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Hodgkin's disease: new possibilities for clinical research
Inl. 1. Radiation Oncology Bioi. Phys., Vol. 17, pp. I I I9- I 12 I Printed in the U.S.A. All rights reserved.
Copyright
03~3016/89 $3.00 + .I0 0 1989 Pergamon Press plc
0 Editorial HODGKIN’S DISEASE: NEW POSSIBILITIES FOR CLINICAL RESEARCH HUIBM.VRIESENDORP, Johns Hopkins
M.D.,PHD.ANDSTANLEYE.ORDER,M.D.,SC.D.
Radiation
Oncology,
Johns Hopkins
University,
Baltimore,
MD 2 1205
Hodgkin’s Disease, Bone marrow transplantation. from the Memorial Sloan Kettering Hospital in New York (2 1). Retreatment of Hodgkin’s Disease is possible by repeating the initial chemotherapy regimen, by switching to a new combination of chemotherapeutic agents or by switching to a new modality, that is to radiation if chemotherapy was used first or vice versa. A significant proportion of the patients with recurrent disease can be cured with this approach if their disease is limited to lymph nodes and they have had a long disease-free interval (> 1 year (8, 15)). In patients with more aggressive disease or in patients that fail second line chemotherapy or radiation, further dose intensification remains the only, potentially curative treatment option. It is the logical extension of the earlier mentioned treatment paradigm: the higher the dose, the higher the chance of cure. Dose intensification causes prolonged and potentially lethal bone marrow damage that requires sophisticated hematological support. Following the lead provided by Dicke and co-workers in their study of patients with acute leukemia (6) autologous bone marrow transplantation has been applied to patients with persistent Hodgkin’s Disease (1, 12). An absolute requirement for such a study is the ability to harvest and cryopreserve enough good quality bone marrow cells (the equivalent of at least 50 million, normal, bone marrow cells per kilogram of the recipient (18). The helpful property of hematopoietic stem cells to cross the bloodmarrow barrier and “home” into the hemopoietic parenchyma simplifies the transplant procedure to an ordinary intravenous infusion of bone marrow cells (17). In the setting of a bone marrow transplant, the pretreatment of the patient (“conditioning”) can be dose intensified for chemotherapeutic agents as well as for radiation (1, 3, 12). In a recent review, both approaches were found to have curative potential (3). Unfortunately, dose intensification is also reflected in side effects (long hospital stay) and mortality rate (approximately 15%) of patients. In patients with “responsive” disease, approximately 50%
Hodgkin’s disease is a relatively rare disorder with approximately 6000new cases per year in the United States. A convincing counterpart of this malignancy in an experimental animal model has not been found (13). Nevertheless, patients with this disease have been studied extensively and continue to provide important new leads for improvements in cancer treatment. The polymorphic histological architecture found in specimens of Hodgkin’s Disease sets it apart from other human malignancies. The etiology and the clonogenic cells responsible for the progressive nature of the disorder remain to be identified ( 11, 13, 14). Most stages of Hodgkin’s Disease are confined to the lymphatic system. It proceeds through the lymphatic system in a predictable manner, by so-called “contiguous spread”. This allows for the successful application of large field, external beam, radiation therapy in early stages of the disease (10). In advanced stages, high cure rates can be obtained with the appropriate application of systemic multiagent chemotherapy (2, 5). Dose intensity is crucial to the success of chemotherapy as well as radiation, while dose rate appears to be more important for chemotherapy than for radiation therapy (4,9). Hematological side effects (thrombocytopenia and granulopenia) are the most common acute dose-limiting side effects of either treatment modality. Thus, the “lessons” learned from the study of Hodgkin’s Disease include: field design of regional radiation therapy, design of combination chemotherapy, need for dose intensity and hematological side effects of cancer treatment. Such paradigms have been extrapolated successfully to the treatment of other malignancies. Despite the justified optimism of patients and their doctors at the initiation of treatment, recurrence or disease persistence is met in a subpopulation of patients (approximately 30%, mainly the elderly or advanced stage patient). Fortunately, this resistant form of the disease has also provided opportunity for study, as evidenced by the report in this issue by Yahalom and his co-workers
Reprint
requests
to: Huib M. Vriesendorp,
M.D., Ph.D.
Accepted 1119
for publication
7 July 1989.
1120
I. J. Radiation Oncology 0 Biology 0 Physics
can obtain a long lasting complete response and possibly proven to be cured in long-term follow-up (11 and R. Jones, personal communication June 1989). Responsive disease is defined as Hodgkin’s Disease that still responds to regular dose chemotherapy prior to the high dose chemotherapy and/or radiation followed by bone marrow transplantation and provides a low tumor burden at the time of transplantation. The investigators from Memorial Sloan-Kettering Cancer Center have made important and new contributions to the field. They have been very successful and inventive in their selection of “normal” dose chemotherapy prior to the high dose radiation and chemotherapy for which bone marrow support was needed. All of their 17 patients appear to have had “responsive” disease as defined in the previous paragraph. They have limited their study to patients that had not received any prior radiation. In their conditioning protocol, radiation played a major role, that is 5 daily fractions of 300 rad to bulky disease, followed by three daily 167 rad fractions to a mantle and inverted Y field (on the same day) for 4 days to a total dose of 2000 rad. The high response rate and initial disease-free survival observed are very encouraging. Obviously, radiation can be given in many different ways. It is doubtful that the New York investigators have selected the optimal radiation schedule in their first try. Many radiation biologists would question whether the accelerated hyperfractionated radiation as used in the SloanKettering study, would not cause an undue increase in acute side effects ( 16). Late effects do occur after high dose chemotherapy/radiation regimens, but are not lethal or dose-limiting with the exception of radiation pneumonitis (7). Therefore, if radiation pneumonitis can be prevented, acute side effects will determine the applicability of bone marrow transplantation. The mortality rate was high in the Yahalom study (4/ 17) and probably indicated an increased level of acute side effects, in comparison to studies using different radiation schedules (3).
November 1989, Volume 17, Number 5
However, one of their more important observations, that radiation can be a very effective agent in persistent Hodgkin’s Disease, stands. Alternative modes of delivering the radiation (such as changes in fields, doses and fractionations) can be explored. We have found a high complete response rate (5/ 10) in a Phase I-II study of intravenous 9”Yttrium labeled polyclonal antiferritin (19 and unpublished observations). The only acute side effects observed so far after radiolabeled immunoglobulin infusion has been bone marrow toxicity. The therapeutic ratio of bone marrow transplantation for persistent Hodgkin’s Disease might be increased by the incorporation of radiolabeled antibodies in the conditioning protocol. In addition, disease-free survival might be improved upon. Calculations require the assumption of clonogenic tumor cells. As indicated such cells are assumed to be present in Hodgkin’s disease but have not been identified morphologically. The tumor control probability can be obtained from Poisson statistics P (cure) = eecSFxM),in which SF is Surviving Fraction and M the original number of clonogens in the tumor (20). The assumption is that on average the patient populations for study will have the same M. For a cure probability of 50% (p = 0.5), the formula indicates that on average 0.693 clonogens survive per patient. For a cure probability of 90% (p = 0.9) only 0.095 clonogens survive per patient. Radiolabeled antibodies would only have to give an additional decrease in the surviving fraction after conditioning of less than a log (0.095: 0.693 - 0.14) to increase cure rates to 90%. This appears to be a realistic goal in view of the response rates found in the Phase I-II study. Probably similar speculations could be made for other agents that could be added to the conditioning regimen. However, we are biased towards radiolabeled antibodies, as they provide “systemic” radiation at a low toxicity rate. Thus, Hodgkin’s Disease continues to offer exciting possibilities for clinical research.
REFERENCES 1. Appelbaum, F. R.; Sullivan, K. M.; Thomas, E. D.; Buckner, C. D.; Clift, R. A.; Deeg, H. J.; Newman, P. E.; Sanders, J. E.; Stewart, P.; Storb R. Allogeneic marrow transplantation in the treatment of MOPP-resistant Hodgkin’s Disease. J. Clin. Oncol. 1:1490-1494; 1985. S. Combination 2. Bonadonna, G.; Zuculi, R.; Montardino, chemotherapy of Hodgkin’s disease with Adriamycin, Bleomycin, Vinblastine and Immidazole carboxamide versus MOPP. Cancer 36:252-257; 1975. 3. Canellos, G. P.; Nadler, L.; Takvorian, T. Autologous bone marrow transplantation in the treatment of malignant lymphoma and Hodgkin’s disease. Sem. Hematol. 25(2):58-65; 1988. R.; Rosenberg, S. A dose and time 4. Carde, P.; MacKintosh, response analysis of the treatment of Hodgkin’s Disease with MOPP chemotherapy. J. Clin. Oncol. 1:146-153; 1983. 5. DeVita, V. T.; Set-pick, A.; Carbone, P. P. Combination chemotherapy in the treatment of advanced Hodgkin’s Disease. Ann. Intern. Med. 73:891-895, 1970.
6. Dicke, K. A.; Zander, A. R.; Spitzer, G.; Peters, L.; McCredie, K. B.; Verma, D. S.; Vellekoop, L.; Hester, J. Autologous bone marrow transplantation in adult leukemia in relapse. Lancet; 1:5 14-5 17; 1979. 7. Dyk, J. van; Keane, T. J.; Kan, S.; Rider, W. D.; Fryer, C. J. H. Radiation pneumonitis following single large dose irradiation: A re-evaluation based on absolute dose to lung. Int. J. Rad. Oncol. Biol. Phys. 7:461-467; 1981. 8. Fisher, R. I.; DeVita, V. T.; Hubbard, S. P.; Simon, R.; Young, R. C. Prolonged disease-free survival in Hodgkin’s disease with MOPP reinduction after first failure. Ann. Intern. Med. 90:761-763; 1979. M.; Pearlman, A. W.; Turgeon, L. Hodgkin’s 9. Friedman, disease. Am. J. Roentgenol. 99:843-852; 1967. 10. Glatstein, E.; Wasserman, T. H. Hodgkin’s disease. Chapter 56. In: Perez, C. A. and Brady, L. W., eds. Philadelphia, PA: Lippincott Co.; 1987:1057-1072. 11. Jagannath, S.; Armitage, J. 0.; Dicke, K. A.; Tucker, S. L.; Velasquez, W. S.; Smith, K.; Vaughan, W. P.; Kessinger,
Hodgkin’s disease: New possibilities for clinical research 0 H. M. VRIESENDORPAND S.E.ORDER
12.
13. 14. 15.
16.
A.; Horowitz, L. J.; Hagemeister, F. B.; Cabanillas, F.; Spitzer, G. Timing of high dose CBV and autologous bone marrow transplantation in the management of relapsed or refractory Hodgkin’s disease. In: Dicke, K.A., Spitzer, G., Jagannati, S. and Evinger-Hodges, M.J., eds. Autologous Bone Marrow Transplantation. Proceedings of the Fourth International Symposium, Univ. Texas, M. D. Anderson Cancer Center, 1989:275-283. Jagannath, S.; Dicke, K. A.; Armitage, J. 0.; Cabanillas, F. F.; Horowitz, L. J.; Vellekoop, L.; Zander, A. R.; Spitzer, G. High dose Cyclophosphamide, Carmustine and Etoposide and autologous bone marrow transplantation for relapsed Hodgkin’s disease. Ann. Intern. Med. 104:163-168; 1986. Kaplan, H. S. Hodgkin’s disease, 2nd edition. Cambridge, MA: Harvard University Press; 1980. Order, S. E.; Hellman, S. Pathogenesis of Hodgkin’s disease. Lancet; 1571-573; 1972. Roach III, M.; Kapp, D. S.; Rosenberg, S. A.; Hoppe, R. T. Radiotherapy with curative intent. An option in selected patients relapsing after chemotherapy for advanced Hodgkin’s disease. J. Clin. Oncol. 5:550-555; 1987. Thames, H. D.; Withers, H. R.; Peters, L. J.; Fletcher,
17.
18.
19.
20.
21.
1121
G. H. Changes in early and late response with altered dose fractionation: Implications for dose survival relationships. Int. J. Rad. Oncol. Biol. Phys. 8:219-226, 1982. Vriesendorp, H. M. Engraftment of Hemopoietic Cells. In: van Bekkum, D. W. and Lowe&erg, B. (eds). Bone Marrow Transplantation: Biological Mechanisms and Clinical Practice. New York: M. Dekker; 1985:73-145. Vriesendorp, H. M.; van Bekkum, D. W. Role of Total Body Irradiation in Conditioning for Bone Marrow Transplantation. In: Thierfelder, S., Rodt, H., Kolb, H., eds. Immunobiology of Bone Marrow Transplantation, Hematology and Blood Transfusions, 25:349-364; 1980. Vriesendorp, H. M.; Herpst, J. M.; Leichner, P. K.; Klein, J. L.; Order, S. E. Polyclonal90-Yttrium labeled antiferritin for refractory Hodgkin’s disease. Int. J. Rad. Oncol. Biol. Phys., in press. Withers, H. R.; Peters, L. J. Biological aspects of Radiation Therapy. In: Fletcher, G. H. Textbook of Radiotherapy 3rd edition, Philadelphia: Lea & Febiger; 1989: 103. Yahalom, J.; Gulati, S.; Shank, B.; Clarkson, B.; Fuks, Z. Total Lymphoid Irradiation, high dose chemotherapy and autologous bone marrow transplantation for chemotherapy resistant Hodgkin’s Disease. Int. J. Rad. Oncol. Biol. Phys., 1989. in press.
Copyright
03~3016/89 $3.00 + .I0 0 1989 Pergamon Press plc
0 Editorial HODGKIN’S DISEASE: NEW POSSIBILITIES FOR CLINICAL RESEARCH HUIBM.VRIESENDORP, Johns Hopkins
M.D.,PHD.ANDSTANLEYE.ORDER,M.D.,SC.D.
Radiation
Oncology,
Johns Hopkins
University,
Baltimore,
MD 2 1205
Hodgkin’s Disease, Bone marrow transplantation. from the Memorial Sloan Kettering Hospital in New York (2 1). Retreatment of Hodgkin’s Disease is possible by repeating the initial chemotherapy regimen, by switching to a new combination of chemotherapeutic agents or by switching to a new modality, that is to radiation if chemotherapy was used first or vice versa. A significant proportion of the patients with recurrent disease can be cured with this approach if their disease is limited to lymph nodes and they have had a long disease-free interval (> 1 year (8, 15)). In patients with more aggressive disease or in patients that fail second line chemotherapy or radiation, further dose intensification remains the only, potentially curative treatment option. It is the logical extension of the earlier mentioned treatment paradigm: the higher the dose, the higher the chance of cure. Dose intensification causes prolonged and potentially lethal bone marrow damage that requires sophisticated hematological support. Following the lead provided by Dicke and co-workers in their study of patients with acute leukemia (6) autologous bone marrow transplantation has been applied to patients with persistent Hodgkin’s Disease (1, 12). An absolute requirement for such a study is the ability to harvest and cryopreserve enough good quality bone marrow cells (the equivalent of at least 50 million, normal, bone marrow cells per kilogram of the recipient (18). The helpful property of hematopoietic stem cells to cross the bloodmarrow barrier and “home” into the hemopoietic parenchyma simplifies the transplant procedure to an ordinary intravenous infusion of bone marrow cells (17). In the setting of a bone marrow transplant, the pretreatment of the patient (“conditioning”) can be dose intensified for chemotherapeutic agents as well as for radiation (1, 3, 12). In a recent review, both approaches were found to have curative potential (3). Unfortunately, dose intensification is also reflected in side effects (long hospital stay) and mortality rate (approximately 15%) of patients. In patients with “responsive” disease, approximately 50%
Hodgkin’s disease is a relatively rare disorder with approximately 6000new cases per year in the United States. A convincing counterpart of this malignancy in an experimental animal model has not been found (13). Nevertheless, patients with this disease have been studied extensively and continue to provide important new leads for improvements in cancer treatment. The polymorphic histological architecture found in specimens of Hodgkin’s Disease sets it apart from other human malignancies. The etiology and the clonogenic cells responsible for the progressive nature of the disorder remain to be identified ( 11, 13, 14). Most stages of Hodgkin’s Disease are confined to the lymphatic system. It proceeds through the lymphatic system in a predictable manner, by so-called “contiguous spread”. This allows for the successful application of large field, external beam, radiation therapy in early stages of the disease (10). In advanced stages, high cure rates can be obtained with the appropriate application of systemic multiagent chemotherapy (2, 5). Dose intensity is crucial to the success of chemotherapy as well as radiation, while dose rate appears to be more important for chemotherapy than for radiation therapy (4,9). Hematological side effects (thrombocytopenia and granulopenia) are the most common acute dose-limiting side effects of either treatment modality. Thus, the “lessons” learned from the study of Hodgkin’s Disease include: field design of regional radiation therapy, design of combination chemotherapy, need for dose intensity and hematological side effects of cancer treatment. Such paradigms have been extrapolated successfully to the treatment of other malignancies. Despite the justified optimism of patients and their doctors at the initiation of treatment, recurrence or disease persistence is met in a subpopulation of patients (approximately 30%, mainly the elderly or advanced stage patient). Fortunately, this resistant form of the disease has also provided opportunity for study, as evidenced by the report in this issue by Yahalom and his co-workers
Reprint
requests
to: Huib M. Vriesendorp,
M.D., Ph.D.
Accepted 1119
for publication
7 July 1989.
1120
I. J. Radiation Oncology 0 Biology 0 Physics
can obtain a long lasting complete response and possibly proven to be cured in long-term follow-up (11 and R. Jones, personal communication June 1989). Responsive disease is defined as Hodgkin’s Disease that still responds to regular dose chemotherapy prior to the high dose chemotherapy and/or radiation followed by bone marrow transplantation and provides a low tumor burden at the time of transplantation. The investigators from Memorial Sloan-Kettering Cancer Center have made important and new contributions to the field. They have been very successful and inventive in their selection of “normal” dose chemotherapy prior to the high dose radiation and chemotherapy for which bone marrow support was needed. All of their 17 patients appear to have had “responsive” disease as defined in the previous paragraph. They have limited their study to patients that had not received any prior radiation. In their conditioning protocol, radiation played a major role, that is 5 daily fractions of 300 rad to bulky disease, followed by three daily 167 rad fractions to a mantle and inverted Y field (on the same day) for 4 days to a total dose of 2000 rad. The high response rate and initial disease-free survival observed are very encouraging. Obviously, radiation can be given in many different ways. It is doubtful that the New York investigators have selected the optimal radiation schedule in their first try. Many radiation biologists would question whether the accelerated hyperfractionated radiation as used in the SloanKettering study, would not cause an undue increase in acute side effects ( 16). Late effects do occur after high dose chemotherapy/radiation regimens, but are not lethal or dose-limiting with the exception of radiation pneumonitis (7). Therefore, if radiation pneumonitis can be prevented, acute side effects will determine the applicability of bone marrow transplantation. The mortality rate was high in the Yahalom study (4/ 17) and probably indicated an increased level of acute side effects, in comparison to studies using different radiation schedules (3).
November 1989, Volume 17, Number 5
However, one of their more important observations, that radiation can be a very effective agent in persistent Hodgkin’s Disease, stands. Alternative modes of delivering the radiation (such as changes in fields, doses and fractionations) can be explored. We have found a high complete response rate (5/ 10) in a Phase I-II study of intravenous 9”Yttrium labeled polyclonal antiferritin (19 and unpublished observations). The only acute side effects observed so far after radiolabeled immunoglobulin infusion has been bone marrow toxicity. The therapeutic ratio of bone marrow transplantation for persistent Hodgkin’s Disease might be increased by the incorporation of radiolabeled antibodies in the conditioning protocol. In addition, disease-free survival might be improved upon. Calculations require the assumption of clonogenic tumor cells. As indicated such cells are assumed to be present in Hodgkin’s disease but have not been identified morphologically. The tumor control probability can be obtained from Poisson statistics P (cure) = eecSFxM),in which SF is Surviving Fraction and M the original number of clonogens in the tumor (20). The assumption is that on average the patient populations for study will have the same M. For a cure probability of 50% (p = 0.5), the formula indicates that on average 0.693 clonogens survive per patient. For a cure probability of 90% (p = 0.9) only 0.095 clonogens survive per patient. Radiolabeled antibodies would only have to give an additional decrease in the surviving fraction after conditioning of less than a log (0.095: 0.693 - 0.14) to increase cure rates to 90%. This appears to be a realistic goal in view of the response rates found in the Phase I-II study. Probably similar speculations could be made for other agents that could be added to the conditioning regimen. However, we are biased towards radiolabeled antibodies, as they provide “systemic” radiation at a low toxicity rate. Thus, Hodgkin’s Disease continues to offer exciting possibilities for clinical research.
REFERENCES 1. Appelbaum, F. R.; Sullivan, K. M.; Thomas, E. D.; Buckner, C. D.; Clift, R. A.; Deeg, H. J.; Newman, P. E.; Sanders, J. E.; Stewart, P.; Storb R. Allogeneic marrow transplantation in the treatment of MOPP-resistant Hodgkin’s Disease. J. Clin. Oncol. 1:1490-1494; 1985. S. Combination 2. Bonadonna, G.; Zuculi, R.; Montardino, chemotherapy of Hodgkin’s disease with Adriamycin, Bleomycin, Vinblastine and Immidazole carboxamide versus MOPP. Cancer 36:252-257; 1975. 3. Canellos, G. P.; Nadler, L.; Takvorian, T. Autologous bone marrow transplantation in the treatment of malignant lymphoma and Hodgkin’s disease. Sem. Hematol. 25(2):58-65; 1988. R.; Rosenberg, S. A dose and time 4. Carde, P.; MacKintosh, response analysis of the treatment of Hodgkin’s Disease with MOPP chemotherapy. J. Clin. Oncol. 1:146-153; 1983. 5. DeVita, V. T.; Set-pick, A.; Carbone, P. P. Combination chemotherapy in the treatment of advanced Hodgkin’s Disease. Ann. Intern. Med. 73:891-895, 1970.
6. Dicke, K. A.; Zander, A. R.; Spitzer, G.; Peters, L.; McCredie, K. B.; Verma, D. S.; Vellekoop, L.; Hester, J. Autologous bone marrow transplantation in adult leukemia in relapse. Lancet; 1:5 14-5 17; 1979. 7. Dyk, J. van; Keane, T. J.; Kan, S.; Rider, W. D.; Fryer, C. J. H. Radiation pneumonitis following single large dose irradiation: A re-evaluation based on absolute dose to lung. Int. J. Rad. Oncol. Biol. Phys. 7:461-467; 1981. 8. Fisher, R. I.; DeVita, V. T.; Hubbard, S. P.; Simon, R.; Young, R. C. Prolonged disease-free survival in Hodgkin’s disease with MOPP reinduction after first failure. Ann. Intern. Med. 90:761-763; 1979. M.; Pearlman, A. W.; Turgeon, L. Hodgkin’s 9. Friedman, disease. Am. J. Roentgenol. 99:843-852; 1967. 10. Glatstein, E.; Wasserman, T. H. Hodgkin’s disease. Chapter 56. In: Perez, C. A. and Brady, L. W., eds. Philadelphia, PA: Lippincott Co.; 1987:1057-1072. 11. Jagannath, S.; Armitage, J. 0.; Dicke, K. A.; Tucker, S. L.; Velasquez, W. S.; Smith, K.; Vaughan, W. P.; Kessinger,
Hodgkin’s disease: New possibilities for clinical research 0 H. M. VRIESENDORPAND S.E.ORDER
12.
13. 14. 15.
16.
A.; Horowitz, L. J.; Hagemeister, F. B.; Cabanillas, F.; Spitzer, G. Timing of high dose CBV and autologous bone marrow transplantation in the management of relapsed or refractory Hodgkin’s disease. In: Dicke, K.A., Spitzer, G., Jagannati, S. and Evinger-Hodges, M.J., eds. Autologous Bone Marrow Transplantation. Proceedings of the Fourth International Symposium, Univ. Texas, M. D. Anderson Cancer Center, 1989:275-283. Jagannath, S.; Dicke, K. A.; Armitage, J. 0.; Cabanillas, F. F.; Horowitz, L. J.; Vellekoop, L.; Zander, A. R.; Spitzer, G. High dose Cyclophosphamide, Carmustine and Etoposide and autologous bone marrow transplantation for relapsed Hodgkin’s disease. Ann. Intern. Med. 104:163-168; 1986. Kaplan, H. S. Hodgkin’s disease, 2nd edition. Cambridge, MA: Harvard University Press; 1980. Order, S. E.; Hellman, S. Pathogenesis of Hodgkin’s disease. Lancet; 1571-573; 1972. Roach III, M.; Kapp, D. S.; Rosenberg, S. A.; Hoppe, R. T. Radiotherapy with curative intent. An option in selected patients relapsing after chemotherapy for advanced Hodgkin’s disease. J. Clin. Oncol. 5:550-555; 1987. Thames, H. D.; Withers, H. R.; Peters, L. J.; Fletcher,
17.
18.
19.
20.
21.
1121
G. H. Changes in early and late response with altered dose fractionation: Implications for dose survival relationships. Int. J. Rad. Oncol. Biol. Phys. 8:219-226, 1982. Vriesendorp, H. M. Engraftment of Hemopoietic Cells. In: van Bekkum, D. W. and Lowe&erg, B. (eds). Bone Marrow Transplantation: Biological Mechanisms and Clinical Practice. New York: M. Dekker; 1985:73-145. Vriesendorp, H. M.; van Bekkum, D. W. Role of Total Body Irradiation in Conditioning for Bone Marrow Transplantation. In: Thierfelder, S., Rodt, H., Kolb, H., eds. Immunobiology of Bone Marrow Transplantation, Hematology and Blood Transfusions, 25:349-364; 1980. Vriesendorp, H. M.; Herpst, J. M.; Leichner, P. K.; Klein, J. L.; Order, S. E. Polyclonal90-Yttrium labeled antiferritin for refractory Hodgkin’s disease. Int. J. Rad. Oncol. Biol. Phys., in press. Withers, H. R.; Peters, L. J. Biological aspects of Radiation Therapy. In: Fletcher, G. H. Textbook of Radiotherapy 3rd edition, Philadelphia: Lea & Febiger; 1989: 103. Yahalom, J.; Gulati, S.; Shank, B.; Clarkson, B.; Fuks, Z. Total Lymphoid Irradiation, high dose chemotherapy and autologous bone marrow transplantation for chemotherapy resistant Hodgkin’s Disease. Int. J. Rad. Oncol. Biol. Phys., 1989. in press.