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Management of polycythemia vera
MANAGEMENT
OF POLYCYTHEMIA
VERA
In the management of chronic disease two factors are often overlooked. One of these is concerned with the nature of the disorder, its natural course and prognosis, and the limitations as well as the potentialities of therap>-. It is obvious that if the condition in question is comparatively benign and its course is slow the therapy which is undertaken must not be more dangerous than the disease. The second factor is related to the simplicity or complexit)- of the therapeutic measures chosen and their cost. If the course of the disease is prolonged, long-term success will naturally depend a good deal on the character of the measures chosen and on whether or not they tax the patient’s financial resources. Polycythemia Vera is a disease of insidious onset and chronic course, usually affecting those in the later years of life, and is characterized by an increase in the total blood volume and a variety of symptoms and signs such as a sense of fullness, headache, dizziness, ringing in the ears, visual disturbances, dyspnea, lassitude, or weakness. There may be such a multiplicity of symptoms that neurasthenia is suspected. A curious symptom is intense itching after a bath or when warm in bed. On the other hand, the symptoms may be insignificant, and the polycythemia may be discovered only accidentall>-. The disorder is dangerous because of the complications which may. ensue. Vascular disease is extremely common and vascular accidents are frequent and in many instances are the cause of death. Venous thromboses, varicosities, arterial occlusion with gangrene, phlebitis, coronary thrombosis, claudication, and hypertension are encountered in many cases. An unusually high proportion Intercurrent infections, especiall?- of the of patients develop peptic ulcer. respiratory tract, chronic bronchitis, cirrhosis of the liver, and gout represent other less frequent complications. Although considerable attention has been given from time to time to various hypotheses concerning the nature of polycythemia Vera, there has been little to change the view which is most generally held; namely, that this disorder represents a comparatively benign neoplastic condition which is related to chronic myelocytic leukemia and probably also to myelofibrosis. There is no doubt that, even prior to the use of radiation in the treatment of this disorder, a transition in some cases to chronic myelocytic leukemia or to acute myeloblastic leukemia took place.1,5 Both the symptoms of polycythemia vera and the nying complications can be relieved by appropriate blood volume can be achieved by one of three means: venesection; (2) impairment of blood formation by the chemical agents, such as nitrogen mustard or related struction of blood by the use of phenylhydrazine. In
frequency of its accompatherapy. Reduction in (1) removal of blood by use of radiation or certain compounds; and (3) depractice it is often found
Volume 1 Number 4
EDITORIALS
463
that, in the course of the disease, all three methods need to be used at one time or another. Venesection is the surest and safest means for reducing the blood volume. The amount removed depends on the original blood level. The goal is to bring the hemoglobin level and volume of packed red cells to normal or to approxiThe latter is suggested because sometimes mately the upper limit of normal. these patients are found to be more comfortable at a level somewhat higher than The frequency of venesections will depend on the symptoms the normal mean. One pint of blood may be removed every other and the pleasure of the patient. The theorectical objection to venesection, day, or even daily in some patients. namely, that this stimulates erythropoiesis, is of little practical importance. The use of an iron-deficient diet to augment the iron deficiency produced by the venesections is impractical. Venesection, however, often becomes a troublesome type of therapy if this procedure needs to be repeated at frequent intervals. For this reason it is the favored and recommended practice to reduce the blood volume to normal levels by venesection and to attempt to maintain it at such levels by other means. For this purpose radiation has many advantages.‘04 As between roentgen therapy and radioactive phosphorus, the latter has the advantage that it is easily administered and there are no unpleasant aftereffects. The material can be given orally or intravenously but there is some value in intravenous administration in that there is no uncertainty regarding absorption. Although radioactive phosphorus has a widespread action at first because of the extensive participation of phosphorus in general biochemical processes, within one week appreciable amounts are deposited in bone and bone marrow and there the beta radiation affects the myeloid elements. A special advantage is derived from the fact that uptake of radioactive phosphorus by rapidly dividing cells is greater than by normal cells. Generally a dose of 3 to 5 millicuries is recommended for the initial administration. The patient is seen at intervals of three to four weeks following this. If, after three or four months, it is apparent from the volume of packed red cells that the blood is not being maintained at near normal levels, another injection may be given, the amount depending on the blood level at the time. It is always wise to err on the side of giving too little rather than t.oo much for, in the former case, blood can be removed if necessary, whereas if too much has been administered little can be done to correct the damage done. From time to time some undesirable effect on the hemopoietic system is produced by administration of radioactive phosphorus, such as thrombocytopenia or granulocytopenia. Furthermore, radioactive phosphorus is not available in In such situations the administration of phenylhydrazine some communities. is to be recommended. This drug when given judiciously produces few or no ill effects and may be extremely valuable. The reports of thrombosis and severe hemolytic anemia associated with the administration of phenylhydrazine emanate from those who have used the drug for the initial reduction of blood volume to normal rather than for maintenance after preliminary venesection. The latter objective is achieved readily by giving 0.1 Gm. phenylhydrazine hydrochloride
464
EDITORIALS
J. Chron. Dis. April. 1955
in capsules, by mouth, two to six times a week. Until the required dose has been determined, the blood should be examined weekly. After a steady state has been achieved, these intervals may be prolonged but readjustment of the dose may be necessary from time to time.
In view of the effectiveness of the procedures described, there seems to be little justification for the use of agents of the toxicity of nitrogen mustard3 or triethylene melamine.* By the judicious use of venesections, radioactive phosphorus, and phenylhydrazine the viscosity of the blood, as well as the total blood volume, can be reduced to satisfactory levels with a minimum of risk. The incidence of complications, especially vascular ones, has been greatly reduced in treated cases.1*4 Whether or not the incidence of leukemia is somewhat higher in patients treated with radioactive phosphorus than in those not receiving this form of therapy is uncertain. In any event, the differences reported are not such as to dissuade one from the use of this valuable therapeutic agent. M. M. WINTRORE REFERENCES
1. 2. 3. 4. 5.
Lawrence, J. H., Berlin, N. I., and Huff, R. L.: The Nature and Treatment of Poiycythemia. Studies on 263 Patients, Medicine 32:323, 19.53. Rosenthal, N:, and Rosenthal, R. L.: Treatment of Polycythemia Vera With Triethylene Melamine. Summary of Thirty Cases, Arch. Int. Med. 90:379, 1952. Spurr, C. L., Smith, T. R., Block, M., and Jacobson, L. 0.: A Clinical Study of the Use of N’&zgen Mustard Therapy m Polycythemla Vera, J. Lab. & Clin. Med. 35:252, Therapy, Proc. Staff Meet., Strobel, C.’ F. : Current Status of Radiophosphorus Clin. 29:1, 1954. Wintrobe, M. M.: Clinical Hematology, ed. 3, Philadelphia, 1951, Lea & Febiger.
Mayo
OF POLYCYTHEMIA
VERA
In the management of chronic disease two factors are often overlooked. One of these is concerned with the nature of the disorder, its natural course and prognosis, and the limitations as well as the potentialities of therap>-. It is obvious that if the condition in question is comparatively benign and its course is slow the therapy which is undertaken must not be more dangerous than the disease. The second factor is related to the simplicity or complexit)- of the therapeutic measures chosen and their cost. If the course of the disease is prolonged, long-term success will naturally depend a good deal on the character of the measures chosen and on whether or not they tax the patient’s financial resources. Polycythemia Vera is a disease of insidious onset and chronic course, usually affecting those in the later years of life, and is characterized by an increase in the total blood volume and a variety of symptoms and signs such as a sense of fullness, headache, dizziness, ringing in the ears, visual disturbances, dyspnea, lassitude, or weakness. There may be such a multiplicity of symptoms that neurasthenia is suspected. A curious symptom is intense itching after a bath or when warm in bed. On the other hand, the symptoms may be insignificant, and the polycythemia may be discovered only accidentall>-. The disorder is dangerous because of the complications which may. ensue. Vascular disease is extremely common and vascular accidents are frequent and in many instances are the cause of death. Venous thromboses, varicosities, arterial occlusion with gangrene, phlebitis, coronary thrombosis, claudication, and hypertension are encountered in many cases. An unusually high proportion Intercurrent infections, especiall?- of the of patients develop peptic ulcer. respiratory tract, chronic bronchitis, cirrhosis of the liver, and gout represent other less frequent complications. Although considerable attention has been given from time to time to various hypotheses concerning the nature of polycythemia Vera, there has been little to change the view which is most generally held; namely, that this disorder represents a comparatively benign neoplastic condition which is related to chronic myelocytic leukemia and probably also to myelofibrosis. There is no doubt that, even prior to the use of radiation in the treatment of this disorder, a transition in some cases to chronic myelocytic leukemia or to acute myeloblastic leukemia took place.1,5 Both the symptoms of polycythemia vera and the nying complications can be relieved by appropriate blood volume can be achieved by one of three means: venesection; (2) impairment of blood formation by the chemical agents, such as nitrogen mustard or related struction of blood by the use of phenylhydrazine. In
frequency of its accompatherapy. Reduction in (1) removal of blood by use of radiation or certain compounds; and (3) depractice it is often found
Volume 1 Number 4
EDITORIALS
463
that, in the course of the disease, all three methods need to be used at one time or another. Venesection is the surest and safest means for reducing the blood volume. The amount removed depends on the original blood level. The goal is to bring the hemoglobin level and volume of packed red cells to normal or to approxiThe latter is suggested because sometimes mately the upper limit of normal. these patients are found to be more comfortable at a level somewhat higher than The frequency of venesections will depend on the symptoms the normal mean. One pint of blood may be removed every other and the pleasure of the patient. The theorectical objection to venesection, day, or even daily in some patients. namely, that this stimulates erythropoiesis, is of little practical importance. The use of an iron-deficient diet to augment the iron deficiency produced by the venesections is impractical. Venesection, however, often becomes a troublesome type of therapy if this procedure needs to be repeated at frequent intervals. For this reason it is the favored and recommended practice to reduce the blood volume to normal levels by venesection and to attempt to maintain it at such levels by other means. For this purpose radiation has many advantages.‘04 As between roentgen therapy and radioactive phosphorus, the latter has the advantage that it is easily administered and there are no unpleasant aftereffects. The material can be given orally or intravenously but there is some value in intravenous administration in that there is no uncertainty regarding absorption. Although radioactive phosphorus has a widespread action at first because of the extensive participation of phosphorus in general biochemical processes, within one week appreciable amounts are deposited in bone and bone marrow and there the beta radiation affects the myeloid elements. A special advantage is derived from the fact that uptake of radioactive phosphorus by rapidly dividing cells is greater than by normal cells. Generally a dose of 3 to 5 millicuries is recommended for the initial administration. The patient is seen at intervals of three to four weeks following this. If, after three or four months, it is apparent from the volume of packed red cells that the blood is not being maintained at near normal levels, another injection may be given, the amount depending on the blood level at the time. It is always wise to err on the side of giving too little rather than t.oo much for, in the former case, blood can be removed if necessary, whereas if too much has been administered little can be done to correct the damage done. From time to time some undesirable effect on the hemopoietic system is produced by administration of radioactive phosphorus, such as thrombocytopenia or granulocytopenia. Furthermore, radioactive phosphorus is not available in In such situations the administration of phenylhydrazine some communities. is to be recommended. This drug when given judiciously produces few or no ill effects and may be extremely valuable. The reports of thrombosis and severe hemolytic anemia associated with the administration of phenylhydrazine emanate from those who have used the drug for the initial reduction of blood volume to normal rather than for maintenance after preliminary venesection. The latter objective is achieved readily by giving 0.1 Gm. phenylhydrazine hydrochloride
464
EDITORIALS
J. Chron. Dis. April. 1955
in capsules, by mouth, two to six times a week. Until the required dose has been determined, the blood should be examined weekly. After a steady state has been achieved, these intervals may be prolonged but readjustment of the dose may be necessary from time to time.
In view of the effectiveness of the procedures described, there seems to be little justification for the use of agents of the toxicity of nitrogen mustard3 or triethylene melamine.* By the judicious use of venesections, radioactive phosphorus, and phenylhydrazine the viscosity of the blood, as well as the total blood volume, can be reduced to satisfactory levels with a minimum of risk. The incidence of complications, especially vascular ones, has been greatly reduced in treated cases.1*4 Whether or not the incidence of leukemia is somewhat higher in patients treated with radioactive phosphorus than in those not receiving this form of therapy is uncertain. In any event, the differences reported are not such as to dissuade one from the use of this valuable therapeutic agent. M. M. WINTRORE REFERENCES
1. 2. 3. 4. 5.
Lawrence, J. H., Berlin, N. I., and Huff, R. L.: The Nature and Treatment of Poiycythemia. Studies on 263 Patients, Medicine 32:323, 19.53. Rosenthal, N:, and Rosenthal, R. L.: Treatment of Polycythemia Vera With Triethylene Melamine. Summary of Thirty Cases, Arch. Int. Med. 90:379, 1952. Spurr, C. L., Smith, T. R., Block, M., and Jacobson, L. 0.: A Clinical Study of the Use of N’&zgen Mustard Therapy m Polycythemla Vera, J. Lab. & Clin. Med. 35:252, Therapy, Proc. Staff Meet., Strobel, C.’ F. : Current Status of Radiophosphorus Clin. 29:1, 1954. Wintrobe, M. M.: Clinical Hematology, ed. 3, Philadelphia, 1951, Lea & Febiger.
Mayo