- Email: [email protected]
Second Malignant Neoplasms after Successful Treatment of Childhood Cancers
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
S. A. Feig
Second Malignant Neoplasms after Successful Treatment of Childhood Cancers Submitted 05/17/01 (Communicated by M. Lichtman, M.D., 05/31/01)
Stephen A. Feig1 ABSTRACT: Improved treatment and supportive care have increased the survival of children diagnosed with cancer. This success has resulted in a growing population at risk of long-term complications of therapy, including secondary malignancy. These neoplasms may result from the direct effect of the modalities used in treatment of the primary tumor, more indirect effects of the treatment or supportive care, the genetic predisposition of the patient, or to interactions among these factors. The increasing success of cancer therapy is producing a rapidly growing population of patients at risk of second malignancy. This is a result of the increasing intensity of treatments and the increasing duration of survival, which provides the time to manifest the late effects of therapy. The concept that a patient is “cured” at some arbitrary time after treatment does not diminish the need for follow-up of all cancer survivors to identify and treat secondary malignancies. These risks have led to an increased effort to define phenotypic and genotypic categories of patients that may be cured with less intensive therapy and to develop molecularly targeted drugs that have fewer noxious effects on normal tissues. © 2001 Academic Press
INTRODUCTION
RADIATION EFFECTS
The past 35 years have seen dramatic improvement in the outcome of the treatment of many pediatric cancers. These advances have been the result of improved diagnosis and staging, as well as more effective treatments and methods of supportive care. The result of this success is a progressively enlarging population of cancer survivors with a myriad of medical problems that derive from their initial disease and therapy. For example, approximately 25% of the mortality after treatment for Hodgkin lymphoma is due to secondary malignancy (1). A wide variety of secondary cancers have been seen, including leukemias, other lymphomas, and solid tumors, especially breast and thyroid cancer (2). This paper will review one of the medical issues faced by cancer survivors: second malignant neoplasms.
Breast cancer was seen exclusively in females with Hodgkin lymphoma who were treated with radiation (2). It was usually observed within the field of radiation and the risk is proportional to the dose of radiation. The risk of developing breast cancer is 75 times higher than in a control population (2). Bilateral disease occurred in nearly one of three patients. Breast cancer was seen most frequently among patients who received radiation therapy between the ages of 10 and 16 years (2). Whereas all secondary leukemias had occurred within ten years of initial treatment, new breast cancers continued to appear for the entire period of follow-up. Although Hodgkin lymphoma is most common in adolescents and young adults, these data suggest that the oncogenic effect of radiation on the breast is greatest during puberty, when breast growth occurs. As yet, no relation-
Correspondence and reprint requests to author: Department of Pediatrics, Mattel Children’s Hospital at UCLA, 10833 Le Conte, Los Angeles, CA 90095-1752. E-mail: [email protected]. 1 Gwynne Hazen Cherry Memorial Laboratories, The UCLA–Jonsson Comprehensive Cancer Center and Division of Hematology/Oncology, Department of Pediatrics, Mattel Children’s Hospital at UCLA, Los Angeles, California 90095. 1079-9796/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved
662
S. A. Feig
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
ship between a secondary breast cancer and breast cancer susceptibility genes has been shown. The substantial risk of breast cancer with chest radiation has led to an increasing dependence upon chemotherapy as the preferred primary modality for the treatment of childhood with Hodgkin lymphoma. While low-dose involved field radiation therapy is effective in these patients, the beneficial effect may be counterbalanced, by the increased incidence of cancer among female survivors (Nachman, personal comment). The risk of secondary breast cancer after low-dose involved field radiation has not been quantified as yet.
TABLE 1 Secondary Malignant Neoplasms
Radiation
Alkylating agents
Tumor type
Solid tumors
MDS/AML
Dose effect
Cumulative
Cumulative
Latency
Topoisomerase inhibitors Acute leukemia Scheduledependent 2 years
Long, 5–7 years continuous Proposed ? mutation (s) Loss of Neo-oncogene mechanism heterozygosity
Note. MDS, myelodysplastic syndrome; AML, acute myelogenous leukemia.
CHEMOTHERAPY EFFECTS
risk of development of alkylating agent-induced leukemia include the cumulative drug dose, additional exposure to radiation therapy, and increasing age (7). A more acute form of leukemia has been described after chemotherapy with inhibitors of topoisomerase II, such as etoposide (6, 7). These patients present with typical acute leukemia, with a median latency of less than 2 years from initial therapy. There have been no predisposing risk factors other than the drug schedule identified; the use of greater intervals between doses (3 to 4 weeks) is associated with a lower risk of secondary leukemia (5). This form of secondary leukemia appears to be the result of the formation of a “neo-oncogene” as the result of an illegitimate chromosomal recombination. These patients often show recombination involving 11q23, the location of the MLL gene, although other recombinations have been described, including those arising in de novo leukemia, such as t(15;17), t(8;21), inv (16), and others. The relationship of second malignant neoplasms to causative agents is presented in Table 1.
The risk of developing acute myeloblastic leukemia is reported to be more than 300 times higher in patients with Hodgkin lymphoma than in a control population. While reporting bias may inflate the risk somewhat, there can be no doubt about the fundamental importance of this observation. The risk of secondary leukemias is not unique to Hodgkin lymphoma patients, although that is the context in which they were originally recognized (3). Acute leukemias have been described after the primary treatment of various neoplasms (4, 5). The secondary leukemias fall into two general categories, one more acute and the other more indolent (6, 7). Secondary acute leukemia was initially recognized among survivors of Hodgkin lymphoma, although this entity is seen also after the use of intensive alkylating agent therapy for various neoplasms (3). Among Hodgkin lymphoma patients treated at St. Jude Children’s Research Hospital, the time to development of secondary leukemia was relatively short, compared to the time to development of breast cancer (8). This form of secondary leukemia presents with a typical latency of 5 to 7 years. Patients usually present with pancytopenia as a manifestation of clonal myeloid disease; chromosome analysis of the bone marrow often shows monosomy 7, monosomy 5, or deletion of part or all of the long arm of either chromosome 7 or 5. Factors which may increase the
STEM CELL TRANSPLANTATION AND SECONDARY NEOPLASMS Another setting in which secondary malignancy has been described following hematopoietic stem cell transplantation (SCT) (9 –13) (Table 2). An increased risk of lymphoma, leukemia, and solid tumors has been reported among transplant 663
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
the safety of blood products have improved markedly, testing is not perfect. Moreover, there is a large cohort of patients transfused prior to the ability to eliminate blood units with hepatitis viruses A, B, and C by screening. Among patients with posttransfusion hepatitis, there is an elevated risk of hepatic cancer.
TABLE 2 Second Malignant Neoplasms after Hematopoietic Stem Cell Transplantation Risk factor Auto-SCT
Allo-SCT
Topoisomerase II inhibitors Radiation therapy Radiation therapy Immune suppression
S. A. Feig
Second malignancy Acute leukemia Solid tumors (esp skin) Solid tumors (esp skin) B-cell lymphocytic neoplasms
INHERITED PREDISPOSITION TO SECONDARY CANCERS
Note. SCT, stem cell transplant; auto, autologous; allo, allogeneic.
There are well-described syndromes that predispose a patient to cancer (Table 3). These conditions almost certainly predispose the patient to secondary malignancy as well after exposure to the oncogenic effects of chemotherapy or radiation treatment. Genetic diseases which may increase the risk of secondary cancers include ataxia telangiectasia, xeroderma pigmentosum, Bloom’s syndrome, Cockayne syndrome, neurofibromatosis type 1, retinoblastoma, and the Li-Fraumeni syndrome. The presumed mechanism of leukemogenesis in the presence of gene deletion is loss of heterozygosity for a tumor suppressor gene; the presence of other altered tumor suppressor genes such as NF-1 or p53 may augment the risk of leukemogenesis (7). Mutations of genes that encode enzymes involved in the detoxification of alkylating agents, such as glutathione S-trans-
survivors (9). Among patients conditioned with total body irradiation, the risk of solid tumors is increased, especially that of skin cancers, including melanoma. Other soft tissue tumors have also been described among these patients. Secondary acute leukemias have been reported among recipients of autologous transplants (12, 13). These patients were often treated with etoposide, and since the post-transplant hematopoiesis is that of the patient, the hematopoietic progenitors would be at risk of aberrant recombination events. In contrast, lymphomas have been reported more often among recipients of allogeneic transplants (10, 11). The risk of secondary lymphomas appears to be increased with greater degrees of HLA disparity between donor and recipient, T-cell depletion of the stem cells used for transplant, and aggressive treatment of graft-versus-host disease with either anti-thymocyte globulin or monoclonal antibodies to CD3. These are covariables with respect to the risk and treatment of severe GVHD; the end result is prolonged immune suppression and lymphocytic neoplasm (usually B-cell in origin) as a result of infection with Epstein–Barr virus. This is fundamentally the same process observed in recipients of solid organ transplants.
TABLE 3 Causes of Second Malignant Neoplasms Direct result of therapy Radiation (8) Alkylating agents (1) Topoisomerase II inhibitors (7) Indirect effects of therapy Immune suppression (10, 11) Hepatitis Genetic predisposition Primary (6) NF-1, Rb, p53, Ataxia telangiectasia Xeroderma pigmentosum Bloom’s syndrome Cockayne syndrome Secondary (14) Glutathione S-transferase p450
POSTTRANSFUSION VIRAL-RELATED HEPATIC CANCERS Another indirect cause of secondary malignancy in cancer survivors is hepatitis. Many of the treatments programs in use today, require intensive transfusion support. While methods to ensure 664
S. A. Feig
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
ferase, may also increase the risk of secondary leukemia (14). Alterations in the activation or breakdown of chemotherapeutic agents might alter the susceptibility to secondary cancers. Enzymes that might be involved in such a process include p450 and glutathione S-transferase.
tional lymphoma chemotherapy may be used with all its attendant side effects. REFERENCES 1.
TREATMENT OF SECONDARY TUMORS 2.
The treatment of second malignant neoplasms can be problematic. Solid tumors, such as breast and skin cancer, are treated with customary therapy, dependent upon the stage of disease. In light of the risk of multifocal, bilateral breast cancer among Hodgkin lymphoma survivors, some patients have preferred prophylactic bilateral mastectomy. The management of secondary leukemias has been particularly difficult. While those patients with chromosome translocations seen in lower risk, de novo leukemia, such as t(15;17) and t(8; 21), may respond to conventional approaches to treatment, these are seen less often than recombinations involving the MLL gene (11q23) and complete or partial deletions of chromosome 5 or 7, which are chromosome alterations that are associated with resistance to treatment. The achievement of remission may be difficult, and the duration of remission, if achieved, is usually brief. Allogeneic hematopoietic stem cell transplantation is usually recommended if a donor is available and the patient’s condition is good. The prognosis of secondary lymphocytic neoplasms is variable. Some patients respond to the diminution or elimination of immunosuppressive drugs. Treatment with antiviral agents, such as acyclovir and gancyclovir has been used with variable success, as has immune stimulation with interferon-. In patients whose tumor has failed to respond to modulation of the immune suppression, therapy with monoclonal antibodies may be of benefit. Selection of the particular agent should target the immune phenotype of the proliferating lymphoid cells (e.g., CD20). Such therapy may cause tumor lysis syndrome and result in prolonged immune dysfunction. Finally, conven-
3.
4.
5.
6.
7.
8.
9.
10.
11.
665
Wolden, S. L., Lamborn, K. R., Cleary, S. F., Tate, D. J., and Donaldson, S. S. (1998) Second cancers following pediatric Hodgkin’s disease. J. Clin. Oncol. 16, 536 –544. Bhatia, S., Robison, L. L., Oberlin, O., Greenberg, M., Bunin, G., Fossati-Bellani, F., and Meadows, A. T. (1996) Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N. Engl. J. Med. 334, 745–751. Rowley, J., Golomb, H., and Vardiman, J. (1997) Non-random chromosomal abnormalities in acute nonlymphocytic leukemia in patients treated for Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 50, 759 –770. Bokemeyer, C., and Schmoll, H-J. (1995) Treatment of testicular cancer and the development of secondary malignancies. J. Clin. Oncol. 13, 283–292. Pui, C-H., Ribeiro, R. C., Hancock, M. S., Rivera, G. K., Evans, W. E., Raimondi, S. C., Head, D. R., Behm, F. G., Mahmoud, M. H., Sandlund, J. T., and Crist, W. M. (1991) Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N. Engl. J. Med. 325, 1682– 1687. Karp, J. E., and Smith, M. A. (1997) The molecular pathogenesis of treatment-induced (secondary) leukemias: Foundations for treatment and prevention. Semin. Oncol. 24, 103–113. Felix, C. A. (1998) Secondary leukemias induced by topoisomerase-targeted drugs. Biochim. Biophys. Acta 1400, 233–255. Beaty, O., Hudson, M. M., Greenwald, C., Luo, X., Fang, L., Wilimas, J. A., Thompson, E. I., Kun, L. E., and Pratt, C. B. (1995) Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease. J. Clin. Oncol. 13, 603– 609. Witherspoon, R. P., Fisher, L. D., Schoch, G., Martin, P., Sullivan, K. M., Sanders, J., Deeg, H. J., Doney, K., Thomas, D., Storb, R., and Thomas, E. D. (1989) Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N. Engl. J. Med. 321, 784 –789. Deeg, H J., and Witherspoon, R. P. (1993) Risk factors for the development of secondary malignancies after marrow transplantation. Hematol. Oncol. Clin. N. Am. 7, 417– 429. Bhatia, S., Ramsay, N., Steinbuch, M., Dusenbery, K. E., Shapiro, R. S., Weisdorf, D. J., Robison, L. L., Miller, J. S., and Neglia, J. P. (1996) Malignant neo-
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
plasms following bone marrow transplantation. Blood 87, 3633–3639. 12. Traweek, S. T., Slovak, M. L., Nademanee, A. P., Brynes, R. K., Niland, J. C., and Forman, S. J. (1994) Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin’s Disease and non-Hodgkin’s lymphoma. Blood 84, 957–963. 13. Darrington, D. L., Vose, J. M., Anderson, J. R., Bierman, P. J., Bishop, M. R., Chan, W. C., Morris, M. E., Reed, E. C., Sanger, W. G., Tarantolo, S. R., Weisen-
S. A. Feig
14.
666
burger, D. D., Kessinger, A., and Armitage, J. O. (1994) Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J. Clin. Oncol. 12, 2527–2534. Chen, H., Sandler, D. P., Taylor, J. A., Shore, D. L., Liu, E., Bloomfield, C. D., and Bell, D. A. (1996) Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta l (GSTT1) gene defect. Lancet 347, 295–297.
S. A. Feig
Second Malignant Neoplasms after Successful Treatment of Childhood Cancers Submitted 05/17/01 (Communicated by M. Lichtman, M.D., 05/31/01)
Stephen A. Feig1 ABSTRACT: Improved treatment and supportive care have increased the survival of children diagnosed with cancer. This success has resulted in a growing population at risk of long-term complications of therapy, including secondary malignancy. These neoplasms may result from the direct effect of the modalities used in treatment of the primary tumor, more indirect effects of the treatment or supportive care, the genetic predisposition of the patient, or to interactions among these factors. The increasing success of cancer therapy is producing a rapidly growing population of patients at risk of second malignancy. This is a result of the increasing intensity of treatments and the increasing duration of survival, which provides the time to manifest the late effects of therapy. The concept that a patient is “cured” at some arbitrary time after treatment does not diminish the need for follow-up of all cancer survivors to identify and treat secondary malignancies. These risks have led to an increased effort to define phenotypic and genotypic categories of patients that may be cured with less intensive therapy and to develop molecularly targeted drugs that have fewer noxious effects on normal tissues. © 2001 Academic Press
INTRODUCTION
RADIATION EFFECTS
The past 35 years have seen dramatic improvement in the outcome of the treatment of many pediatric cancers. These advances have been the result of improved diagnosis and staging, as well as more effective treatments and methods of supportive care. The result of this success is a progressively enlarging population of cancer survivors with a myriad of medical problems that derive from their initial disease and therapy. For example, approximately 25% of the mortality after treatment for Hodgkin lymphoma is due to secondary malignancy (1). A wide variety of secondary cancers have been seen, including leukemias, other lymphomas, and solid tumors, especially breast and thyroid cancer (2). This paper will review one of the medical issues faced by cancer survivors: second malignant neoplasms.
Breast cancer was seen exclusively in females with Hodgkin lymphoma who were treated with radiation (2). It was usually observed within the field of radiation and the risk is proportional to the dose of radiation. The risk of developing breast cancer is 75 times higher than in a control population (2). Bilateral disease occurred in nearly one of three patients. Breast cancer was seen most frequently among patients who received radiation therapy between the ages of 10 and 16 years (2). Whereas all secondary leukemias had occurred within ten years of initial treatment, new breast cancers continued to appear for the entire period of follow-up. Although Hodgkin lymphoma is most common in adolescents and young adults, these data suggest that the oncogenic effect of radiation on the breast is greatest during puberty, when breast growth occurs. As yet, no relation-
Correspondence and reprint requests to author: Department of Pediatrics, Mattel Children’s Hospital at UCLA, 10833 Le Conte, Los Angeles, CA 90095-1752. E-mail: [email protected]. 1 Gwynne Hazen Cherry Memorial Laboratories, The UCLA–Jonsson Comprehensive Cancer Center and Division of Hematology/Oncology, Department of Pediatrics, Mattel Children’s Hospital at UCLA, Los Angeles, California 90095. 1079-9796/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved
662
S. A. Feig
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
ship between a secondary breast cancer and breast cancer susceptibility genes has been shown. The substantial risk of breast cancer with chest radiation has led to an increasing dependence upon chemotherapy as the preferred primary modality for the treatment of childhood with Hodgkin lymphoma. While low-dose involved field radiation therapy is effective in these patients, the beneficial effect may be counterbalanced, by the increased incidence of cancer among female survivors (Nachman, personal comment). The risk of secondary breast cancer after low-dose involved field radiation has not been quantified as yet.
TABLE 1 Secondary Malignant Neoplasms
Radiation
Alkylating agents
Tumor type
Solid tumors
MDS/AML
Dose effect
Cumulative
Cumulative
Latency
Topoisomerase inhibitors Acute leukemia Scheduledependent 2 years
Long, 5–7 years continuous Proposed ? mutation (s) Loss of Neo-oncogene mechanism heterozygosity
Note. MDS, myelodysplastic syndrome; AML, acute myelogenous leukemia.
CHEMOTHERAPY EFFECTS
risk of development of alkylating agent-induced leukemia include the cumulative drug dose, additional exposure to radiation therapy, and increasing age (7). A more acute form of leukemia has been described after chemotherapy with inhibitors of topoisomerase II, such as etoposide (6, 7). These patients present with typical acute leukemia, with a median latency of less than 2 years from initial therapy. There have been no predisposing risk factors other than the drug schedule identified; the use of greater intervals between doses (3 to 4 weeks) is associated with a lower risk of secondary leukemia (5). This form of secondary leukemia appears to be the result of the formation of a “neo-oncogene” as the result of an illegitimate chromosomal recombination. These patients often show recombination involving 11q23, the location of the MLL gene, although other recombinations have been described, including those arising in de novo leukemia, such as t(15;17), t(8;21), inv (16), and others. The relationship of second malignant neoplasms to causative agents is presented in Table 1.
The risk of developing acute myeloblastic leukemia is reported to be more than 300 times higher in patients with Hodgkin lymphoma than in a control population. While reporting bias may inflate the risk somewhat, there can be no doubt about the fundamental importance of this observation. The risk of secondary leukemias is not unique to Hodgkin lymphoma patients, although that is the context in which they were originally recognized (3). Acute leukemias have been described after the primary treatment of various neoplasms (4, 5). The secondary leukemias fall into two general categories, one more acute and the other more indolent (6, 7). Secondary acute leukemia was initially recognized among survivors of Hodgkin lymphoma, although this entity is seen also after the use of intensive alkylating agent therapy for various neoplasms (3). Among Hodgkin lymphoma patients treated at St. Jude Children’s Research Hospital, the time to development of secondary leukemia was relatively short, compared to the time to development of breast cancer (8). This form of secondary leukemia presents with a typical latency of 5 to 7 years. Patients usually present with pancytopenia as a manifestation of clonal myeloid disease; chromosome analysis of the bone marrow often shows monosomy 7, monosomy 5, or deletion of part or all of the long arm of either chromosome 7 or 5. Factors which may increase the
STEM CELL TRANSPLANTATION AND SECONDARY NEOPLASMS Another setting in which secondary malignancy has been described following hematopoietic stem cell transplantation (SCT) (9 –13) (Table 2). An increased risk of lymphoma, leukemia, and solid tumors has been reported among transplant 663
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
the safety of blood products have improved markedly, testing is not perfect. Moreover, there is a large cohort of patients transfused prior to the ability to eliminate blood units with hepatitis viruses A, B, and C by screening. Among patients with posttransfusion hepatitis, there is an elevated risk of hepatic cancer.
TABLE 2 Second Malignant Neoplasms after Hematopoietic Stem Cell Transplantation Risk factor Auto-SCT
Allo-SCT
Topoisomerase II inhibitors Radiation therapy Radiation therapy Immune suppression
S. A. Feig
Second malignancy Acute leukemia Solid tumors (esp skin) Solid tumors (esp skin) B-cell lymphocytic neoplasms
INHERITED PREDISPOSITION TO SECONDARY CANCERS
Note. SCT, stem cell transplant; auto, autologous; allo, allogeneic.
There are well-described syndromes that predispose a patient to cancer (Table 3). These conditions almost certainly predispose the patient to secondary malignancy as well after exposure to the oncogenic effects of chemotherapy or radiation treatment. Genetic diseases which may increase the risk of secondary cancers include ataxia telangiectasia, xeroderma pigmentosum, Bloom’s syndrome, Cockayne syndrome, neurofibromatosis type 1, retinoblastoma, and the Li-Fraumeni syndrome. The presumed mechanism of leukemogenesis in the presence of gene deletion is loss of heterozygosity for a tumor suppressor gene; the presence of other altered tumor suppressor genes such as NF-1 or p53 may augment the risk of leukemogenesis (7). Mutations of genes that encode enzymes involved in the detoxification of alkylating agents, such as glutathione S-trans-
survivors (9). Among patients conditioned with total body irradiation, the risk of solid tumors is increased, especially that of skin cancers, including melanoma. Other soft tissue tumors have also been described among these patients. Secondary acute leukemias have been reported among recipients of autologous transplants (12, 13). These patients were often treated with etoposide, and since the post-transplant hematopoiesis is that of the patient, the hematopoietic progenitors would be at risk of aberrant recombination events. In contrast, lymphomas have been reported more often among recipients of allogeneic transplants (10, 11). The risk of secondary lymphomas appears to be increased with greater degrees of HLA disparity between donor and recipient, T-cell depletion of the stem cells used for transplant, and aggressive treatment of graft-versus-host disease with either anti-thymocyte globulin or monoclonal antibodies to CD3. These are covariables with respect to the risk and treatment of severe GVHD; the end result is prolonged immune suppression and lymphocytic neoplasm (usually B-cell in origin) as a result of infection with Epstein–Barr virus. This is fundamentally the same process observed in recipients of solid organ transplants.
TABLE 3 Causes of Second Malignant Neoplasms Direct result of therapy Radiation (8) Alkylating agents (1) Topoisomerase II inhibitors (7) Indirect effects of therapy Immune suppression (10, 11) Hepatitis Genetic predisposition Primary (6) NF-1, Rb, p53, Ataxia telangiectasia Xeroderma pigmentosum Bloom’s syndrome Cockayne syndrome Secondary (14) Glutathione S-transferase p450
POSTTRANSFUSION VIRAL-RELATED HEPATIC CANCERS Another indirect cause of secondary malignancy in cancer survivors is hepatitis. Many of the treatments programs in use today, require intensive transfusion support. While methods to ensure 664
S. A. Feig
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
ferase, may also increase the risk of secondary leukemia (14). Alterations in the activation or breakdown of chemotherapeutic agents might alter the susceptibility to secondary cancers. Enzymes that might be involved in such a process include p450 and glutathione S-transferase.
tional lymphoma chemotherapy may be used with all its attendant side effects. REFERENCES 1.
TREATMENT OF SECONDARY TUMORS 2.
The treatment of second malignant neoplasms can be problematic. Solid tumors, such as breast and skin cancer, are treated with customary therapy, dependent upon the stage of disease. In light of the risk of multifocal, bilateral breast cancer among Hodgkin lymphoma survivors, some patients have preferred prophylactic bilateral mastectomy. The management of secondary leukemias has been particularly difficult. While those patients with chromosome translocations seen in lower risk, de novo leukemia, such as t(15;17) and t(8; 21), may respond to conventional approaches to treatment, these are seen less often than recombinations involving the MLL gene (11q23) and complete or partial deletions of chromosome 5 or 7, which are chromosome alterations that are associated with resistance to treatment. The achievement of remission may be difficult, and the duration of remission, if achieved, is usually brief. Allogeneic hematopoietic stem cell transplantation is usually recommended if a donor is available and the patient’s condition is good. The prognosis of secondary lymphocytic neoplasms is variable. Some patients respond to the diminution or elimination of immunosuppressive drugs. Treatment with antiviral agents, such as acyclovir and gancyclovir has been used with variable success, as has immune stimulation with interferon-. In patients whose tumor has failed to respond to modulation of the immune suppression, therapy with monoclonal antibodies may be of benefit. Selection of the particular agent should target the immune phenotype of the proliferating lymphoid cells (e.g., CD20). Such therapy may cause tumor lysis syndrome and result in prolonged immune dysfunction. Finally, conven-
3.
4.
5.
6.
7.
8.
9.
10.
11.
665
Wolden, S. L., Lamborn, K. R., Cleary, S. F., Tate, D. J., and Donaldson, S. S. (1998) Second cancers following pediatric Hodgkin’s disease. J. Clin. Oncol. 16, 536 –544. Bhatia, S., Robison, L. L., Oberlin, O., Greenberg, M., Bunin, G., Fossati-Bellani, F., and Meadows, A. T. (1996) Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N. Engl. J. Med. 334, 745–751. Rowley, J., Golomb, H., and Vardiman, J. (1997) Non-random chromosomal abnormalities in acute nonlymphocytic leukemia in patients treated for Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 50, 759 –770. Bokemeyer, C., and Schmoll, H-J. (1995) Treatment of testicular cancer and the development of secondary malignancies. J. Clin. Oncol. 13, 283–292. Pui, C-H., Ribeiro, R. C., Hancock, M. S., Rivera, G. K., Evans, W. E., Raimondi, S. C., Head, D. R., Behm, F. G., Mahmoud, M. H., Sandlund, J. T., and Crist, W. M. (1991) Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N. Engl. J. Med. 325, 1682– 1687. Karp, J. E., and Smith, M. A. (1997) The molecular pathogenesis of treatment-induced (secondary) leukemias: Foundations for treatment and prevention. Semin. Oncol. 24, 103–113. Felix, C. A. (1998) Secondary leukemias induced by topoisomerase-targeted drugs. Biochim. Biophys. Acta 1400, 233–255. Beaty, O., Hudson, M. M., Greenwald, C., Luo, X., Fang, L., Wilimas, J. A., Thompson, E. I., Kun, L. E., and Pratt, C. B. (1995) Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease. J. Clin. Oncol. 13, 603– 609. Witherspoon, R. P., Fisher, L. D., Schoch, G., Martin, P., Sullivan, K. M., Sanders, J., Deeg, H. J., Doney, K., Thomas, D., Storb, R., and Thomas, E. D. (1989) Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N. Engl. J. Med. 321, 784 –789. Deeg, H J., and Witherspoon, R. P. (1993) Risk factors for the development of secondary malignancies after marrow transplantation. Hematol. Oncol. Clin. N. Am. 7, 417– 429. Bhatia, S., Ramsay, N., Steinbuch, M., Dusenbery, K. E., Shapiro, R. S., Weisdorf, D. J., Robison, L. L., Miller, J. S., and Neglia, J. P. (1996) Malignant neo-
Blood Cells, Molecules, and Diseases (2001) 27(3) May/June: 662– 666 doi:10.1006/bcmd.2001.0436, available online at http://www.idealibrary.com on
plasms following bone marrow transplantation. Blood 87, 3633–3639. 12. Traweek, S. T., Slovak, M. L., Nademanee, A. P., Brynes, R. K., Niland, J. C., and Forman, S. J. (1994) Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin’s Disease and non-Hodgkin’s lymphoma. Blood 84, 957–963. 13. Darrington, D. L., Vose, J. M., Anderson, J. R., Bierman, P. J., Bishop, M. R., Chan, W. C., Morris, M. E., Reed, E. C., Sanger, W. G., Tarantolo, S. R., Weisen-
S. A. Feig
14.
666
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