B.K. MACDOUGALL, MD, FRcP[c]; B.H. WEINERMAN, MD, FRCP[C]; S. KEMEL, B SC, MS
Table I-Age and sex of ptfents with polycyttuemla vera grouped according to prixnarytnde.ftrentment
No.
Mean (and %) age fyr) of mama Treatment 17(71) 57.5 Phlebotomy, n 24 S Cbemoth;rapy, t. 24 .7.O
.P pitis citevue-
tbeaapy,n=.24
61.O
32
57.6
1.Z(5.)
(Only one thromboembolic event was counted per patient.) In the phlebotomy group there were 10 fatal thrombotic episodes; hence, 42% of the group died in this way. One other patient had a stroke and then died of pneumonia. There were no cases of acute leukemia in the phlebotomy group, but there was one in the chemotherapy group (4%), four in the 31P group (6%) and six in the 35P plus chemotherapy group (25%) (Table III). There was a significant difference in incidence between the phlebotomy group and the '.P plus chemotherapy group (P < 0.02). The mean intervals between the onset of treatment and the development of leukemia did not differ significantly between the treatment groups. We reviewed the survival of the individuals in whom acute leukemia developed to assess the impact of this complication on the outcome of treatment of polycythemia vera. In the group of patients who received 32P plus chemotherapy the survival was significantly shorter (P < 0.05) in those in whom leukemia developed than in those in whom it did not develop. The sample, however, was too small for a meaningful estimate of how much survival was shortened. When the patients in whom acute leukemia developed as a complication of the use of 3P plus chemotherapy were compared with the phlebotomy group the evidence was not sufficient to conclude that the survival of the two groups was different.3 Malignant diseases other than acute leukemia were seen in all the treatment groups (Table IV). There was no significant difference in the incidence of other malignant diseases between the groups or between the entire patient group and the general population of Manitoba, for which the expected incidence
during 1955-76 was determined from Manitoba Cancer Registry data. The survival of each treatment group is shown in Fig. 1. There was no significant difference in the 5or 10-year survival between the phlebotomy group and the "P group or between the 32P group and the chemotherapy or the "P plus chemotherapy group. There was, however, a significant difference between the phlebotomy group and the chemotherapy group (P < 0.01)
FIG. 1-Survival curves for patients with polycythemia vera according to treatment.
582 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121
and between the phlebotomy group and the "P plus chemotherapy group (P < 0.01), despite the increased incidence of leukemia in the latter. Discussion
There is still no universal agreement on the optimal therapy for polycythemia vera. No significant advances have been made since a panel discussion was published in 1968.46 Our study is the only one published to date that compares the four modes of therapy at the same institution. Radioactive phosphorus was the mainstay of therapy until the mid-l 960s, when treatment was changed to phlebotomy alone or chemotherapy (mainly busulfan) plus intermittent phlebotomy because of the concern of acute leukemia developing with .'P therapy. The usual method of treating this disease at the Manitoba Cancer Foundation thereafter was to institute phlebotomy alone unless there was an inordinately elevated platelet count, in which case chemotherapy was added. This may mean that patients undergoing chemotherapy were more likely to display thromboembolic phenomena. Our data suggest that survival in patients treated with phlebotomy alone is significantly shorter than that of patients receiving chemotherapy or "P plus chemotherapy. Much of the decreased survival can be attributed to thromboembolic phenomena, which were often fatal. There was no difference in survival or in the incidence of thromboembolic events between the phlebotomy group and the '2P group. Chievitz and Thiede7 reviewed the records of 250 patients who had died of polycythemia vera between 1933 and 1961. Of those treated with phlebotomy alone 50% had died within 3.5 years of the diagnosis of polycythemia vera, and of those receiving no therapy 50% had died within 18 months of diagnosis. In a preliminary review of a prospective study of 474 patients with polycythemia vera randomly assigned to one of three modes of treatment, Wasserman8 pointed out that of 26 patients in the phlebotomy group with thrombotic events 10 had recurrences (fre-
quency 38%; mortality 25%), as compared with none of 19 patients in the chiorambucil group and 3 of 21 patients in the '2P group. Phlebotomy as the primary mode of therapy also has the disadvantages of being ineffectual in controlling splenomegaly, pruritis, leukocytosis, thrombocytosis and elevated uric acid concentrations. The exact contribution of the elevated platelet count and hematocrit to the hypercoagulability remains controversial. Pearson and Wetherley-Mein9 retrospectively studied 69 patients treated with phlebotomy plus chemotherapy. They reported 56 vascular occlusive episodes in 38 individuals. The hematocrit at the time of the event correlated positively with the number of episodes, and they therefore recommended that the hematocrit be kept no higher than 45%. They found no significant correlation between the platelet count and the 'vascular occlusive episodes. Wu'0 studied the relation between platelet hyperaggregability and thrombosis in 28 patients with thrombocythemia (7 with polycythemia vera) due to myeloproliferative disease. Of the six patients with thromboembolism (one of whom had polycythemia vera) all but one had evidence of platelet hyperaggregability. After treatment with acetylsalicylic acid plus dipyridamole, striking responses were seen in four patients who had digital ischemia or transient ischemic attacks. The platelet counts of the patients with polycythemia vera ranged from 580 to 4500 x 1 O./l; the data suggested that the prophylactic use of antiplatelet agents was of benefit only for those with platelet counts greater than 500 x 1O./l. Since abnormal platelet aggregation is common in patients with polycythemia vera there is a significant risk of provoking bleeding episodes with the use of antiplatelet agents. The incidence of acute leukemia in patients with polycythemia vera treated with phlebotomy alone is extremely low.4'8 There were no such cases in our series. Modan and Lilienfeld,'1 in an extensive review of data from seven centres, reported an incidence of acute leukemia of 11 % in patients treated with 32P. Similarly, others have reported rates of 10% to 15%.1214 In con-
trast, however, Calabresi and References Meyer15 found no cases of acute 1. CUTLER SJ, EDERER F: Maximum leukemia in 97 patients treated with utilization of the life table method in analyzing survival. J Chronic Dis 32P, and Szur and Lewis16 reported 18: 699, 1958 an incidence of only 2.5% in 169 2. BROWNLEE KA: Statistical theory patients. We noted four cases (6%) and methodology, in Science and in the 32P group and six cases Engineering, 2nd ed, Wiley, New (25%) in the 32P plus chemotherYork, 1965, p 163 3. GEHAN EA: A generalized Wilcoxon apy group. test for comparing arbitrarily singleThe incidence of acute leukemia censored samples. Bio,netrika 52: in patients treated with chemother1965 apy alone has not been well de- 4. 203, DAMESHEK W: The case for phlefined. Landau12 noted only 8 cases botomy in polycythemia vera. Blood 32: 488, 1968 in the literature but compiled an 5. OSGOOD EE: The case for 32p in additional 24 cases from a questreatment of polycythemia vera. tionnaire sent to hematologists. In Ibid, p 492 the large study reviewed by Wasser- 6. GILBERT HS: Problems relating to man8 a total of seven cases of acute control of polycythemia vera: the use of alkylating agents. Ibid, p 500 leukemia were found, five in the chlorambucil group (3%) and one 7. CHJEvITZ E, THIEDE T: Complications and causes of death in polyin the 32P group (0.6%). A study cythaemia vera. A ca Med Scand cases in Scandinavia detected eight 172: 513, 1962 of acute leukemia in 120 patients 8. WASSERMAN LR: The treatment of polycythemia vera. Semin Hemwol observed from 1970 to 1976.17 Four 13: 57, 1976 of the eight had received chemoTC, WETHERLEY-MEIN G: 9. PEARSON therapy as the main mode of therVascular occlusive episodes and as apy and four had received it venous haematocrit in primary prolthe sole mode of therapy. Other iferative polycythaem ia. Lancet 2: 1219, 1978 series6'18 have suffered from short follow-up periods. We observed 10. Wu KK-Y: Platelet hyperaggregability and thrombosis in patients one case of acute leukemia in our with thrombocythemia. Anti Intern group treated by chemotherapy Med 88: 7, 1978 alone but six cases in the group 11. MODAN B, LILIENFELD AM: Polytreated with 32P plus chemotherapy. cythemia vera and leukemia - the It is unclear why the incidence is role of radiation treatment. Medicine (Baltimore) 44: 305, 1965 increased in the latter group. 12. LANDAU SA: Acute leukemia in poinWe found no increase in the lycythemia vera. Semin Heinatol 13: other diseases of malignant cidence 1976 than acute leukemia in any of 13. 33, EE: Polycythemia vera: age OsGooD the treatment groups. Modan and relationships and survival. Blood 26: inLilienfeld" also found no such 243, 1965 crease in patients with polycythe- 14. TUBIANA M, FLAMANT R, ATTIE E, mia vera treated with 32P; however, et al: A study of hematological complications occurring in patients with Lawrence,19 in a review of 264 polycythemia vera treated with 2P cases of polycythemia vera, discov(based on a series of 296 patients). ered 20 cases of cancer in patients Blood 32: 536, 1968 who had received radioactive iso- 15. CALABRESI P, MEYER 00: Polytopes - a rate significantly greater cythemia vera. Course and therapy. Ann Intern Med 50: 1203, 1959 than that expected in the general population. 16. SZUR L, LEwis SM: The haematological complications of polycyThe retrospective method of this thaemia vera and treatment with randomized, study did not allow radioactive phosphorus. Br J Radiol unbiased allocation of treatment, 39: 122, 1966 and clinical evidence suggests that 17. WEINFELD A, WESTIN J, RIDELL B, the use of 32P plus chemotherapy et al: Polycythaemia vera terminmay, at least during some periods, ating in acute leukaemia. Scand J Haematol 19: 255, 1977 have been reserved for the more complicated or advanced cases. In 18. LOGUE GL, GUTTERMAN JU, Mc GINN TG, et al: Melphalan therapy the face of this possible bias, the of polycythemia vera. Blood 36: 70, poorer survival of patients receiving 1970 phlebotomy assumes even more im- 19. LAWRENCE JH: The incidence of portance and raises a serious quescancer in chronic leukemia and polycythemia vera. Am J Med Sci 237: tion about the value of this treat488, 1959 ment.
584 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121
Table I-Age and sex of ptfents with polycyttuemla vera grouped according to prixnarytnde.ftrentment
No.
Mean (and %) age fyr) of mama Treatment 17(71) 57.5 Phlebotomy, n 24 S Cbemoth;rapy, t. 24 .7.O
.P pitis citevue-
tbeaapy,n=.24
61.O
32
57.6
1.Z(5.)
(Only one thromboembolic event was counted per patient.) In the phlebotomy group there were 10 fatal thrombotic episodes; hence, 42% of the group died in this way. One other patient had a stroke and then died of pneumonia. There were no cases of acute leukemia in the phlebotomy group, but there was one in the chemotherapy group (4%), four in the 31P group (6%) and six in the 35P plus chemotherapy group (25%) (Table III). There was a significant difference in incidence between the phlebotomy group and the '.P plus chemotherapy group (P < 0.02). The mean intervals between the onset of treatment and the development of leukemia did not differ significantly between the treatment groups. We reviewed the survival of the individuals in whom acute leukemia developed to assess the impact of this complication on the outcome of treatment of polycythemia vera. In the group of patients who received 32P plus chemotherapy the survival was significantly shorter (P < 0.05) in those in whom leukemia developed than in those in whom it did not develop. The sample, however, was too small for a meaningful estimate of how much survival was shortened. When the patients in whom acute leukemia developed as a complication of the use of 3P plus chemotherapy were compared with the phlebotomy group the evidence was not sufficient to conclude that the survival of the two groups was different.3 Malignant diseases other than acute leukemia were seen in all the treatment groups (Table IV). There was no significant difference in the incidence of other malignant diseases between the groups or between the entire patient group and the general population of Manitoba, for which the expected incidence
during 1955-76 was determined from Manitoba Cancer Registry data. The survival of each treatment group is shown in Fig. 1. There was no significant difference in the 5or 10-year survival between the phlebotomy group and the "P group or between the 32P group and the chemotherapy or the "P plus chemotherapy group. There was, however, a significant difference between the phlebotomy group and the chemotherapy group (P < 0.01)
FIG. 1-Survival curves for patients with polycythemia vera according to treatment.
582 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121
and between the phlebotomy group and the "P plus chemotherapy group (P < 0.01), despite the increased incidence of leukemia in the latter. Discussion
There is still no universal agreement on the optimal therapy for polycythemia vera. No significant advances have been made since a panel discussion was published in 1968.46 Our study is the only one published to date that compares the four modes of therapy at the same institution. Radioactive phosphorus was the mainstay of therapy until the mid-l 960s, when treatment was changed to phlebotomy alone or chemotherapy (mainly busulfan) plus intermittent phlebotomy because of the concern of acute leukemia developing with .'P therapy. The usual method of treating this disease at the Manitoba Cancer Foundation thereafter was to institute phlebotomy alone unless there was an inordinately elevated platelet count, in which case chemotherapy was added. This may mean that patients undergoing chemotherapy were more likely to display thromboembolic phenomena. Our data suggest that survival in patients treated with phlebotomy alone is significantly shorter than that of patients receiving chemotherapy or "P plus chemotherapy. Much of the decreased survival can be attributed to thromboembolic phenomena, which were often fatal. There was no difference in survival or in the incidence of thromboembolic events between the phlebotomy group and the '2P group. Chievitz and Thiede7 reviewed the records of 250 patients who had died of polycythemia vera between 1933 and 1961. Of those treated with phlebotomy alone 50% had died within 3.5 years of the diagnosis of polycythemia vera, and of those receiving no therapy 50% had died within 18 months of diagnosis. In a preliminary review of a prospective study of 474 patients with polycythemia vera randomly assigned to one of three modes of treatment, Wasserman8 pointed out that of 26 patients in the phlebotomy group with thrombotic events 10 had recurrences (fre-
quency 38%; mortality 25%), as compared with none of 19 patients in the chiorambucil group and 3 of 21 patients in the '2P group. Phlebotomy as the primary mode of therapy also has the disadvantages of being ineffectual in controlling splenomegaly, pruritis, leukocytosis, thrombocytosis and elevated uric acid concentrations. The exact contribution of the elevated platelet count and hematocrit to the hypercoagulability remains controversial. Pearson and Wetherley-Mein9 retrospectively studied 69 patients treated with phlebotomy plus chemotherapy. They reported 56 vascular occlusive episodes in 38 individuals. The hematocrit at the time of the event correlated positively with the number of episodes, and they therefore recommended that the hematocrit be kept no higher than 45%. They found no significant correlation between the platelet count and the 'vascular occlusive episodes. Wu'0 studied the relation between platelet hyperaggregability and thrombosis in 28 patients with thrombocythemia (7 with polycythemia vera) due to myeloproliferative disease. Of the six patients with thromboembolism (one of whom had polycythemia vera) all but one had evidence of platelet hyperaggregability. After treatment with acetylsalicylic acid plus dipyridamole, striking responses were seen in four patients who had digital ischemia or transient ischemic attacks. The platelet counts of the patients with polycythemia vera ranged from 580 to 4500 x 1 O./l; the data suggested that the prophylactic use of antiplatelet agents was of benefit only for those with platelet counts greater than 500 x 1O./l. Since abnormal platelet aggregation is common in patients with polycythemia vera there is a significant risk of provoking bleeding episodes with the use of antiplatelet agents. The incidence of acute leukemia in patients with polycythemia vera treated with phlebotomy alone is extremely low.4'8 There were no such cases in our series. Modan and Lilienfeld,'1 in an extensive review of data from seven centres, reported an incidence of acute leukemia of 11 % in patients treated with 32P. Similarly, others have reported rates of 10% to 15%.1214 In con-
trast, however, Calabresi and References Meyer15 found no cases of acute 1. CUTLER SJ, EDERER F: Maximum leukemia in 97 patients treated with utilization of the life table method in analyzing survival. J Chronic Dis 32P, and Szur and Lewis16 reported 18: 699, 1958 an incidence of only 2.5% in 169 2. BROWNLEE KA: Statistical theory patients. We noted four cases (6%) and methodology, in Science and in the 32P group and six cases Engineering, 2nd ed, Wiley, New (25%) in the 32P plus chemotherYork, 1965, p 163 3. GEHAN EA: A generalized Wilcoxon apy group. test for comparing arbitrarily singleThe incidence of acute leukemia censored samples. Bio,netrika 52: in patients treated with chemother1965 apy alone has not been well de- 4. 203, DAMESHEK W: The case for phlefined. Landau12 noted only 8 cases botomy in polycythemia vera. Blood 32: 488, 1968 in the literature but compiled an 5. OSGOOD EE: The case for 32p in additional 24 cases from a questreatment of polycythemia vera. tionnaire sent to hematologists. In Ibid, p 492 the large study reviewed by Wasser- 6. GILBERT HS: Problems relating to man8 a total of seven cases of acute control of polycythemia vera: the use of alkylating agents. Ibid, p 500 leukemia were found, five in the chlorambucil group (3%) and one 7. CHJEvITZ E, THIEDE T: Complications and causes of death in polyin the 32P group (0.6%). A study cythaemia vera. A ca Med Scand cases in Scandinavia detected eight 172: 513, 1962 of acute leukemia in 120 patients 8. WASSERMAN LR: The treatment of polycythemia vera. Semin Hemwol observed from 1970 to 1976.17 Four 13: 57, 1976 of the eight had received chemoTC, WETHERLEY-MEIN G: 9. PEARSON therapy as the main mode of therVascular occlusive episodes and as apy and four had received it venous haematocrit in primary prolthe sole mode of therapy. Other iferative polycythaem ia. Lancet 2: 1219, 1978 series6'18 have suffered from short follow-up periods. We observed 10. Wu KK-Y: Platelet hyperaggregability and thrombosis in patients one case of acute leukemia in our with thrombocythemia. Anti Intern group treated by chemotherapy Med 88: 7, 1978 alone but six cases in the group 11. MODAN B, LILIENFELD AM: Polytreated with 32P plus chemotherapy. cythemia vera and leukemia - the It is unclear why the incidence is role of radiation treatment. Medicine (Baltimore) 44: 305, 1965 increased in the latter group. 12. LANDAU SA: Acute leukemia in poinWe found no increase in the lycythemia vera. Semin Heinatol 13: other diseases of malignant cidence 1976 than acute leukemia in any of 13. 33, EE: Polycythemia vera: age OsGooD the treatment groups. Modan and relationships and survival. Blood 26: inLilienfeld" also found no such 243, 1965 crease in patients with polycythe- 14. TUBIANA M, FLAMANT R, ATTIE E, mia vera treated with 32P; however, et al: A study of hematological complications occurring in patients with Lawrence,19 in a review of 264 polycythemia vera treated with 2P cases of polycythemia vera, discov(based on a series of 296 patients). ered 20 cases of cancer in patients Blood 32: 536, 1968 who had received radioactive iso- 15. CALABRESI P, MEYER 00: Polytopes - a rate significantly greater cythemia vera. Course and therapy. Ann Intern Med 50: 1203, 1959 than that expected in the general population. 16. SZUR L, LEwis SM: The haematological complications of polycyThe retrospective method of this thaemia vera and treatment with randomized, study did not allow radioactive phosphorus. Br J Radiol unbiased allocation of treatment, 39: 122, 1966 and clinical evidence suggests that 17. WEINFELD A, WESTIN J, RIDELL B, the use of 32P plus chemotherapy et al: Polycythaemia vera terminmay, at least during some periods, ating in acute leukaemia. Scand J Haematol 19: 255, 1977 have been reserved for the more complicated or advanced cases. In 18. LOGUE GL, GUTTERMAN JU, Mc GINN TG, et al: Melphalan therapy the face of this possible bias, the of polycythemia vera. Blood 36: 70, poorer survival of patients receiving 1970 phlebotomy assumes even more im- 19. LAWRENCE JH: The incidence of portance and raises a serious quescancer in chronic leukemia and polycythemia vera. Am J Med Sci 237: tion about the value of this treat488, 1959 ment.
584 CMA JOURNAL/SEPTEMBER 8, 1979/VOL. 121
