disease states in which repeated blood transfusions are needed to maintain the patient's well-being, early studies have shown that this is a cost effective and safe way of maintaining the patient's hemoglobin. 27, 38, 41 The key in the future will be to better define which individuals in these various disease states could benefit from erythropoietin therapy. LUNG CANCER
In 1991 there will be over 160,000 new cases of lung cancer diagnosed in the United States. IS Of these, more than 90% of the patients will die of their cancer within 5 years. s New and innovative therapies in this malignancy are needed to offset this devastating toll. The number of cases of small cell lung carcinoma (SCLC) in the United States will be approximately 48,000 cases, more cases than all of Hodgkin's and non-Hodgkin's lymphoma combined. Approximately one third of these cases' of SCLC will be confined to the chest after extensive staging and are called limited stage SCLC. These patients have the best chance of cure, and many studies show a 3-year survival
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of 10% to 15%. 7H In SCLC, which has been traditionally treated with chemotherapy, there have been exciting advances in the use of combined modality therapy with chemotherapy and radiation therapy. Based on experimental studies done at the National Cancer Institute by Carney et al, 12 in vitro cell work has shown that SCLC cell lines are much more sensitive in vitro to the effects of radiation therapy when the radiation is given in smaller divided doses with an interval of approximately 4 hours between radiation treatments, thus allowing for repopulation of normal cells at the expense of continued killing of tumor cells. This experimental cell biology work has been taken to the bedside in a series of early trials that have demonstrated improvements in survival of patients given combination cis-platinum/etoposide (VP16) with twice daily radiation. 45. SI Several cooperative groups are currently enrolling patients in continuing trials comparing standard once daily radiation therapy plus cis-platinumIVP-16 versus twice a day radiation plus cis-platinumIVP-16 in the hopes of improving the longterm survival of patients with limited stage SCLC. Nonsmall cell lung carcinoma (NSCLC), which currently accounts for 75% of all lung cancer diagnosed in the United States, has had some new clinical information come to light. Next to prevention, the best treatment for early stage NSCLC (stage 1, II) is clearly surgical removal of the cancer and adjacent lymph nodes. In the treatment of stage II NSCLC, two studies are well worth noting. Patients who have had totally resected NSCLC have traditionally undergone external beam radiation therapy in hopes of preventing local recurrence of the cancer in the chest as well as preventing distant metastasis. A recently reported trial from the Lung Cancer Study Group,S3 however, demonstrated that in totally resected stage It III squamous carcinoma of the lung, external beam radiation therapy does not influence long-term survival and the subsequent development of distant metastasis. There is an improvement in prevention of tumor recurring in the chest; however, this has not been translated into a long-term survival advantage. It is hoped that patients who have had totally resected NSCLC treated with adjuvant chemotherapy would have improved long-term survival as has been seen in other cancers, such as breast and colon. The Lung Cancer Study Group 42 recently completed a trial using cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), and cisplatinum chemotherapy in totally resected stage II and III adenocarcinoma of the lung in an adjuvant setting compared with a control group treated with BCG. This study has had some criticism in that the control group was not a true no treatment group; however, in this study, there was a survival advantage in terms of the treatment group receiving chemotherapy. To confirm this preliminary data exploring whether chemotherapy with or without irradiation added to total resection will lead to improved long-term survival in lung cancer, further trials are continuing. Stage II NSCLC has been reported by many to be very heterogeneous in origin. 65 Several single institution trials have shown an advantage to treating patients with combination chemotherapy followed either
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by surgery, radiation therapy, or both with the hope of improving long-term survival in these traditionally poor-risk patients. 4u The Cancer and Leukemia Group recently reported a prospective randomized cooperative group study using two cycles of combination chemotherapy consisting of cisplatinum and vinblastine prior to radiation therapy versus radiation therapy alone in the hopes of improving long-term survival. 19 This recently reported trial did show improvement in survival of the group receiving chemotherapy prior to radiation therapy as compared with the group receiving radiation therapy alone. Several studies are currently underway to confirm this exciting finding. From the previously mentioned studies, one can see that the integration of radiation therapy and chemotherapy in novel and innovative ways through cooperative group studies is leading to improvement in the care of patients with lung cancer. It is hoped that with the use of both cell and molecular biology in the study of both SCLC and NSCLC that new and innovative treatment options, such as twice a day irradiation, will be available to our patients in years to come. 4 BREAST CANCER
Breast cancer remains the most common life-threatening malignancy among women. In 1991, an estimated 175,000 women will be diagnosed with a new case of breast cancer and 44,500 women will succumb to this disease. 2 Fortunately, more women are being diagnosed with smaller primary tumors and without axillary node involvement. Although evidence from prospective, randomized clinical trials indicates that adjuvant chemotherapy and adjuvant endocrine manipulation can be of benefit to certain axillary node-negative (ANN) breast cancer patients, approximately 70% of such women will not experience recurrence after definitive local therapy (lumpectomy, axillary dissection followed by radiation therapy, or modified radical mastectomy).18,56 Therefore, considerable attention has been focused on the use of various prognostic variables that may help identify patients with axillary node negative breast cancer at increased risk of recurrence. Tumor size appears to be closely related to recurrence and survival. Data gathered by the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute suggest a direct relationship of primary tumor size to the 92% 5-year survival rate in patients with a primary tumor smaller than 2 cm,13 Rosen et aF5 published a long-term follow-up study of 474 women with ANN breast cancer. The median duration of follow-up exceeded 18 years. The probability of recurrence calculated for women with tumors sized 1 cm or smaller was 14% and 31 % for women with tumors 1.1 to 2 cm. Because a significant number of women with ANN breast cancer present with tumors 2 cm in diameter or smaller, size is an important prognostic indicator.
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Estrogen receptor (ER) measurement in breast cancer tumor specimens has become commonplace. The National Surgical Adjuvant Bowel and Breast Project (NSABP) has reported a significant survival advantage for ANN patients whose tumors were found to contain estrogen receptors 29; however, the magnitude of difference in survival was only 8% (74% versus 66%). For this reason, some investigators have concluded that ER alone should not be used to make an adjuvant treatment decision. The role of histologic nuclear grading as a prognostic factor for patients with ANN breast cancer has recently been evaluated. 57 Nuclear grades 1 and 2 were grouped into a "good" category and grade 3 called "poor" based on disease-free survival of patients with ANN treated by surgery without systemic adjuvant therapy. Although there are problems with inter-observer variance, nuclear grade should be universally available for use as an adjunct in decision making. The increasing availability of flow cytometry is making the measurement of proliferative rate (%S phase) and ploidy more widely available. Clark et aP6 measured %S phase and ploidy in 345 ANN breast cancers. Patients with diploid tumors had a 12% probability of recurrence versus 26% probability of recurrence within 5 years (P = 0.02). If ploidy is associated with %S phase, however, the probability of recurrence in patients with diploid tumors and low %S phase was 10% versus 29% for those patients with diploid tumors and high S phase (P = 0.007). Patients with aneuploid tumors in this study could not be similarly segregated into groups with differing probabilities of relapse. Reproducible application of flow cytometry will be an increasingly important prognostic factor in selecting candidates for adjuvant therapy. Cathepsin D levels appear to be an important marker of risk of recurrence and death in patients with ANN breast cancer. Tandon et alSO examined cathepsin D levels in 199 patients with ANN breast cancer. Actuarial 5-year recurrence rates in women with aneuploid tumors and high cathepsin D levels were 60% versus 29% in women with aneuploid tumors and low cathepsin D levels, whereas the risk of recurrence in all diploid tumors was 22%. This study found cathepsin D level elevation to be associated with aneuploidy but not associated with patient age, tumor size, or estrogen or progesterone receptor status. Cathepsin D levels, in patients with ANN breast cancer, when generally available, will likely be an important predictor of highrecurrence risk. Decisions regarding adjuvant chemotherapy for patients with ANN breast cancer can be difficult. Evaluation of available prognostic factors can help to better estimate recurrence risk and assist in better analyzing the potential benefits and risks of adjuvant therapy. As more data from clinical trials become available, a better framework for decision making will evolve, allowing adjuvant therapy to be targeted at individuals who will benefit most from treatment.
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COLORECTAL CANCER
Colorectal cancer is the third most commonly diagnosed lifethreatening malignancy in the United States. 2 Approximately 157,500 citizens will be diagnosed with colorectal cancer in 1991, and an additional 60,500 persons will die as a result of these cancers. Because a large number of persons eventually die of recurrent colorectal cancer after undergoing potentially curative surgery and because the treatment of advanced metastatic disease is rarely curative, considerable resources have been devoted to developing effective adjuvant treatment strategies. A variety of adjuvant therapies have been applied in patients with resected colon cancer. Until 1989, there were no data from randomized, prospective studies that conclusively supported any form of adjuvant treatment; however, Laurie et al s1 performed a three-armed, randomized, prospective study that compared postoperative observation with surgery followed by levamisole or levamisole plus 5-fluorouracil in patients with Duke's B or C carcinoma. A statistically significant (P = 0.003) reduction in recurrence rate (31 %) was demonstrated for the treatment group receiving levamisole plus 5-fluorouracil. Subset analysis revealed the advantage for levamisole plus 5-fluorouracil to be significant only in patients classified as having Duke's C carcinoma. Because of these data, a national, intergroup study comparing observation to levamisole or levamisole plus 5-fluorouracil was conducted in patients with resected Duke's B2 and C colon cancer. Among those patients with Duke's C cancers, therapy with levamisole plus 5-fluorouracil reduced the risk of recurrence by 41 % (P
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In 1991, Krook et a1 48 reported the results from a North Central Cancer Treatment Group trial in which patients with stage II and III rectal cancer were grouped randomly (after resection with curative intent) to receive either combined modality therapy including methylCCNU, 5-fluorouracil, and radiation therapy or radiation therapy alone. Both a reduction in recurrence (P = 0.0016) and improved survival (P = 0.026) were demonstrated in patients who received combined modality therapy; however, because of the concern for long-term toxicity related to methyl-CCNU therapy, an intergroup trial tested combined modality therapy with and without methyl-CCNU in a manner identical to the aforementioned study.7o At an interim analysis performed after 50% of the predicted recurrences had occurred, a 1.2 times higher recurrence rate was noted in the group of patients who received methyl-CCNU, which statistically ruled out the possibility that methyl-CCNU conferred an advantage in disease control. No survival data were yet mature. These data led the National Cancer Institute to release a "clinical announcement" that concluded that "preliminary information suggests that substantial treatment benefits may be achieved (in rectal cancer) using irradiation and standard doses of 5fluorouracil."67 Currently, prospective, randomized trials are determining whether levamisole and leucovorin may contribute to the adjuvant therapy of rectal cancer, both in terms of relapse and recurrence rates. PREVENTION OF CANCER
The goal of all physicians is to prevent illness. In no disease is this more evident than in cancer. Clearly, the most single preventable cause of cancer in North America and emerging rapidly in the world is cigarette smoking. It is estimated in the United States that one third of all cancer-related deaths are a direct effect of tobacco. Five percent of all deaths in the United States are lung cancer alone. s Clearly, this single action would have major health effects in both the United States and around the world. Unfortunately, other actions in the prevention of lung cancer have not been so successful. Two large multicenter trials compared early intervention with either yearly chest radiographs, sputum cytologies, or both with control arms. 31 - 33 These studies have not revealed an increase in survival in patients screened more frequently. The development of newer more innovative means, such as the development of monoclonal staining of sputum cytologies, may change this and will be the subject of further trials in the next several years. 63 Breast Cancer
The increasing use of mammography to detect early breast cancer has changed the face of breast cancer in North America. 2o . 76 In most
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studies prior to the large-scale use of mammography, noninvasive breast cancer accounted for less than 2% of all breast cancer reported. Today, in many large series of patients undergoing mammography, noninvasive breast cancer accounts for more than 20% of all breast cancer. The changing face of breast cancer in the United States is largely a result of intensive mammographic screening. Despite this advance in early detection, a large number of women in the United States have misconceptions concerning breast cancer treatment and screening. Many women still believe that mastectomy is the only means to treat breast cancer despite large cooperative group trials, such as the National Surgical Adjuvant Breast Project (NSABP) studies, clearly demonstrating that in the vast majority of women with invasive breast cancer, segmental mastectomy and irradiation are equally effective in both local control and long-term survivaJ.28 The overwhelming majority of women who preserve their breast feel they have excellent cosmetic results. 77 It is hoped that with more open communication about breast cancer and its treatment more women will undergo breast cancer screening and have their cancer detected at earlier and more favorable stages. Colon Cancer
Colon cancer remains a very lethal but preventable cancer in the United States. Unfortunately, in a large population-based series, fecal blood testing has not resulted in an efficient way of screening patients for colon cancer. 1, 8 Several large groups have advocated the use of flexible sigmoidoscopy of the lower colon for detecting adenomatous polyps or early cancers. 22, 84 Many of these studies have demonstrated approximately a 5% incidence of either adenomatous polyps or cancer in patients older than age 50. There has been no study to show the advantage of long-term survival and colon cancer screening as has been shown with mammography in breast cancer. The exact cause for this may relate to the long natural history of the development of a polyp and its subsequent development into a cancer. Another cause for the lack of aggressive screening has been the high cost of endoscopic evaluation. At our institution, Maule 54 has studied having nurse endoscopists perform screening flexible sigmoidoscopy (SFS), thus increasing the number of patients able to undergo this test. 54 Maule has been able to demonstrate the ability of nurse endoscopists to perform SFS in an equally effective and efficient manner as physician endoscopists with widespread patient acceptance. 55 It is hoped that studies such as this will increase the availability of this modality to larger groups of patients in a more cost-effective way. Other Cancers
The use of cervical cytology in early detection of cervical cancer is clearly the goal that all screening tests should try to emulate. 21
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Other cancers that are actively undergoing cancer screening trials include those of the prostate and ovary. Prostate cancer is a major cause of morbidity and mortality in older men. 5 Early studies have shown that prostate-specific antigen, digital-rectal examination, and transrectal ultrasound may be useful in detecting early prostate cancers.14, 59 Before this information is taken into large scale public use, it should be understood that the clinical significance of many of the prostate cancers detected is unknown. 36 Many prostate cancers will remain clinically insignificant for years as has been seen in autopsy series. Being able to predict which prostate cancers are biologically important remains in question. As our population ages, this predictability will become a more common problem and one that requires further study. Ovarian cancer is the leading cause of gynecologic cancer mortality.s Questions about screening for ovarian cancer have become increasingly common. 6 The use of the serum assay of the glycoprotein CA-125 in the follow-up of resected ovarian cancer patients has been quite successful in predicting relapse; however, being able to incorporate this test along with pelvic and vaginal ultrasound use in the screening of high-risk individuals for ovarian carcinoma has not clearly been demonstrated. Trials are currently underway to establish its efficacy. SUMMARY
As one can see, there are a number of new and exciting advances in the prevention, detection, and treatment of various malignancies. We anxiously await the future to see the exact integration of the tremendous advances taking place in the cellular and molecular biopsy of disease and its application to the therapy of patients. ACKNOWLEDGMENT The authors acknowledge Janet Hirstius for her technical assistance with the manuscript.
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