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Interstitial pneumonitis following total body irradiation for bone marrow transplantation using two different dose rates
In/ .I Rudrarum Onmlo~~ Lb/ Php., Vol. Ii. Printed in the US A. All nghts reserved
0360.3016/E $03.00 + 02 Copyright 0 1985 Pergamon Press Ltd
PP. 1285-1291
??Original Contribution
INTERSTITIAL PNEUMONITIS FOLLOWING TOTAL BODY IRRADIATION FOR BONE MARROW TRANSPLANTATION USING TWO DIFFERENT DOSE RATES TAIK H. KIM, M.D.‘,
WITOLD
B. RYBKA, M.D., F.R.C.P.(C)2, SHIRLEY LEHNERT, PH.D. ‘, ERVIN B. PODGORSAK, PH.D., F.C.C.P.M.’ AND CAROLYN R. FREEMAN, M.B., B.S., F.R.C.P.(C).’ ‘Department
of Radiation Oncology and *Division of Hematology, Department The Montreal General Hospital, Montreal, Quebec, Canada
of Medicine,
A total of 22 patients with leukemia (10 ALL, 11 AML, 1 CML) have undergone allogeneic bone marrow transplantation (BMT) by the Quebec Co-operative Group for Marrow Transplantation from 1980 to 1982. All patients received 900 cGy total body irradiation (TBI), in a single fraction, on the day preceding BMT. The first 11 patients were treated on a cobalt unit at a constant dose rate of 4.7 to 6.3 cGy/min. Six of these patients developed interstitial pneumonitis (IP). The clinical course of three patients, two with idiopathic and one with drug-induced pneumonitis, was mild and recovery was complete in all. The other three patients developed severe infectious IP and two died. The next 11 patients were treated with a sweeping beam technique on a 4 MV linear accelerator delivering a total tumor dose of 900 cGy at an average dose rate of 6.0 to 6.5 cGy/min but an instantaneous dose rate of 21.0 to 23.5 cGy/min. Eight patients developed severe IP. Five of these were idiopathic and four died. Three were infectious and all died. The fatality of interstitial pneumonitis appeared to be greater in the group treated with the sweeping beam technique. Interstitial pneumonitis, technique, Dose rate.
Total
body irradiation,
Bone marrow
transplantation,
Leukemia,
Sweeping
beam
INTRODUCTION
been attempted with beam attenuators.8,‘83’9 Although some of these innovations have resulted in a decreased incidence of fatal pneumonitis,‘~9,“3’2 IP remains a leadTotal body irradiation (TBI) has been considered an ing cause of death following BMT.2.18’2’,26,27 integral component in the preparation of patients with Between February 1980 and March 1982, 22 consechematological malignancies for bone marrow transplantation (BMT).‘3238~12321323326*27 One of the major causes utive patients received allogeneic bone marrow grafts of death following BMT is interstitial pneumonitis for the treatment of hematological malignancies by the Quebec Co-operative Group for Marrow Transplantation. (IP). 4,16,18,29The incidence and fatality rate of this complication vary considerably. 1~2~4~8~11~16~18,2’ The ~24~26~27 The prescribed tumor dose was 900 cGy for all patients. pathogenesis of IP is complex with multifactorial etiolThe first 11 consecutive patients received TBI using a ogies,16,18of which TBI may be one of the more imporcobalt source at a low constant dose rate while the tant, especially in cases of the idiopathic variety.” In an remaining 11 patients were treated with a sweeping attempt to reduce the incidence of this complication, a beam technique on a 4 MV linear accelerator.” The number of TBI parameters, such as fractionation,‘2.26 major difference between these two techniques is in the dose rate,] and total dose” have been studied.13 In instantaneous dose rate. Although the total dose, delivery addition, reduction of the pulmonary absorbed dose has times and average dose rates are identical for both
of the members of the Quebec Co-operative Group for Marrow Transplantation: Drs. A. Lebrun and D. Noel (HBpital du Sacr& Coeur), S. Caplan (Sir Mortimer B. Davis Jewish General Hospital), P. Koch and V. M. Whitehead (The Montreal Children’s Hospital), G. Blake and J. L. Hutchison (The Montreal General Hospital), J. F. Prchal and C. Shustik (The Royal Victoria Hospital). Accepted for publication 6 February 1985.
Presented at the American Society of Therapeutic Radiologists’ 24th Annual Meeting, Orlando, Florida, October 25-29, 1982. W. B. Rybka was supported in part by the T. H. P. Molson Award. Reprint requests to: W. B. Rybka, M.D., F.R.C.P.(C), Rm. 7 129, The Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec, Canada, H3G lA4. Acknowledgments-We wish to acknowledge the participation 1285
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Oncology
0 Biology 0 Physics
methods, the instantaneous dose rate with the sweeping beam is three to four times that of continuous irradiation with the cobalt unit. As there appeared to be an increased incidence of fatal idiopathic IP with the sweeping beam technique, we postulate that the instantaneous dose rate may be an important variable in the genesis of IP.
METHODS
AND
MATERIALS
Marrow transplantation was performed in a manner similar to that reported by the Seattle marrow transplant team.23.24 Twenty-two patients received marrow grafts from human leucocyte antigen (HLA) matched, mixed lymphocyte culture (MLC) compatible siblings as part of their treatment for hematological malignancies. The diagnosis was acute lymphoblastic leukemia (ALL) in 10 patients (2 in remission, 8 in relapse), acute nonlymphoblastic leukemia (ANL) in remission in 11 patients, and chronic myelogenous leukemia (CML) in the chronic phase in one patient. The patients ranged in age from 14 to 39 years, with a median age of 27 years. Antileukemic therapy included cyclophosphamide 60 mgm/ kgm given twice, on the 5th and 4th days prior to transplantation. Three patients received cytosine arabinoside, vincristine, and methylprednisolone in addition. All patients received 900 cGy TBI the day prior to BMT. Following transplantation, patients were treated with gastrointestinal sterilization in reverse isolation until recovery of circulating neutrophils.‘” All patients received prophylaxis against graft versus host disease (GVHD) with intravenous methotrexate 15 mgm/M2 on Day 1, 10 mgm/M* on Days 3, 6, 11, and 18 following transplantation and then 10 mgm/M2 intravenously alternating weekly with 12 mgm intrathecally until 102 days following transplantation. TBI was delivered in the Department of Radiation Oncology at the Montreal General Hospital. One of two methods was used to deliver TBI, as summarized in Table 1. The first I 1 consecutive patients were treated with 6”Co gamma rays, with the cobalt unit positioned horizontally and the patient placed in a lateral recumbent position at a source-to-skin distance (SSD) of 380 cm. The patient was turned three times during the treatment period for two anterior and two posterior exposures to deliver the total tumor dose of 900 cGy over a period of 140 to 190 min. The treatment had to be frequently interrupted because of patient discomfort. The second group, also of 11 patients, was treated with a newly developed technique, which uses a sweeping beam on a 4 MV linear accelerator. The impetus for the development of this technique came primarily from the practical problems posed by the continued use of the cobalt technique, notably uncomfortable patient position, difficulties imposed by this position on lung shielding with lead cut outs and an increasing overall treatment time because of the decay of the cobalt source. The
technical
details
and
physical
aspects
of this
tech-
July
1985, Volume
Table
1I, Number
7
I. Physical characteristics
of the cobalt and sweeping beam TBI techniques Stationary cobalt beam
Source SSD Maximum size Dose rate Average
field
Instantaneous Patient Delivery
position method
Lung compensation
Total tumor dose Total treatment time
Sweeping linac beam
6oCo
4 MV X rays?
gamma-rays* 380 cm 200 cm X 70 cm
190 cm 70 cm X 70 cm
4.1-6.3 cGy/min 4.7-6.3 cGy/min Lateral recumbent Anterior and posterior 2 mm lead on anterior and posterior chest wall 900 cGy 140-190 min
6.0-6.5 cGy/min 2 I .O-23.5 cGy/min Prone and supine Anterior and posterior 2 mm lead on anterior and posterior chest wall 900 cGy 140-150 min
* Theratron 780, Atomic Energy of Canada, Ltd, Ottawa, Ontario, Canada. t Therapi 4, SHM Nuclear Corporation, Sunnyvale, CA.
nique have been previously described” and are illustrated in Figure 1. We attempted to reproduce the conditions of TBI with the cobalt unit as closely as possible for the sweeping beam method. The field size for the linear accelerator at an SSD of 190 cm is only 70 X 70 cm2, thus no more than one-third of the patient can be in the beam at a given time. TBI is achieved by having a motorized machine head sweep the beam over the patient with an average interval of 30 set per sweep. The prescribed dose of 900 cGy is delivered over a period of 140 to 150 min. The dose rate during exposure (instantaneous dose rate) is 21.0 to 23.5 cGy/min., whereas the average dose rate is 6.0 to 6.5 cGy/min., similar to that for the cobalt technique. Thus, the time required to deliver the total dose is similar for the cobalt and sweeping beam techniques. In both techniques, the lung dose was normalized to the actual tumor dose using 2 mm lead cutouts positioned over the thorax. Previous measurements” using thermoluminescent dosimetry techniques had shown that the lung dose in a humanoid phantom could exceed the prescribed dose by up to 13% for both the cobalt and the sweeping beam techniques, and that lung dose and prescribed tumor dose are equalized if 2 mm thick lead attenuators are placed over the lungs of the phantom. The CT determined density of the phantom lung was 0.5 g/cm3. While lung densities were not determined for individual patients it is known that lung density in young adults is between 0.3 and 0.35 g/cm3.20 On the
Interstitial pneumonitis 0 T. H. KIM et al
f, DISTANCE FROM CENTER
1287
ccm )
Fig. 1. Schematic diagram of the sweeping beam total body irradiation technique. Source to skin distance l is 190 cm on the vertical beam axis and the monitor chamber is 150 cm from the source. Also shown are the position of the 2 mm thick lung attenuators and the patient midline dose, normalized to 100% at midline on the vertical beam axis.
basis of the dosimetric measurements made in the phantom and with the knowledge of the densities of phantom and human lung. it was estimated that no patient treated by either technique would receive a dose which exceeded the prescribed tumor dose by more than 5%. Positioning of the lung compensator was considerably easier with the sweeping beam technique than with the cobalt beam technique and a larger portion of the lung could be encompassed with improved accuracy. With the new method, the patient was also turned three times alternating between prone and supine positions for anterior and posterior exposures. Interruptions occasioned by patient discomfort were less frequent with this technique. The occurrence of interstitial pneumonia was recognized by clinical and radiological criteria. Pulmonary biopsies were obtained from all patients who developed IP. Bacterial, fungal and viral cultures were attempted in all cases. Idiopathic interstitial pneumonia was determined by the absence of characteristic viral inclusions and negative viral or bacteriological cultures. All of these patients were hospitalized. The majority of patients with idiopathic IP were treated with corticosteriods. All surviving patients have been followed for at least 18 months. Statistical analyses were obtained using a two tailed Fisher’s Exacr Test and the Student’s T Test.
RESULTS The groups
patient treated
profiles and by the cobalt
individual results for the and sweeping beam tech-
niques are outlined in Table 2a and 2b, respectively. The diagnoses in the cobalt group included seven with ALL (two in second remission and five in relapse) and four with ANL (three in first remission, two in third remission). The diagnoses in the sweeping beam group included seven with ANL (five in first remission, two in second remission), three with ALL (all in relapse) and two in the chronic phase of chronic myelogenous leukemia. The median age was 25 years (range 14 to 39 yrs) for the patients in the cobalt group and 31 yrs (range 22 to 36 yrs) for patients in the sweeping beam group. These differences are not statistically significant (p = 0.09). The incidence and fatality of IP increased with patient age, with older age related to higher incidence and greater severity of IP, particularly in the fourth decade (Table 3). There were six cases of IP in the cobalt group and eight in the sweeping beam group (Table 4). Only two patients in the cobalt group developed idiopathic IP, whereas five of the eight in the sweeping beam group were idiopathic. Both patients with idiopathic IP in the cobalt group recovered completely after a mild clinical course, whereas four of the five patients with idiopathic IP in the sweeping beam group died. Two of three patients with infectious IP in the cobalt group and all three of those in the sweeping beam group died of IP. One patient (no. 4 of the cobalt group) had a peculiar granalomatous histological pattern, considered compatible with drug-induced IP. This patient recovered completely following a mild clinical course. The statistical comparisons are given in Table 4. A trend is noted toward greater fatality of IP in the sweeping beam group.
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July 1985, Volume 1I. Number
Radiation Oncology 0 Biology 0 Physics Table 2a. Patients
treated
with the cobalt TBI technique
sex
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Il.
28M 14F 30M 22F 29M 18M 14M 39F 18M 34M 25M
Diagnosis ALL ALL ALL ALL ALL ALL ALL ANL ANL ANL ANL
(2nd (5th (2nd (1st ( 1st (2nd (3rd (3rd (1st (1st ( 1st
No No
Rem) Rel) Rel) Rel) Rel) Rem) Rel) Rem) Rem) Rem) Rem)
Onset (day)
IP
AcGVHD
1980 to May 198 1 (900 cGy)
from February
Age, No.
No No Idiopathic Granulomatous Idiopathic Pneumocystis No CMV No Pneumocystis No
No Yes No
Yes No
Yes No
Yes Yes
7
Survival (days)
Cause of death
>1249 305 > 1075 >1026 >990 356 140 65 >85 1 118 >810
59 110 110 90 40 80 -
Leukemia
Leukemia Leukemia GVHD/IP 1P
AcGVHD = Acute graft versus host disease 2 Grade II; IP = Interstitial pneumonitis; ALL = Acute lymphoblastic ANL = Acute nonlymphoblastic leukemia: Rem = Remission: Rel = Relapse: CMV = Cytomegalovirus.
transplantation is still unknown, evidence has accumulated that factors modulating radiation response influence the incidence of IP.‘7.‘8 These include total dose,8,“-‘7 dose rate’,4,5,‘4 and fractionation.‘2.‘4.‘5,‘8.26 The importance of these factors has been clearly demonstrated in the pathogenesis of radiation-induced pneumonitis following half body irradiation2’ and whole lung irradiation.22 Indeed, radiation-induced pneumonitis is a relatively common observation in daily radiation therapy practice. Idiopathic interstitial pneumonitis, comprising 30-40s of cases of IP following BMT,“~‘x shows similarities in histological and clinical features with typical radiation-induced pneumonitis.” The timing is similar to that seen for the onset of radiation-induced pneumonitis, which frequently occurs within two to three months following radiation of the lung. However, radiation is not the sole factor implicated in the pathogenesis of IP after BMT. IP may occur following BMT for aplastic anemia, a situation in which TBI is not used or is restricted to a low dose.3,‘6 Also, IP is rarely seen following syngeneic transplants, although in these cases the lung is fully irradiated.lh Over half the cases of IP are of infectious etiology, usually pneumo-
A latent period (time to onset) of greater than 90 days was associated with a mild reversible course of pneumonitis (Table 5). A trend was noted toward greater fatality of IP associated with a latent period shorter than 90 days (p = 0.09). The differences in latent period between the sweeping beam and the cobalt groups were not statistically significant (p = 0.6). A total of 12 patients developed Grade I1 or greater acute GVHD following BMT: 5 in the cobalt and 7 in the sweeping beam groups. Concurrent IP and GVHD were observed in 10 patients: 4 in the cobalt and 6 in the sweeping beam groups. Neither the incidence nor the fatality rates were significantly different in terms of this variable between the two groups (Table 6). During the same period, two additional patients were treated with TBI using the cobalt technique prior to syngeneic grafts for acute lymphoblastic leukemia in remission. Neither developed IP and neither is included in the present analysis. DISCUSSION Although the exact role of irradiation in the pathogenesis of interstitial pneumonitis following marrow Table 2b. Patients
No. 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
1I.
Age, sex 34F 36M 22M 27F 26M 26M 31M 36F 34F 31F 25M
treated
Diagnosis ANL ANL ANL ANL ANL CML ALL ALL ANL ANL ALL
(I st Rem) (1 st Rem) (1 st Rem) (2nd Rem) (1st Rem) (chronic) (1st Rel) (4th Rel) (1st Rem) (2nd Rem) (2nd ReI)
with the sweeping
beam TBI technique
Yes Yes Yes No
Yes Yes No No
Yes Yes No
from June
1981 to March
Onset (day)
Survival (days)
No
-
Idiopathic Idiopathic No Mucormycosis Idiopathic CMV Idiopathic CMV Idiopathic No
130 160
215 150 >766 >619 60 135 51 66 56 58 >507
IP
AcGVHD
leukemia;
AcGVHD = Acute graft versus host disease 2 Grade II; IP = Interstitial ANL = Acute nonlymphoblastic leukemia; CML = Chronic myelogenous = Relapse; CMV = Cytomegalovirus.
54 55 40 15 45 50
1982 (900 cGy)
Cause of death Leukemia IP
GVHD/Mucormycosis IP IP IP IP IP
pneumonitis: ALL = Acute Iymphoblastic leukemia; leukemia in chronic phase; Rem = Remission; Rel
Interstitial pneumonitis 0 T. H. Table 3. Interstitial pneumonitis
(IP) and age
Age (yrs)
No. grafted
No. IP
No. fatal IP
IO-19 20-29 30-39
4 9 9
1 (25%)’ 5 (56%)3 8 (89%)5
02 2 (22%)4 7 (78%)6
Statistical comparisons (1) vs. (3) p = 0.05 (3) vs. (5) p = 0.01* (I) vs. (5) p = 0.001* * Significant.
(Fisher’s Exact Test): (2) vs. (4) p = 0.54 (4) vs. (6) p = 0.002* (2) vs. (6) p = 0.02*
cystis carinii and cytomegalovirus.1’~‘6~‘8~29 The importance of radiation in the pathogenesis of these cases is unclear. We have been able to compare the response of two groups of patients treated with different TBI techniques. One, modelled after that used by the Seattle group, used a fixed beam of cobalt gamma rays while the other, developed to overcome a number of practical problems, used a sweeping beam of 4 MV X rays. For both techniques, the total dose of radiation was the same and the overall treatment time was similar. While the total incidence of IP was similar in the two groups, we observed that the incidence of fatal disease was higher in the sweeping beam group. The number of patients in the two treatment groups, however, was small and the difference in IP incidence not statistically significant. It is possible that other factors may have been of importance in modifying the incidence and mortality of IP observed in our patients. Thomas et uf. have demonstrated that non-leukemic mortality was higher in older age groups.25 In our patients, the incidence of fatal IP increased with increasing age. The median age of the sweeping beam group was slightly higher than that of the cobalt group, but the difference in age was not statistically significant. However, the possibility that age did influence the incidence of IP for patients in the sweeping beam group cannot be excluded on the basis of small sample studied. In contrast, the sweeping beam group included a majority of patients in first remission of acute nonlym-
Table 4. Interstitial pneumonitis No. transplanted
No. with IP
Fatal IP
All etiologies 6(‘Co SB
11 11
6 8 p = 0.66*
2 7 p = 0.08*
Idiopathic 6OCo SB
I1 11
2 5 p = 0.36*
0 4 p = 0.09*
IP = Interstitial pneumonitis; * Fisher’s Exact Test.
et a/.
KIM
1289
Table 5. Latent period to development interstitial pneumonitis (IP) Latent period
No. with IP
~90 days
9
290 days
5
of
No. with fatal IP 7 p = 0.09* 1
* Fisher’s Exact Test.
phoblastic leukemia, which is considered a favorable prognostic factor,24 while the cobalt group included a majority of patients with advanced disease. Moreover, the efficiency of lung shielding was greater with the sweeping beam technique because of easier and more reproducible patient positioning allowing accurate and generous lead cutouts. I9 In spite of these favorable factors, the non-leukemic mortality was higher in the sweeping beam group. Fatal IP was associated with a short latent period in our patients. Thomas et al. have also reported that most cases of fatal IP developed within 90 days of transplantation, 60% of them before day 75.‘6,26 However, the differences in latent period between our two treatment groups were not statistically significant. Graft versus host disease has been linked to IP, especially following TBI.16 The incidence of GVHD was similar for both the cobalt and the sweeping beam group; however, again, because of the small sample size, the possibility that GVHD might have contributed to the incidence of fatal IP in the sweeping beam group cannot be dismissed. The technical differences between the two methods are first, the sources of radiation used (@‘Co versus a 4 MV linear accelerator) and second, the higher instantaneous dose rate in the sweeping beam technique. Feola et al. reported almost identical relative biological effectiveness (RBE) between 6oCo and 10 MV X rays with the same dose rate.6 Barrett, in a survey of European centers using stationary cobalt gamma rays or megavoltage X rays for TBI, concluded that the incidence of IP was not affected by the source of radiation.’ It appears therefore unlikely that there was a biologically significant difference in RBE between the two sources used. Dose rate is known to influence cell survival. It has been shown experimentally that reduction of the dose
Table 6. Interstitial pneumonitis (IP) and acute graft versus host disease 2 Grade II AcGVHD Group
AcGVHD
AcGVHD and IP
AcGVHD and fatal IP
6OCo Sweeping beam
5 7
4* 6*
2* 4*
SB = Sweeping beam. * Differences not significant.
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Radiation Oncology 0 Biology 0 Physics
rate has a sparing effect for both in vivo and in vitro systems. 739.‘4Barrett’ reported a very low incidence of IP of both idiopathic and infectious forms following BMT, by using a very low dose rate (2.8 cGy/min.), while maintaining a high lung dose (850-950 cGy). However, in this study, other factors such as the use of cyclosporin A may also account for the differences observed.4 In the present study, the total absorbed &se and total delivery time are comparable in both techniques, resulting in identical average dose rates. The instantaneous dose rate, however, is some three to four times higher for the sweeping beam technique. In the sweeping beam technique, the dose is delivered by a series of small increments approximating continuous irradiation as delivered by the cobalt technique. Since there were essentially no other differences between the two TBI techniques, we assumed that the RBE would be equivalent. Our limited series of observations suggests, however. that this is not the case and that the sweeping beam technique produces a greater biological effect, at least in
July 1985, Volume 11. Number 7
terms of the lung, than the cobalt total dose.
method
for the same
CONCLUSION We have observed a trend towards a greater incidence of fatal interstitial pneumonitis, predominantly of the idiopathic variety, when we used a new total body irradiation technique with a sweeping beam on a 4 MV linear accelerator compared to our former technique with a static beam on a cobalt unit. All the parameters of total body irradiation other than the instantaneous dose rate were identical in the two techniques. Although our small study population did not allow significant statistical confirmation, we suggest that the higher instantaneous dose rate in the sweeping beam technique may have resulted in a more potent biological effect than that seen after continuous lose dose rate irradiation using a conventional cobalt source. Although there is no other clinical or experimental evidence to support this conclusion, we feel that further investigation of this effect is warranted.
REFERENCES (TBI) before bone 1. Barrett, A.: Total body irradiation marrow transplantation in acute leukaemia: A co-operative study from the European Group for Bone Marrow Transplantation. Brit. J. Radiol. 55, 562-567, 1982. 2 Blume, K.G., Beutler, F., Bross, K.J., Chillar, R.K., Ellington, D.B., Fahey, J.L., Farbstein, M.J., Forman, S.J., Schmidt, G., Scott, E.P., Spruce, W.E., Turner, M.A., Wolf, J.L.: Bone marrow ablation and allogeneic marrow transplantation in acute leukemia. N. Engl. J. Med. 302: 1041-1046, 1980. 3. Bortin, M.M., Gale. R.P., Rimm, A.A.: Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. J. A. M. A. 245: 1132-l 139, 1981. 4. Bortin, M.M., Kay, H.E.M., Gale, R.P., Rimm, A.A.: Factors associated with interstitial pneumonitis after bone marrow transplantation for acute leukemia. Lancrt 1: 437-439, 1982. A., Loirette, M., Boisserie, G.: 5. Dutreix, J., Wambersie. Time factors in total body irradiation. Path. Biol. 27: 365-369, 1979. 6. Feola, J.M., Song, C.W., Kahn, F.M., Levitt, S.H.: Lethal response of C57Bl mice to 10 MeV Xrays and to “‘Co gamma-rays. Int. J. Radiat. Biol. 26: 161-165, 1974. 7. Fu. K., Phillips, T.L., Kane, L.J., Smith, V.: Tumor and normal tissue response to irradiation in viva: Variation with decreasing dose rates. Radiology 114: 709-7 16, 1975. E., Devergie, A., Dutreix, A., Dutreix, J.. 8. Gluckman. Boiron, M., Bernard, J.: Total body irradiation in bone marrow transplantation. Hopital Saint-Louis results. Path. Biol. 27: 349-352, 1979. 9. Hall, E.J.: Radiation dose rate: A factor of importance in radiobiology and radiotherapy. Brit. J. Radiol. 45: 81-97, 1972. IO. Keable, H., Rybka, W.B., Ty, T., Richards, G.K.: Low dose gastrointestinal sterilization regimen in bone marrow transplantation (BMT) (Abstr.). Annals RCPSC 14: 200, 1981.
11 Keane, T.J., Van Dyk, J., Rider, W.D.: Idiopathic interstitial pneumonia following bone marrow transplantation: The relationship with total body irradiation. Int. J. Radiat. Oncol. Biol. Phys. 7: 1365-I 370, 198 1. 12. Kim, J.H.. Chu, F.C., Grossbard, E., Hopfan, S., Simpson, L., Shank, B., Reid, A., Finegan, D.M., O’Reilly, R.J.: A new radiation dose fractionation schedule for total body irradiation in bone marrow transplantation for refractory leukemia (Abstr. C-464). Proc. Am. Sot. Clin. Oncol. 21: 436, 1980. 13. Kim, T.H., Khan, F.M., Galvin, J.M.: A report of the work party: Comparison of total body irradiation techZnt. J. Radial. niques for bone marrow transplantation. Oncol. Biol. Phys. 6: 779-784, 1980. 14. Kolb, H.J., Rieder, I., Bodenberger, U., Netzel, B., Schaffer, E., Kolb, H., Thierfelder, S., and the Munich co-operative group for bone marrow transplantation: Dose rate and dose fractionation studies in total body irradiation in dogs. Path. Biol. 27: 370-372, 1979. 15. Lichter, A.S., Tracy, D., Lam, W-C., Order, S.E.: Total body irradiation in bone marrow transplantation: The influence of fractionation and delay of marrow infusion. Int. J. Radial. Oncol. Biol. PhJ1.s. 6: 301-309, 1980. 16. Neiman, P.E., Thomas, E.D., Reeves, W.C., Ray, C.G., Sale, G., Lerner, K.G.. Buckner, C.D., Clift, R.A., Storb, R., Weiden, P.L., Fefer, A.: Opportunistic infection and interstitial pneumonitis following marrow transplantation for aplastic anemia and hematologic malignancy. Transplant. Proc. 7: 663-667, 1976. 17. Peters, L.J., Withers, H.R., Cundiff. J.H.. Dicke, K.A.: Radiobiological considerations in the use of total body irradiation for bone marrow transplantation. Radiology 131: 243-247, 1979. 18. Pino y Torres. J.L., Bross, D.S., Lam, W.L.. Wharam. M.D., Santos, G.W., Order, S.E.: Risk factors in interstitial pneumonitis following allogeneic bone marrow transplantation. Int. J. Radial. Oncol. Biol. Phys. 8: 1301-1307, 1981.
Interstitial pneumonitis 0 T. H. KIM et al. 19. Pla, M., Chenery, S.G., Podgorsak, E.B.: Total body irradiation with a sweeping beam. Int. J. Radiat. Oncol.
Biol. Phys. 9: 83-89, 1983. 20. Ryder, W.D. and Van Dyk, J.: Total and partial body irradiation. In Radiation Therapy Planning, Bleehen, N.M., Glatstein, E., and Haybittle, J. (Eds.). NY, Marcel Dekker, Inc. 1983, p. 584. 21. Speck, B., Cornu, P., Nissen, C., Grafwohl, A., Sartorius, J.: The Base1 experience with total body irradiation for conditioning patients with acute leukemia for allogeneic bone marrow transplantation. Path. Biol. 27: 353-355,
1979. 22. Tefft, M.: Radiaiton Tumor
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related toxicities in National Wilm’s 1. Int. J. Radiat. Oncol. Biol. Phys.
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E.D.. Buckner, C.D., Banaji, M., Clift, R.A., Fefer, A., Flournoy, N., Goodell, B.W., Hickman, R.O., Lerner, K.G., Neiman, P.E., Sale, G.E., Sanders, J.E., Singer, J., Stevens, M., Storb, R., Weiden, P.L.: One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49: 51 l-533, 1977. 24. Thomas, E.D., Buckner, C.D., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Sale, G.E., Sanders, J.E.,
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Singer, J., Shulman, H., Storb, R., Weiden, P.L.: Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301: 579-599, 1979. 25. Thomas, E.D., Clift, R.A., Buckner, C.D.: Marrow transplantation for patients with acute nonlymphoblastic leukemia who achieve a first remission. Cancer Treat. Rep.
66: 1463-1466, 1982. 26. Thomas, E.D., Clift, R.A.,
Hersman, J., Sanders, J.E., Stewart, P., Buckner, C.D., Fefer, A., McGutlin, R., Smith, J.W., Storb, R.: Marrow transplantation for nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int. J. Radiat. Oncol. Biol. Phys.
8: 817-821. 1982. 27. UCLA Bone Marrow
Transplant Team: A phase II trial of fractionated total body irradiation in bone marrow transplantation for acute leukemia. Transplant. Proc. 11: 205-207, 1979. 28. Van Dyk, J., Keane, T.J., Kan, S., Rider, W.D., Fryer, C.J.: Radiation pneumonitis following large single dose irradiation: A re-evaluation based on absolute dose to the lung. Int. J. Radiat. Oncol. Biol. Phys. 7: 46 I-467, 198 1. 29. Winston, D.J., Gale, R.P., Myer, D.V.. Young, L.D.: Infectious complications of human bone marrow transplantation. Medicine 48: l-32, 1979.
0360.3016/E $03.00 + 02 Copyright 0 1985 Pergamon Press Ltd
PP. 1285-1291
??Original Contribution
INTERSTITIAL PNEUMONITIS FOLLOWING TOTAL BODY IRRADIATION FOR BONE MARROW TRANSPLANTATION USING TWO DIFFERENT DOSE RATES TAIK H. KIM, M.D.‘,
WITOLD
B. RYBKA, M.D., F.R.C.P.(C)2, SHIRLEY LEHNERT, PH.D. ‘, ERVIN B. PODGORSAK, PH.D., F.C.C.P.M.’ AND CAROLYN R. FREEMAN, M.B., B.S., F.R.C.P.(C).’ ‘Department
of Radiation Oncology and *Division of Hematology, Department The Montreal General Hospital, Montreal, Quebec, Canada
of Medicine,
A total of 22 patients with leukemia (10 ALL, 11 AML, 1 CML) have undergone allogeneic bone marrow transplantation (BMT) by the Quebec Co-operative Group for Marrow Transplantation from 1980 to 1982. All patients received 900 cGy total body irradiation (TBI), in a single fraction, on the day preceding BMT. The first 11 patients were treated on a cobalt unit at a constant dose rate of 4.7 to 6.3 cGy/min. Six of these patients developed interstitial pneumonitis (IP). The clinical course of three patients, two with idiopathic and one with drug-induced pneumonitis, was mild and recovery was complete in all. The other three patients developed severe infectious IP and two died. The next 11 patients were treated with a sweeping beam technique on a 4 MV linear accelerator delivering a total tumor dose of 900 cGy at an average dose rate of 6.0 to 6.5 cGy/min but an instantaneous dose rate of 21.0 to 23.5 cGy/min. Eight patients developed severe IP. Five of these were idiopathic and four died. Three were infectious and all died. The fatality of interstitial pneumonitis appeared to be greater in the group treated with the sweeping beam technique. Interstitial pneumonitis, technique, Dose rate.
Total
body irradiation,
Bone marrow
transplantation,
Leukemia,
Sweeping
beam
INTRODUCTION
been attempted with beam attenuators.8,‘83’9 Although some of these innovations have resulted in a decreased incidence of fatal pneumonitis,‘~9,“3’2 IP remains a leadTotal body irradiation (TBI) has been considered an ing cause of death following BMT.2.18’2’,26,27 integral component in the preparation of patients with Between February 1980 and March 1982, 22 consechematological malignancies for bone marrow transplantation (BMT).‘3238~12321323326*27 One of the major causes utive patients received allogeneic bone marrow grafts of death following BMT is interstitial pneumonitis for the treatment of hematological malignancies by the Quebec Co-operative Group for Marrow Transplantation. (IP). 4,16,18,29The incidence and fatality rate of this complication vary considerably. 1~2~4~8~11~16~18,2’ The ~24~26~27 The prescribed tumor dose was 900 cGy for all patients. pathogenesis of IP is complex with multifactorial etiolThe first 11 consecutive patients received TBI using a ogies,16,18of which TBI may be one of the more imporcobalt source at a low constant dose rate while the tant, especially in cases of the idiopathic variety.” In an remaining 11 patients were treated with a sweeping attempt to reduce the incidence of this complication, a beam technique on a 4 MV linear accelerator.” The number of TBI parameters, such as fractionation,‘2.26 major difference between these two techniques is in the dose rate,] and total dose” have been studied.13 In instantaneous dose rate. Although the total dose, delivery addition, reduction of the pulmonary absorbed dose has times and average dose rates are identical for both
of the members of the Quebec Co-operative Group for Marrow Transplantation: Drs. A. Lebrun and D. Noel (HBpital du Sacr& Coeur), S. Caplan (Sir Mortimer B. Davis Jewish General Hospital), P. Koch and V. M. Whitehead (The Montreal Children’s Hospital), G. Blake and J. L. Hutchison (The Montreal General Hospital), J. F. Prchal and C. Shustik (The Royal Victoria Hospital). Accepted for publication 6 February 1985.
Presented at the American Society of Therapeutic Radiologists’ 24th Annual Meeting, Orlando, Florida, October 25-29, 1982. W. B. Rybka was supported in part by the T. H. P. Molson Award. Reprint requests to: W. B. Rybka, M.D., F.R.C.P.(C), Rm. 7 129, The Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec, Canada, H3G lA4. Acknowledgments-We wish to acknowledge the participation 1285
1286
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Oncology
0 Biology 0 Physics
methods, the instantaneous dose rate with the sweeping beam is three to four times that of continuous irradiation with the cobalt unit. As there appeared to be an increased incidence of fatal idiopathic IP with the sweeping beam technique, we postulate that the instantaneous dose rate may be an important variable in the genesis of IP.
METHODS
AND
MATERIALS
Marrow transplantation was performed in a manner similar to that reported by the Seattle marrow transplant team.23.24 Twenty-two patients received marrow grafts from human leucocyte antigen (HLA) matched, mixed lymphocyte culture (MLC) compatible siblings as part of their treatment for hematological malignancies. The diagnosis was acute lymphoblastic leukemia (ALL) in 10 patients (2 in remission, 8 in relapse), acute nonlymphoblastic leukemia (ANL) in remission in 11 patients, and chronic myelogenous leukemia (CML) in the chronic phase in one patient. The patients ranged in age from 14 to 39 years, with a median age of 27 years. Antileukemic therapy included cyclophosphamide 60 mgm/ kgm given twice, on the 5th and 4th days prior to transplantation. Three patients received cytosine arabinoside, vincristine, and methylprednisolone in addition. All patients received 900 cGy TBI the day prior to BMT. Following transplantation, patients were treated with gastrointestinal sterilization in reverse isolation until recovery of circulating neutrophils.‘” All patients received prophylaxis against graft versus host disease (GVHD) with intravenous methotrexate 15 mgm/M2 on Day 1, 10 mgm/M* on Days 3, 6, 11, and 18 following transplantation and then 10 mgm/M2 intravenously alternating weekly with 12 mgm intrathecally until 102 days following transplantation. TBI was delivered in the Department of Radiation Oncology at the Montreal General Hospital. One of two methods was used to deliver TBI, as summarized in Table 1. The first I 1 consecutive patients were treated with 6”Co gamma rays, with the cobalt unit positioned horizontally and the patient placed in a lateral recumbent position at a source-to-skin distance (SSD) of 380 cm. The patient was turned three times during the treatment period for two anterior and two posterior exposures to deliver the total tumor dose of 900 cGy over a period of 140 to 190 min. The treatment had to be frequently interrupted because of patient discomfort. The second group, also of 11 patients, was treated with a newly developed technique, which uses a sweeping beam on a 4 MV linear accelerator. The impetus for the development of this technique came primarily from the practical problems posed by the continued use of the cobalt technique, notably uncomfortable patient position, difficulties imposed by this position on lung shielding with lead cut outs and an increasing overall treatment time because of the decay of the cobalt source. The
technical
details
and
physical
aspects
of this
tech-
July
1985, Volume
Table
1I, Number
7
I. Physical characteristics
of the cobalt and sweeping beam TBI techniques Stationary cobalt beam
Source SSD Maximum size Dose rate Average
field
Instantaneous Patient Delivery
position method
Lung compensation
Total tumor dose Total treatment time
Sweeping linac beam
6oCo
4 MV X rays?
gamma-rays* 380 cm 200 cm X 70 cm
190 cm 70 cm X 70 cm
4.1-6.3 cGy/min 4.7-6.3 cGy/min Lateral recumbent Anterior and posterior 2 mm lead on anterior and posterior chest wall 900 cGy 140-190 min
6.0-6.5 cGy/min 2 I .O-23.5 cGy/min Prone and supine Anterior and posterior 2 mm lead on anterior and posterior chest wall 900 cGy 140-150 min
* Theratron 780, Atomic Energy of Canada, Ltd, Ottawa, Ontario, Canada. t Therapi 4, SHM Nuclear Corporation, Sunnyvale, CA.
nique have been previously described” and are illustrated in Figure 1. We attempted to reproduce the conditions of TBI with the cobalt unit as closely as possible for the sweeping beam method. The field size for the linear accelerator at an SSD of 190 cm is only 70 X 70 cm2, thus no more than one-third of the patient can be in the beam at a given time. TBI is achieved by having a motorized machine head sweep the beam over the patient with an average interval of 30 set per sweep. The prescribed dose of 900 cGy is delivered over a period of 140 to 150 min. The dose rate during exposure (instantaneous dose rate) is 21.0 to 23.5 cGy/min., whereas the average dose rate is 6.0 to 6.5 cGy/min., similar to that for the cobalt technique. Thus, the time required to deliver the total dose is similar for the cobalt and sweeping beam techniques. In both techniques, the lung dose was normalized to the actual tumor dose using 2 mm lead cutouts positioned over the thorax. Previous measurements” using thermoluminescent dosimetry techniques had shown that the lung dose in a humanoid phantom could exceed the prescribed dose by up to 13% for both the cobalt and the sweeping beam techniques, and that lung dose and prescribed tumor dose are equalized if 2 mm thick lead attenuators are placed over the lungs of the phantom. The CT determined density of the phantom lung was 0.5 g/cm3. While lung densities were not determined for individual patients it is known that lung density in young adults is between 0.3 and 0.35 g/cm3.20 On the
Interstitial pneumonitis 0 T. H. KIM et al
f, DISTANCE FROM CENTER
1287
ccm )
Fig. 1. Schematic diagram of the sweeping beam total body irradiation technique. Source to skin distance l is 190 cm on the vertical beam axis and the monitor chamber is 150 cm from the source. Also shown are the position of the 2 mm thick lung attenuators and the patient midline dose, normalized to 100% at midline on the vertical beam axis.
basis of the dosimetric measurements made in the phantom and with the knowledge of the densities of phantom and human lung. it was estimated that no patient treated by either technique would receive a dose which exceeded the prescribed tumor dose by more than 5%. Positioning of the lung compensator was considerably easier with the sweeping beam technique than with the cobalt beam technique and a larger portion of the lung could be encompassed with improved accuracy. With the new method, the patient was also turned three times alternating between prone and supine positions for anterior and posterior exposures. Interruptions occasioned by patient discomfort were less frequent with this technique. The occurrence of interstitial pneumonia was recognized by clinical and radiological criteria. Pulmonary biopsies were obtained from all patients who developed IP. Bacterial, fungal and viral cultures were attempted in all cases. Idiopathic interstitial pneumonia was determined by the absence of characteristic viral inclusions and negative viral or bacteriological cultures. All of these patients were hospitalized. The majority of patients with idiopathic IP were treated with corticosteriods. All surviving patients have been followed for at least 18 months. Statistical analyses were obtained using a two tailed Fisher’s Exacr Test and the Student’s T Test.
RESULTS The groups
patient treated
profiles and by the cobalt
individual results for the and sweeping beam tech-
niques are outlined in Table 2a and 2b, respectively. The diagnoses in the cobalt group included seven with ALL (two in second remission and five in relapse) and four with ANL (three in first remission, two in third remission). The diagnoses in the sweeping beam group included seven with ANL (five in first remission, two in second remission), three with ALL (all in relapse) and two in the chronic phase of chronic myelogenous leukemia. The median age was 25 years (range 14 to 39 yrs) for the patients in the cobalt group and 31 yrs (range 22 to 36 yrs) for patients in the sweeping beam group. These differences are not statistically significant (p = 0.09). The incidence and fatality of IP increased with patient age, with older age related to higher incidence and greater severity of IP, particularly in the fourth decade (Table 3). There were six cases of IP in the cobalt group and eight in the sweeping beam group (Table 4). Only two patients in the cobalt group developed idiopathic IP, whereas five of the eight in the sweeping beam group were idiopathic. Both patients with idiopathic IP in the cobalt group recovered completely after a mild clinical course, whereas four of the five patients with idiopathic IP in the sweeping beam group died. Two of three patients with infectious IP in the cobalt group and all three of those in the sweeping beam group died of IP. One patient (no. 4 of the cobalt group) had a peculiar granalomatous histological pattern, considered compatible with drug-induced IP. This patient recovered completely following a mild clinical course. The statistical comparisons are given in Table 4. A trend is noted toward greater fatality of IP in the sweeping beam group.
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July 1985, Volume 1I. Number
Radiation Oncology 0 Biology 0 Physics Table 2a. Patients
treated
with the cobalt TBI technique
sex
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Il.
28M 14F 30M 22F 29M 18M 14M 39F 18M 34M 25M
Diagnosis ALL ALL ALL ALL ALL ALL ALL ANL ANL ANL ANL
(2nd (5th (2nd (1st ( 1st (2nd (3rd (3rd (1st (1st ( 1st
No No
Rem) Rel) Rel) Rel) Rel) Rem) Rel) Rem) Rem) Rem) Rem)
Onset (day)
IP
AcGVHD
1980 to May 198 1 (900 cGy)
from February
Age, No.
No No Idiopathic Granulomatous Idiopathic Pneumocystis No CMV No Pneumocystis No
No Yes No
Yes No
Yes No
Yes Yes
7
Survival (days)
Cause of death
>1249 305 > 1075 >1026 >990 356 140 65 >85 1 118 >810
59 110 110 90 40 80 -
Leukemia
Leukemia Leukemia GVHD/IP 1P
AcGVHD = Acute graft versus host disease 2 Grade II; IP = Interstitial pneumonitis; ALL = Acute lymphoblastic ANL = Acute nonlymphoblastic leukemia: Rem = Remission: Rel = Relapse: CMV = Cytomegalovirus.
transplantation is still unknown, evidence has accumulated that factors modulating radiation response influence the incidence of IP.‘7.‘8 These include total dose,8,“-‘7 dose rate’,4,5,‘4 and fractionation.‘2.‘4.‘5,‘8.26 The importance of these factors has been clearly demonstrated in the pathogenesis of radiation-induced pneumonitis following half body irradiation2’ and whole lung irradiation.22 Indeed, radiation-induced pneumonitis is a relatively common observation in daily radiation therapy practice. Idiopathic interstitial pneumonitis, comprising 30-40s of cases of IP following BMT,“~‘x shows similarities in histological and clinical features with typical radiation-induced pneumonitis.” The timing is similar to that seen for the onset of radiation-induced pneumonitis, which frequently occurs within two to three months following radiation of the lung. However, radiation is not the sole factor implicated in the pathogenesis of IP after BMT. IP may occur following BMT for aplastic anemia, a situation in which TBI is not used or is restricted to a low dose.3,‘6 Also, IP is rarely seen following syngeneic transplants, although in these cases the lung is fully irradiated.lh Over half the cases of IP are of infectious etiology, usually pneumo-
A latent period (time to onset) of greater than 90 days was associated with a mild reversible course of pneumonitis (Table 5). A trend was noted toward greater fatality of IP associated with a latent period shorter than 90 days (p = 0.09). The differences in latent period between the sweeping beam and the cobalt groups were not statistically significant (p = 0.6). A total of 12 patients developed Grade I1 or greater acute GVHD following BMT: 5 in the cobalt and 7 in the sweeping beam groups. Concurrent IP and GVHD were observed in 10 patients: 4 in the cobalt and 6 in the sweeping beam groups. Neither the incidence nor the fatality rates were significantly different in terms of this variable between the two groups (Table 6). During the same period, two additional patients were treated with TBI using the cobalt technique prior to syngeneic grafts for acute lymphoblastic leukemia in remission. Neither developed IP and neither is included in the present analysis. DISCUSSION Although the exact role of irradiation in the pathogenesis of interstitial pneumonitis following marrow Table 2b. Patients
No. 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
1I.
Age, sex 34F 36M 22M 27F 26M 26M 31M 36F 34F 31F 25M
treated
Diagnosis ANL ANL ANL ANL ANL CML ALL ALL ANL ANL ALL
(I st Rem) (1 st Rem) (1 st Rem) (2nd Rem) (1st Rem) (chronic) (1st Rel) (4th Rel) (1st Rem) (2nd Rem) (2nd ReI)
with the sweeping
beam TBI technique
Yes Yes Yes No
Yes Yes No No
Yes Yes No
from June
1981 to March
Onset (day)
Survival (days)
No
-
Idiopathic Idiopathic No Mucormycosis Idiopathic CMV Idiopathic CMV Idiopathic No
130 160
215 150 >766 >619 60 135 51 66 56 58 >507
IP
AcGVHD
leukemia;
AcGVHD = Acute graft versus host disease 2 Grade II; IP = Interstitial ANL = Acute nonlymphoblastic leukemia; CML = Chronic myelogenous = Relapse; CMV = Cytomegalovirus.
54 55 40 15 45 50
1982 (900 cGy)
Cause of death Leukemia IP
GVHD/Mucormycosis IP IP IP IP IP
pneumonitis: ALL = Acute Iymphoblastic leukemia; leukemia in chronic phase; Rem = Remission; Rel
Interstitial pneumonitis 0 T. H. Table 3. Interstitial pneumonitis
(IP) and age
Age (yrs)
No. grafted
No. IP
No. fatal IP
IO-19 20-29 30-39
4 9 9
1 (25%)’ 5 (56%)3 8 (89%)5
02 2 (22%)4 7 (78%)6
Statistical comparisons (1) vs. (3) p = 0.05 (3) vs. (5) p = 0.01* (I) vs. (5) p = 0.001* * Significant.
(Fisher’s Exact Test): (2) vs. (4) p = 0.54 (4) vs. (6) p = 0.002* (2) vs. (6) p = 0.02*
cystis carinii and cytomegalovirus.1’~‘6~‘8~29 The importance of radiation in the pathogenesis of these cases is unclear. We have been able to compare the response of two groups of patients treated with different TBI techniques. One, modelled after that used by the Seattle group, used a fixed beam of cobalt gamma rays while the other, developed to overcome a number of practical problems, used a sweeping beam of 4 MV X rays. For both techniques, the total dose of radiation was the same and the overall treatment time was similar. While the total incidence of IP was similar in the two groups, we observed that the incidence of fatal disease was higher in the sweeping beam group. The number of patients in the two treatment groups, however, was small and the difference in IP incidence not statistically significant. It is possible that other factors may have been of importance in modifying the incidence and mortality of IP observed in our patients. Thomas et uf. have demonstrated that non-leukemic mortality was higher in older age groups.25 In our patients, the incidence of fatal IP increased with increasing age. The median age of the sweeping beam group was slightly higher than that of the cobalt group, but the difference in age was not statistically significant. However, the possibility that age did influence the incidence of IP for patients in the sweeping beam group cannot be excluded on the basis of small sample studied. In contrast, the sweeping beam group included a majority of patients in first remission of acute nonlym-
Table 4. Interstitial pneumonitis No. transplanted
No. with IP
Fatal IP
All etiologies 6(‘Co SB
11 11
6 8 p = 0.66*
2 7 p = 0.08*
Idiopathic 6OCo SB
I1 11
2 5 p = 0.36*
0 4 p = 0.09*
IP = Interstitial pneumonitis; * Fisher’s Exact Test.
et a/.
KIM
1289
Table 5. Latent period to development interstitial pneumonitis (IP) Latent period
No. with IP
~90 days
9
290 days
5
of
No. with fatal IP 7 p = 0.09* 1
* Fisher’s Exact Test.
phoblastic leukemia, which is considered a favorable prognostic factor,24 while the cobalt group included a majority of patients with advanced disease. Moreover, the efficiency of lung shielding was greater with the sweeping beam technique because of easier and more reproducible patient positioning allowing accurate and generous lead cutouts. I9 In spite of these favorable factors, the non-leukemic mortality was higher in the sweeping beam group. Fatal IP was associated with a short latent period in our patients. Thomas et al. have also reported that most cases of fatal IP developed within 90 days of transplantation, 60% of them before day 75.‘6,26 However, the differences in latent period between our two treatment groups were not statistically significant. Graft versus host disease has been linked to IP, especially following TBI.16 The incidence of GVHD was similar for both the cobalt and the sweeping beam group; however, again, because of the small sample size, the possibility that GVHD might have contributed to the incidence of fatal IP in the sweeping beam group cannot be dismissed. The technical differences between the two methods are first, the sources of radiation used (@‘Co versus a 4 MV linear accelerator) and second, the higher instantaneous dose rate in the sweeping beam technique. Feola et al. reported almost identical relative biological effectiveness (RBE) between 6oCo and 10 MV X rays with the same dose rate.6 Barrett, in a survey of European centers using stationary cobalt gamma rays or megavoltage X rays for TBI, concluded that the incidence of IP was not affected by the source of radiation.’ It appears therefore unlikely that there was a biologically significant difference in RBE between the two sources used. Dose rate is known to influence cell survival. It has been shown experimentally that reduction of the dose
Table 6. Interstitial pneumonitis (IP) and acute graft versus host disease 2 Grade II AcGVHD Group
AcGVHD
AcGVHD and IP
AcGVHD and fatal IP
6OCo Sweeping beam
5 7
4* 6*
2* 4*
SB = Sweeping beam. * Differences not significant.
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Radiation Oncology 0 Biology 0 Physics
rate has a sparing effect for both in vivo and in vitro systems. 739.‘4Barrett’ reported a very low incidence of IP of both idiopathic and infectious forms following BMT, by using a very low dose rate (2.8 cGy/min.), while maintaining a high lung dose (850-950 cGy). However, in this study, other factors such as the use of cyclosporin A may also account for the differences observed.4 In the present study, the total absorbed &se and total delivery time are comparable in both techniques, resulting in identical average dose rates. The instantaneous dose rate, however, is some three to four times higher for the sweeping beam technique. In the sweeping beam technique, the dose is delivered by a series of small increments approximating continuous irradiation as delivered by the cobalt technique. Since there were essentially no other differences between the two TBI techniques, we assumed that the RBE would be equivalent. Our limited series of observations suggests, however. that this is not the case and that the sweeping beam technique produces a greater biological effect, at least in
July 1985, Volume 11. Number 7
terms of the lung, than the cobalt total dose.
method
for the same
CONCLUSION We have observed a trend towards a greater incidence of fatal interstitial pneumonitis, predominantly of the idiopathic variety, when we used a new total body irradiation technique with a sweeping beam on a 4 MV linear accelerator compared to our former technique with a static beam on a cobalt unit. All the parameters of total body irradiation other than the instantaneous dose rate were identical in the two techniques. Although our small study population did not allow significant statistical confirmation, we suggest that the higher instantaneous dose rate in the sweeping beam technique may have resulted in a more potent biological effect than that seen after continuous lose dose rate irradiation using a conventional cobalt source. Although there is no other clinical or experimental evidence to support this conclusion, we feel that further investigation of this effect is warranted.
REFERENCES (TBI) before bone 1. Barrett, A.: Total body irradiation marrow transplantation in acute leukaemia: A co-operative study from the European Group for Bone Marrow Transplantation. Brit. J. Radiol. 55, 562-567, 1982. 2 Blume, K.G., Beutler, F., Bross, K.J., Chillar, R.K., Ellington, D.B., Fahey, J.L., Farbstein, M.J., Forman, S.J., Schmidt, G., Scott, E.P., Spruce, W.E., Turner, M.A., Wolf, J.L.: Bone marrow ablation and allogeneic marrow transplantation in acute leukemia. N. Engl. J. Med. 302: 1041-1046, 1980. 3. Bortin, M.M., Gale. R.P., Rimm, A.A.: Allogeneic bone marrow transplantation for 144 patients with severe aplastic anemia. J. A. M. A. 245: 1132-l 139, 1981. 4. Bortin, M.M., Kay, H.E.M., Gale, R.P., Rimm, A.A.: Factors associated with interstitial pneumonitis after bone marrow transplantation for acute leukemia. Lancrt 1: 437-439, 1982. A., Loirette, M., Boisserie, G.: 5. Dutreix, J., Wambersie. Time factors in total body irradiation. Path. Biol. 27: 365-369, 1979. 6. Feola, J.M., Song, C.W., Kahn, F.M., Levitt, S.H.: Lethal response of C57Bl mice to 10 MeV Xrays and to “‘Co gamma-rays. Int. J. Radiat. Biol. 26: 161-165, 1974. 7. Fu. K., Phillips, T.L., Kane, L.J., Smith, V.: Tumor and normal tissue response to irradiation in viva: Variation with decreasing dose rates. Radiology 114: 709-7 16, 1975. E., Devergie, A., Dutreix, A., Dutreix, J.. 8. Gluckman. Boiron, M., Bernard, J.: Total body irradiation in bone marrow transplantation. Hopital Saint-Louis results. Path. Biol. 27: 349-352, 1979. 9. Hall, E.J.: Radiation dose rate: A factor of importance in radiobiology and radiotherapy. Brit. J. Radiol. 45: 81-97, 1972. IO. Keable, H., Rybka, W.B., Ty, T., Richards, G.K.: Low dose gastrointestinal sterilization regimen in bone marrow transplantation (BMT) (Abstr.). Annals RCPSC 14: 200, 1981.
11 Keane, T.J., Van Dyk, J., Rider, W.D.: Idiopathic interstitial pneumonia following bone marrow transplantation: The relationship with total body irradiation. Int. J. Radiat. Oncol. Biol. Phys. 7: 1365-I 370, 198 1. 12. Kim, J.H.. Chu, F.C., Grossbard, E., Hopfan, S., Simpson, L., Shank, B., Reid, A., Finegan, D.M., O’Reilly, R.J.: A new radiation dose fractionation schedule for total body irradiation in bone marrow transplantation for refractory leukemia (Abstr. C-464). Proc. Am. Sot. Clin. Oncol. 21: 436, 1980. 13. Kim, T.H., Khan, F.M., Galvin, J.M.: A report of the work party: Comparison of total body irradiation techZnt. J. Radial. niques for bone marrow transplantation. Oncol. Biol. Phys. 6: 779-784, 1980. 14. Kolb, H.J., Rieder, I., Bodenberger, U., Netzel, B., Schaffer, E., Kolb, H., Thierfelder, S., and the Munich co-operative group for bone marrow transplantation: Dose rate and dose fractionation studies in total body irradiation in dogs. Path. Biol. 27: 370-372, 1979. 15. Lichter, A.S., Tracy, D., Lam, W-C., Order, S.E.: Total body irradiation in bone marrow transplantation: The influence of fractionation and delay of marrow infusion. Int. J. Radial. Oncol. Biol. PhJ1.s. 6: 301-309, 1980. 16. Neiman, P.E., Thomas, E.D., Reeves, W.C., Ray, C.G., Sale, G., Lerner, K.G.. Buckner, C.D., Clift, R.A., Storb, R., Weiden, P.L., Fefer, A.: Opportunistic infection and interstitial pneumonitis following marrow transplantation for aplastic anemia and hematologic malignancy. Transplant. Proc. 7: 663-667, 1976. 17. Peters, L.J., Withers, H.R., Cundiff. J.H.. Dicke, K.A.: Radiobiological considerations in the use of total body irradiation for bone marrow transplantation. Radiology 131: 243-247, 1979. 18. Pino y Torres. J.L., Bross, D.S., Lam, W.L.. Wharam. M.D., Santos, G.W., Order, S.E.: Risk factors in interstitial pneumonitis following allogeneic bone marrow transplantation. Int. J. Radial. Oncol. Biol. Phys. 8: 1301-1307, 1981.
Interstitial pneumonitis 0 T. H. KIM et al. 19. Pla, M., Chenery, S.G., Podgorsak, E.B.: Total body irradiation with a sweeping beam. Int. J. Radiat. Oncol.
Biol. Phys. 9: 83-89, 1983. 20. Ryder, W.D. and Van Dyk, J.: Total and partial body irradiation. In Radiation Therapy Planning, Bleehen, N.M., Glatstein, E., and Haybittle, J. (Eds.). NY, Marcel Dekker, Inc. 1983, p. 584. 21. Speck, B., Cornu, P., Nissen, C., Grafwohl, A., Sartorius, J.: The Base1 experience with total body irradiation for conditioning patients with acute leukemia for allogeneic bone marrow transplantation. Path. Biol. 27: 353-355,
1979. 22. Tefft, M.: Radiaiton Tumor
Study Number
2: 456-463, 23. Thomas,
related toxicities in National Wilm’s 1. Int. J. Radiat. Oncol. Biol. Phys.
1977.
E.D.. Buckner, C.D., Banaji, M., Clift, R.A., Fefer, A., Flournoy, N., Goodell, B.W., Hickman, R.O., Lerner, K.G., Neiman, P.E., Sale, G.E., Sanders, J.E., Singer, J., Stevens, M., Storb, R., Weiden, P.L.: One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49: 51 l-533, 1977. 24. Thomas, E.D., Buckner, C.D., Clift, R.A., Fefer, A., Johnson, F.L., Neiman, P.E., Sale, G.E., Sanders, J.E.,
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Singer, J., Shulman, H., Storb, R., Weiden, P.L.: Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N. Engl. J. Med. 301: 579-599, 1979. 25. Thomas, E.D., Clift, R.A., Buckner, C.D.: Marrow transplantation for patients with acute nonlymphoblastic leukemia who achieve a first remission. Cancer Treat. Rep.
66: 1463-1466, 1982. 26. Thomas, E.D., Clift, R.A.,
Hersman, J., Sanders, J.E., Stewart, P., Buckner, C.D., Fefer, A., McGutlin, R., Smith, J.W., Storb, R.: Marrow transplantation for nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int. J. Radiat. Oncol. Biol. Phys.
8: 817-821. 1982. 27. UCLA Bone Marrow
Transplant Team: A phase II trial of fractionated total body irradiation in bone marrow transplantation for acute leukemia. Transplant. Proc. 11: 205-207, 1979. 28. Van Dyk, J., Keane, T.J., Kan, S., Rider, W.D., Fryer, C.J.: Radiation pneumonitis following large single dose irradiation: A re-evaluation based on absolute dose to the lung. Int. J. Radiat. Oncol. Biol. Phys. 7: 46 I-467, 198 1. 29. Winston, D.J., Gale, R.P., Myer, D.V.. Young, L.D.: Infectious complications of human bone marrow transplantation. Medicine 48: l-32, 1979.