Silicon lungs.

Between 1967 and 1978 a Phase III cooperative study was performed in polycythaemia vera (PCV) patients who had not been treated previously with any specific therapy other than phlebotomy. 293 patients were included and allocated at random for either radiophosphorus therapy (146) or busulphan treatment (147). Additional phlebotomies were indicated in both groups, to keep the haematocrit at 4247%0. 285 patients were evaluable after the study was completed, of whom 50%O have an 8-year follow-up. Both groups were comparable with respect to age, clinical symptoms and haemato-logical parameters immediately before randomization. The duration of the first remission and the overall survival were significantly better in the busulphan group. This difference remains significant after correction for differences between the two groups with respect to sex-ratio and phlebotomy before the start of therapy. Busul-phan induced a longer first remission (P<0001) and a longer overall survival (P<0 02). the peak incidence occurring in the 6th The disease is generally regarded as one decade. The mean survival time of un-of the several myeloproliferative disorders treated patients is only about 18 months which include chronic myelogenous leu

Summary.-Between 1967 and 1978 a Phase III cooperative study was performed in polycythaemia vera (PCV) patients who had not been treated previously with any specific therapy other than phlebotomy. 293 patients were included and allocated at random for either radiophosphorus therapy (146) or busulphan treatment (147). Additional phlebotomies were indicated in both groups, to keep the haematocrit at 4247%0. 285 patients were evaluable after the study was completed, of whom 50%O have an 8-year follow-up.
Both groups were comparable with respect to age, clinical symptoms and haematological parameters immediately before randomization. The duration of the first remission and the overall survival were significantly better in the busulphan group. This difference remains significant after correction for differences between the two groups with respect to sex-ratio and phlebotomy before the start of therapy. Busulphan induced a longer first remission (P<0001) and a longer overall survival (P<0 02). POLYCYTHAEMIA VERA (PCV) is a rela- (Gilbert, 1975;Gurney, 1970; tively rare disease with an annual inci-1955; Loeb, 1975;Mantel & Haenszel, dence of 4-6 new cases per million popula-1959; Modan, 1975;Osgood, 1965; Perkins tion. The mean age of onset is 55-60 years, et al., 1964;Silverstein & Lanier, 1971). the peak incidence occurring in the 6th The disease is generally regarded as one decade. The mean survival time of un-of the several myeloproliferative disorders treated patients is only about 18 months which include chronic myelogenous leu- kaemia, idiopathic myelofibrosis and essential thrombocytosis (Adamson et al.,1]976; Dameshek, 1951;Gurney, 1970;Lawrence, 1955;Modan, 1965).
The pathogenesis of the disease seems to be an uncontrolled proliferation of marrow cells, caused by an intrinsic defect at the stem-cell level. Evidence for an autonomous proliferating clone of pluripotent stem cells has come from studies of female patients who are also heterozygous for isoenzymes of glucose-6-phosphate dehydrogenase. Whereas normal tissues show both isoenzymes, only one type is found in erythrocytes, granulocytes and platelets in patients with PCV (Adamson et al., 1976).
The fact that erythroid precursor cells in PCV proliferate in vitro in the absence of demonstrable erythropoietin may be taken as additional evidence of autonomous cell growth (Eaves & Eaves, 1978).
However, a considerable debate has arisen over whether transition of PCV into acute leukaemia or myelofibrosis, which occurs in 10-15% of patients, is a complication inherent in the nature of the disease, or whether it arises as a result of the type of therapy (Landaw, 1976;Lawrence, 1955;Lawrence et al., 1969;Ledlie, 1960;Modan & Lelienfeld, 1965;Modan, 1975;Silverstein & Lanier, 1971;Tubiana et al., 1968).
In 1967 a Phase III study was started to assess the effects of both treatments on (1) the duration of remission, (2) the length of survival, and (3) the frequency and types of complications occurring in patients with PCV, especially the incidence of transition to acute leukaemia, to "spent" polycythaemia and to myelofibrosis.

PATIENTS AND METHODS
Since 1967 293 patients, never treated before by 32p or cytostatics, have been included in the trial and allocated at random to treatment: 146 to a 32p group and 147 to a busulphan group. Eight patients out of the 293 were subsequently eliminated from the analysis because they were lost to follow-up.
At the time of reporting 5000 of patients have been followed up for 8 years.
Diagnosis of PCV was based on erythrocytosis with raised RBC mass, normal arterial 02 saturation, splenomegaly and signs of panmyelosis in the marrow. Patients with secondary erythrocytosis were excluded. Previous phlebotomy was not a reason for exclusion.
The dose of 32p was administered i.v.
(0.5-1 0 mCi/10 kg body wt). Busulphan was given orally in a dose of 4-6 mg/day for 4-6 wAeeks, or withheld w%hen the platelet count dropped (< 120,000/ul). In each group the haematocrit was maintained at 42-470 by supplementary phlebotomies, if necessary. When a relapse occurred the same treatment writh either 32p or busulphan was re-administered. All randomized patients were followed carefully w%ith periodic physical and laboratory examination, and the follow-up data were monitored for signs of toxicity, complications of the disease and haematological parameters. The follow-up forms were sent every 6 months to the trial secretary for statistical analysis. The results are evaluated according to the following criteria of assessment: 1. The first remission duration. defined as the period elapsed from randomization to one of the following events, whichever occurred first: clinical relapse of PCV. acute leukaemia, myelosclerosis or death.
2. The complication-free survival, defined as the period of survival elapsed from randomization to the first complication, such as a vascular accident, myelosclerosis, acute leukaemia, cancer or death.
3. The total survival as the time from randomization to death.
4. The frequency and types of complications.

RESULTS
The trial was activated in 1967 and case accrual was completed in 1978, after which date careful follow-up was continued. During I I years, 293 untreated PCV patients entered the study, of which 285 are evaluable. The general status and the haematological parameters of the 2 treatment groups immediately before randomization are summarized in Table I. Both groups are comparable with respect to age and clinical symptoms. The 32P group  somewhat larger in the 32p than in the busulphan group; otherwise the 2 groups at the time of randomization were almost similar. Table II shows the different initial doses of 32p (mean 5-9 mCi) and the doses of busulphan (mean 31 06 mg) during the first remission induction. In each group phlebotomy was used to maintain the haematocrit at 42-47%. The rate of phlebotomy was equal in both groups.

Duration offirst remission
The duration of the first remission is shown in Fig. 1. Patients treated by busulphan show a median first remission duration of 4 years, while those treated by 32p have a median first remission of 2 years. The difference between the two actuarial curves is statistically significant (P< 0001). years 2 3 4 5 6 7 8 9 10 Fo. 1. Dulration of the first remission according to treatment -with 3P ( ) 3r busulpharn (---  It appeared that the first remission is significantly longer in females (P < 0001) and in patients who were not phlebotomized before therapy (P < 0 001).
Because the 2 treatment groups were in these respects somewhat different, a statistical correction was made for sex and phlebotomy, as shown in Table III. It appears that the remission duration is still significantly longer in the busulphan group than in the group 32p (P < 0.001).

Complication-free survival
The percentages of complication-free survival at various times after the start of therapy are not statistically different between the 2 treatment groups, as demonstrated in Fig. 2, whch shows the 2 survival curves. The results are statistically the same, even after correction for sex differences and for previous phlebotomy. The statistical analysis is given in Table IV. Vascular complications were more pronounced in the 32p group:  The types of malignancies are given in Table V. The numbers are too small for any conclusion to be drawn.

DISCUSSION
'I'he significantly better results in duration of first remission and overall survival time which were obtained with busulphan treatment of PCV compared to those obtained with 32p are in contrast to results described in the literature (Lawrence et al., 1969;Osgood, 1968;WVasserman, 1971WVasserman, , 1976. As indicated in Table I, both treatment groups were comparable with respect to age, clinical symptoms and haematological parameters at the time of randomization. According to the trial protocol, patient follow-up and bloodvolume regulations were carried out by the same physician at the same frequency for both groups.
Because the first remission duration was longer in females and in patients who were 6 not phlebotomized previously, a correction was made for both these factors in the analysis of our data. As is shown in Tables III and IV, the differences in treatment results after statistical correction remain significantly better in the busulphan group.
Malignant complications and splenomegaly, which may occur during evolution into postpolycythaemic myeloid metaplasia (Silverstein, 1976), were observed at the same frequency in both groups.
The major difference in overall survival between the 2 groups is due to a much higher frequency of vascular accidents in the 32p group. 32p was given in the same average dose as that used successfully in the treatment of PCV in the literature (Lawrence, 1976;Lawrence et al., 1969;Osgood, 1968;Wasserman, 1976). Retreatment was restricted to 6-month intervals and supplementary phlebotomies were carried out as necessary before and during additional 32p treatment. Busuphan therapy could be reinstituted earlier if necessary, and gave more stable and longer lasting remissions, with less need for additional phlebotomies.
The disadvantages of using phlebotomy are the lack of effect in those cases with thrombocytosis, the difficulty in controlling the RBC volume in active cases, and the depletion of iron stores (Hutton, 1980), whereas the risk of bleeding and thromboembolism is not reduced (Wasserman, 1976). This difference in remission control, which is inherent to the mode of action of 32p, may explain the higher frequency of vascular complications in the group.
Most trials have used as chemotherapeutic agents chlorambucil, melphalan or cyclophosphamide, which require periodic cyclic administration. Busulphan-induced remissions last for months or even years without reinstitution of the drug, a result not achieved with the other alkylating agents. Busulphan should, however, never be used continuously for more than 4-6 weeks in PCV, because of the increased risk of producing persistent thrombocytopenia or leucopenia. In the dosage scheme used in this trial, busulphan was undoubtedly superior to 32p and may therefore be regarded as the treatment of choice in polycythaemia vera.