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Hematological abnormalities of disseminated cancer
Jnf. J. RadioInn
Oncology
Biol. Phys.,
1976, Vol.
I, pp. S25-527.
Pergamon
Press.
Printed
in the U.S.A.
HEMATOLOGICAL ABNORMALITIES DISSEMINATED CANCER EMIL
J FREIREICH,
OF
M.D.
Department of Developmental Therapeutics, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Texas Medical Center, Houston, Texas, U.S.A. Disseminated cancer, Hematological abnormalities. The hematological malignancies, that is, leukemia and lymphoma, have hematological abnormalities as a central part of the disease process. Thus, deficiency of host defense and hemorrhagic diathesis are the most prominent complications.4 For other types of disseminated cancer, hematological abnormalities may affect any of the three formed elements of the blood; red celis, white cells, or platelets.’ For red cells, extensive metastases to the bone marrow can result in myelophthisic anemia. This form of anemia is characterized by a very disturbed red cell maturation, resulting in a high proportion of nucleated red cells circulating in the blood. This hematologic abnormality should lead to bone marrow examination to confirm metastatic disease of the bone marrow. Management, of course, depends on control of the metastatic disease and replacement transfusion with allogeneic red cells. The commonest form of anemia associated with metastatic disease results from blood loss when metastases occur on surfaces which result in bleeding, particularly in the gastrointestinal tract. Hemolytic anemia is characteristically associated with lymphomas and leukemias and rarely seen with other kinds of malignancies. A deficiency of platelets can occur with wide spread metastatic disease of the bone marrow, although this is not very common. Any disorders resulting in splenomegaly will be associated with a lowered concentration of platelets in the blood, but generally not symptomatic. Hematological malignancies like polycythemia vera and chronic granulocy-
tic leukemia can result in thrombocytosis. In the presence of wide spread metastases, a of disseminated intravascular syndrome coagulation can occur. This is most common in acute promyelocytic leukemia; however, it has been observed rarely in other disseminated malignancies, particularly from such primaries as prostate and lung. A lowering of platelets associated with a low fibrinogen concentration of the plasma and an increased level of fibrin split products is diagnostic. A syndrome can be controlled acutely with heparin; however, control of the progress of the disease is fundamental to treatment. Platelet replacement transfusion is not useful in this circumstance because of the very short intravascular life span. With wide spread metastatic bone marrow involvement, a decrease in concentration of granulocytes can be observed rarely: this results in an increased susceptibility to infection. Characteristic of far advanced disseminated malignancy is a progressive decrease in circulating lymphocytes, associated with a progressive loss of immunocompetence. The treatment of disseminated cancer generally requires systemic chemotherapy with adjuvant surgery or radiation therapy for major sites of involvement or for palliation. A limiting side effect of treatment for cancer is toxicity to the rapidly turning over bone marrow stem cells; thus, bone marrow failure is a common side effect in treatment of advanced cancer. Therefore, management of bone marrow failure has become an essential part of the treatment of metastatic disease. Replacement transfusion therapy;* i.e. replacement of red cells by transfusion, is a well
525
526
Radiation Oncology 0 Biology 0 Physics
developed discipline and presents no problem. The immunological compatibility between donor and recipient can be predicted effectively and inexpensively; red cells may be collected and stored for periods up to three weeks at refrigerator temperatures, allowing blood banking as a regular procedure. Post transfusion survival of allogeneic red cells is over 100 days so, transfusion is needed in infrequent intervals. In contrast, platelet transfusion replacement is technically more difficult but can be accomplished with regularity.” Major limitations in platelet transfusion are the much shorter life span of the platelets after transfusion (5-10 days). Thus, even with replacement of effective doses, transfusion must be repeated at least once or twice weekly. The second problem is that storage of platelets generally is not practiced; therefore, only platelets which are freshly collected, or 24-hr-old, or less are an effective platelet transfusion product. The final problem is that the iso-antibodies in platelets are relatively poorly characterized, and regular transfusion with compatible donors is difficult to accomplish in practice. Repeated transfusion from random donors results in alloimmunization and a loss of effectiveness of transfused platelets. The best technique for predicting compatibility is the HLA tissue typing procedure. This is most effective when HLA compatible siblings serve as donors. In general, blood banks capable of performing plateletpheresis procedures should be used; this allows the collection of up to four units of platelets from a single donor in a single procedure, and decreases the number of antigens to which the donor is exposed. Granulocyte replacement therapy is even more difficult: it is still a research procedure. Two techniques can be used, the continuous flow blood separator:.’ and the reversible leuko adhesion technique.3 Using these two procedures, a sufficiently large number of granulocytes (2 x 10” or 20-100 billion) can be collected from a single donor; this will restore the granulocyte concentration to normal in the recipient. However, the intravascular lifespan of granulocytes is approximately six hours, therefore, granulocyte replacement must be
March-April
1976, Vol. 1, Number 5 and Number 6
performed at least once, and preferably twice a during periods of severe day granulocytopenia. Again, allosensitization occurs regularly with random donors and the reactions are more serious than those following platelet transfusion. Thus, the availability of HLA tissue typing for selecting better donors is more important for granulocyte replacement than for platelet replacement transfusion. The combined effects of immunodeficiency and depressed granulocytes leads to a high frequency of infection. The primary approach to the management of infections is the intelligent and aggressive use of antibiotics.’ Recent work has demonstrated that protected environments can reduce sharply the frequency of infection in patients who have a high probability of developing infection, such as leukemia patients.2 However, this technology is still investigative and generally is not available. Ordinary reverse isolation procedures contribute little to the prevention of infection. The treatment of immunodeficiency depends on control of the systemic cancer. Effective response to therapy generally is associated with improved immunocompetence. However, the new field of immunotherapy has great promise.6 The use of the bacillus Calmette-Guerin (BCG) by vaccination can greatly stimulate non specific immune response in patients. The developmental approach to the management of bone marrow failure is bone marrow transplantation.” At present, the techniques for identifying compatibility between allogeneic donors and recipients are not developed sufficiently to predict successful transplantation without immunosuppression. Although this procedure is still developmental, there have been instances of effective control of metastatic malignancies. Auto transplantation with bone marrow collected prior to treatment also has been investigated. Finally, transplantation between identical twins can be accomplished with regularity. This is an important area for future developments. In summary, hematological abnormalities are commonly associated with widely disseminated cancer. Effective therapy for all
Hematological abnormalities of disseminated cancer 0 E. J
hematological abnormalities can be accomplished for patients with progressive unresponsive disease. This treatment is palliative. However, in circumstances where patients are showing very favorable or beneficial responses to systemic chemotherapy, the management of the hematological abnormalities for short periods of time, while normal organ
FREIREICH
521
function recovers, may prove to be a crucial part of the management. The effective management of bone marrow failure can extend the therapeutic index of all forms of cancer therapy. By controlling the periods of temporary myelosuppression, the host’s ability to tolerate more agressive therapy is enhanced.
REFERENCES 1. Bodey, G.P.: Antiobiotic
therapy of infections undergoing cancer chemotherapy, In: Antibio tic and Chemotherapy-chemotherapy Under Special Conditions, ed. by Schonfeld, H., Brockman, R. W., Hahn, F. E., Vol. 18, S. Karger, New York 1972, pp. 49-88. 2. Bodey, G.P., Gehan, E.A., Freireich, E.J., Frei. E.. III: Protected environment-Prophylactic antibiotic program in the chemotherapy of acute leukemia. Am. J. Med. Sci. 262: 138-151. 1971. 3. Djerassi. I., Kim, J.S., Mitrakul, C., et al.: Filtration leukopheresis for separation and concentration of transfusable amounts of norma1 human granulocytes. Medicine 1: 358-361, 1970. 4. Freireich, E.J., Bodey, G.P., De Jongh, D.S., Curtis, J.E., Hersh, E.M.: Supportive therapeutic measures for patients under treatment for leukemia or lymphoma. In: Leukemia Lymphoma (A Collection of Papers Presented at the Fourteenth Annual Clinical Conference on Cancer), 1%9 at the University of Texas,
M.D. Anderson Hospital and Tumor Institute at Houston, Texas, Year Bood Medical Publishers, Chicago, 1970, pp. 275-284. 5. Graw, R.G., Jr.. Herzig, G., Perry, S., Henderson, E.S.: Normal granulocyte transfusions:
6.
7.
8.
9.
Treatment of gram negative bacterial septicemia. New Engl. J. Med. 287: 367-371, 1972. Hersh, E.M., Gutterman, J.U., Mavligit, G.: Immunotherapy of Cancer in Man. Scientific Basis and Current Status. Charles C. Thomas, Springfield, 1973, pp. I-141. Laszlo, J., Kremer, W.B.: Hematologic effects of chemotherapeutic drugs and radiation. In Cancer Medicine, ed. by Holland, J.F., Frei, E. III. Lea & Febiger, Philadelphia, 1973, pp. 1085-l 114. McCredie, K.B., Freireich, E.J.: Blood component therapy. In Cancer Medicine, ed. by Holland, J.F., Frei, E. III. Lea & Febiger, Philadelphia, 1973, pp. 1115-l 129. McCredie, K.B., Freireich, E.J., Hester, J.P., Vallejos, C.: Increased granulocyte collection with the blood cell separator and the addition of etiocholanolone and hydroxyethyl starch. Transfusion
14: 357-364,
1974.
10. McCredie, K.B., Hester, J.P., Vallejos, C., Freireich, E.J.: Platelet and leukocyte tranfusions in acute leukemia. Human Pathol. 5: 699-708, 1974. 11. Rudolph, R.H., Fefer, A., Thomas, E.D., Buckner, C.D., Clift, R.A., Storb, R.: Isogeneic marrow grafts for hematologic malignancy in man. Arch. Int. Med. 132: 279-285, 1973.
Oncology
Biol. Phys.,
1976, Vol.
I, pp. S25-527.
Pergamon
Press.
Printed
in the U.S.A.
HEMATOLOGICAL ABNORMALITIES DISSEMINATED CANCER EMIL
J FREIREICH,
OF
M.D.
Department of Developmental Therapeutics, University of Texas System Cancer Center, M.D. Anderson Hospital and Tumor Institute, Texas Medical Center, Houston, Texas, U.S.A. Disseminated cancer, Hematological abnormalities. The hematological malignancies, that is, leukemia and lymphoma, have hematological abnormalities as a central part of the disease process. Thus, deficiency of host defense and hemorrhagic diathesis are the most prominent complications.4 For other types of disseminated cancer, hematological abnormalities may affect any of the three formed elements of the blood; red celis, white cells, or platelets.’ For red cells, extensive metastases to the bone marrow can result in myelophthisic anemia. This form of anemia is characterized by a very disturbed red cell maturation, resulting in a high proportion of nucleated red cells circulating in the blood. This hematologic abnormality should lead to bone marrow examination to confirm metastatic disease of the bone marrow. Management, of course, depends on control of the metastatic disease and replacement transfusion with allogeneic red cells. The commonest form of anemia associated with metastatic disease results from blood loss when metastases occur on surfaces which result in bleeding, particularly in the gastrointestinal tract. Hemolytic anemia is characteristically associated with lymphomas and leukemias and rarely seen with other kinds of malignancies. A deficiency of platelets can occur with wide spread metastatic disease of the bone marrow, although this is not very common. Any disorders resulting in splenomegaly will be associated with a lowered concentration of platelets in the blood, but generally not symptomatic. Hematological malignancies like polycythemia vera and chronic granulocy-
tic leukemia can result in thrombocytosis. In the presence of wide spread metastases, a of disseminated intravascular syndrome coagulation can occur. This is most common in acute promyelocytic leukemia; however, it has been observed rarely in other disseminated malignancies, particularly from such primaries as prostate and lung. A lowering of platelets associated with a low fibrinogen concentration of the plasma and an increased level of fibrin split products is diagnostic. A syndrome can be controlled acutely with heparin; however, control of the progress of the disease is fundamental to treatment. Platelet replacement transfusion is not useful in this circumstance because of the very short intravascular life span. With wide spread metastatic bone marrow involvement, a decrease in concentration of granulocytes can be observed rarely: this results in an increased susceptibility to infection. Characteristic of far advanced disseminated malignancy is a progressive decrease in circulating lymphocytes, associated with a progressive loss of immunocompetence. The treatment of disseminated cancer generally requires systemic chemotherapy with adjuvant surgery or radiation therapy for major sites of involvement or for palliation. A limiting side effect of treatment for cancer is toxicity to the rapidly turning over bone marrow stem cells; thus, bone marrow failure is a common side effect in treatment of advanced cancer. Therefore, management of bone marrow failure has become an essential part of the treatment of metastatic disease. Replacement transfusion therapy;* i.e. replacement of red cells by transfusion, is a well
525
526
Radiation Oncology 0 Biology 0 Physics
developed discipline and presents no problem. The immunological compatibility between donor and recipient can be predicted effectively and inexpensively; red cells may be collected and stored for periods up to three weeks at refrigerator temperatures, allowing blood banking as a regular procedure. Post transfusion survival of allogeneic red cells is over 100 days so, transfusion is needed in infrequent intervals. In contrast, platelet transfusion replacement is technically more difficult but can be accomplished with regularity.” Major limitations in platelet transfusion are the much shorter life span of the platelets after transfusion (5-10 days). Thus, even with replacement of effective doses, transfusion must be repeated at least once or twice weekly. The second problem is that storage of platelets generally is not practiced; therefore, only platelets which are freshly collected, or 24-hr-old, or less are an effective platelet transfusion product. The final problem is that the iso-antibodies in platelets are relatively poorly characterized, and regular transfusion with compatible donors is difficult to accomplish in practice. Repeated transfusion from random donors results in alloimmunization and a loss of effectiveness of transfused platelets. The best technique for predicting compatibility is the HLA tissue typing procedure. This is most effective when HLA compatible siblings serve as donors. In general, blood banks capable of performing plateletpheresis procedures should be used; this allows the collection of up to four units of platelets from a single donor in a single procedure, and decreases the number of antigens to which the donor is exposed. Granulocyte replacement therapy is even more difficult: it is still a research procedure. Two techniques can be used, the continuous flow blood separator:.’ and the reversible leuko adhesion technique.3 Using these two procedures, a sufficiently large number of granulocytes (2 x 10” or 20-100 billion) can be collected from a single donor; this will restore the granulocyte concentration to normal in the recipient. However, the intravascular lifespan of granulocytes is approximately six hours, therefore, granulocyte replacement must be
March-April
1976, Vol. 1, Number 5 and Number 6
performed at least once, and preferably twice a during periods of severe day granulocytopenia. Again, allosensitization occurs regularly with random donors and the reactions are more serious than those following platelet transfusion. Thus, the availability of HLA tissue typing for selecting better donors is more important for granulocyte replacement than for platelet replacement transfusion. The combined effects of immunodeficiency and depressed granulocytes leads to a high frequency of infection. The primary approach to the management of infections is the intelligent and aggressive use of antibiotics.’ Recent work has demonstrated that protected environments can reduce sharply the frequency of infection in patients who have a high probability of developing infection, such as leukemia patients.2 However, this technology is still investigative and generally is not available. Ordinary reverse isolation procedures contribute little to the prevention of infection. The treatment of immunodeficiency depends on control of the systemic cancer. Effective response to therapy generally is associated with improved immunocompetence. However, the new field of immunotherapy has great promise.6 The use of the bacillus Calmette-Guerin (BCG) by vaccination can greatly stimulate non specific immune response in patients. The developmental approach to the management of bone marrow failure is bone marrow transplantation.” At present, the techniques for identifying compatibility between allogeneic donors and recipients are not developed sufficiently to predict successful transplantation without immunosuppression. Although this procedure is still developmental, there have been instances of effective control of metastatic malignancies. Auto transplantation with bone marrow collected prior to treatment also has been investigated. Finally, transplantation between identical twins can be accomplished with regularity. This is an important area for future developments. In summary, hematological abnormalities are commonly associated with widely disseminated cancer. Effective therapy for all
Hematological abnormalities of disseminated cancer 0 E. J
hematological abnormalities can be accomplished for patients with progressive unresponsive disease. This treatment is palliative. However, in circumstances where patients are showing very favorable or beneficial responses to systemic chemotherapy, the management of the hematological abnormalities for short periods of time, while normal organ
FREIREICH
521
function recovers, may prove to be a crucial part of the management. The effective management of bone marrow failure can extend the therapeutic index of all forms of cancer therapy. By controlling the periods of temporary myelosuppression, the host’s ability to tolerate more agressive therapy is enhanced.
REFERENCES 1. Bodey, G.P.: Antiobiotic
therapy of infections undergoing cancer chemotherapy, In: Antibio tic and Chemotherapy-chemotherapy Under Special Conditions, ed. by Schonfeld, H., Brockman, R. W., Hahn, F. E., Vol. 18, S. Karger, New York 1972, pp. 49-88. 2. Bodey, G.P., Gehan, E.A., Freireich, E.J., Frei. E.. III: Protected environment-Prophylactic antibiotic program in the chemotherapy of acute leukemia. Am. J. Med. Sci. 262: 138-151. 1971. 3. Djerassi. I., Kim, J.S., Mitrakul, C., et al.: Filtration leukopheresis for separation and concentration of transfusable amounts of norma1 human granulocytes. Medicine 1: 358-361, 1970. 4. Freireich, E.J., Bodey, G.P., De Jongh, D.S., Curtis, J.E., Hersh, E.M.: Supportive therapeutic measures for patients under treatment for leukemia or lymphoma. In: Leukemia Lymphoma (A Collection of Papers Presented at the Fourteenth Annual Clinical Conference on Cancer), 1%9 at the University of Texas,
M.D. Anderson Hospital and Tumor Institute at Houston, Texas, Year Bood Medical Publishers, Chicago, 1970, pp. 275-284. 5. Graw, R.G., Jr.. Herzig, G., Perry, S., Henderson, E.S.: Normal granulocyte transfusions:
6.
7.
8.
9.
Treatment of gram negative bacterial septicemia. New Engl. J. Med. 287: 367-371, 1972. Hersh, E.M., Gutterman, J.U., Mavligit, G.: Immunotherapy of Cancer in Man. Scientific Basis and Current Status. Charles C. Thomas, Springfield, 1973, pp. I-141. Laszlo, J., Kremer, W.B.: Hematologic effects of chemotherapeutic drugs and radiation. In Cancer Medicine, ed. by Holland, J.F., Frei, E. III. Lea & Febiger, Philadelphia, 1973, pp. 1085-l 114. McCredie, K.B., Freireich, E.J.: Blood component therapy. In Cancer Medicine, ed. by Holland, J.F., Frei, E. III. Lea & Febiger, Philadelphia, 1973, pp. 1115-l 129. McCredie, K.B., Freireich, E.J., Hester, J.P., Vallejos, C.: Increased granulocyte collection with the blood cell separator and the addition of etiocholanolone and hydroxyethyl starch. Transfusion
14: 357-364,
1974.
10. McCredie, K.B., Hester, J.P., Vallejos, C., Freireich, E.J.: Platelet and leukocyte tranfusions in acute leukemia. Human Pathol. 5: 699-708, 1974. 11. Rudolph, R.H., Fefer, A., Thomas, E.D., Buckner, C.D., Clift, R.A., Storb, R.: Isogeneic marrow grafts for hematologic malignancy in man. Arch. Int. Med. 132: 279-285, 1973.