- Email: [email protected]
Interstitial pneumonitis: Dose-rate vs total dose of radiation
IX15
Correspondence controversial.‘,’ Vereecken cr a/.‘O reported a patient whose therapy failed (local recurrence and distant metastases) despite treatments with radical surgery and pre- and post-operative irradiation. The majority of the reported patients were treated by radical surgery.’ The use of chemotherapy (Cyclophosphamide)“’ has been reported with no prolongation of survival. We realize that it is difficult to draw definite conclusions from Just one reported case. However. our patient had a favorable prognosis and appears to be cured inspite of the limited surgery; this might indicate that a full course of irradiation after a debulking procedure could improve the outcome of this disease. WAGIH M. SHEHATA, M.D.. ABRAHAM A. KERR, M.D. HARRY H. Boss, M.D. THOMAS W. PANKE, M.D. RICHARD L. MEYER, M.D.
Department of Radiation Good Samaritan Hospital Cincinnati. OH 45220
F.F.R.
the adequacy of radiation have to be reconsidered.
to the internal
mammary
lymph nodes will
I.Fo%~RI) R. PROSIT!. M.D. Professor of Therapeutic Radiology Department of Therapeutic Radiology Yale University School of Medicine 333 Cedar Street Yew Haven. CT 06510
I. Strender, L.-E., Wallgren. .4., Arndt, J.. Arner, 0.. Bergstrom. J.. Blomstedt. B.. Granberg. P.-O.. Nilsson. B.. Raf. L... Silfversward. C.: Adjuvant radiotherapy in operable breast cancer: Correlation between dose and internal mammary nodes and propnosrs. Inr J. Radial. Oncol. Biol. Phvs 7: 1319 1325, 1981.
Oncology
I. Attah, E.B.. Powell. M.E.: Atypical stromal hyperplasia of the prostate gland. Am. J. Clin. Pafhol. 61: 324-321. 1971. 2. Chatterjee. A.C.: Leiomyosarcoma of the prostate. Brir. J. Urolog) 47: 577. 1975. 3. Guha, T.: Leiomyosarcoma of the prostate: A case report. Clin. Oncol. 5: 261-265, 1975. 4. Hamman. F.. Bischoff, W.: Histologic changes of a prostatic leiomyosarcoma, case report. Hely. Chir. Acfa 45: 297-300. 1978. 5. MacKenzie. A.R., Sharma. T.C., Whitmore, W.F.. Jr., Melamed. M.R.: Non-extirpative treatment of myosarcomas of the bladder and prostate. Cancer 28: 329-334. I97 I. 6. Mindich, R., Tykoy, H.. Littman. L.. Levowitz, B.S.: Leiomyosarcoma of rectum: report of case. Dis. Colon Recfum l8:233-236. 1975. 7. Mostoh, F.K., Price, E.B.: Tumors of fhe Male Genital Sy.yfem. Fascile 8. Washington, D.C. Armed Forces Institute of Pathology. 1973. pp. 253-356. 8. Schmidt, J.D., Welch, M.J.. Jr.: Sarcoma of the prostate. C‘ancer 37: 1908-1912, 1976. 9. Stallwood, G.. Davidson, J.W.: Leiomyosarcoma of the rectum and prostate. Can. J. Surg. 20:446-9, 1977. IO. Vereecken, R.L.. Lauweryns, J., Droohmano, A., Yan Dijck. M.: Leiomyosarcoma of the prostate: A case report. Europ. J. Ural. 3: 370-2, 1977. I I. Weismann, M.J., Gaeta. J.F., Albert, D.J.: Childhood urogenital sarcoma. J. Surg. Oncol. 4: lO9- I 16, 1972.
REBUTTAL: RELAPSE-FREE SURVIVAL IS NOT A GOOD MEASUREMENT OF SURVIVAL IN BREAST CANCER To the Edifor: Dr. Prosnit supposes that the benetit in relapse-free survival given to the patients of our trial’ by preoperative or postoperative radiotherapy eventually will improve their long run survival. It is true that most patients who have a relapse of breast cancer will die from distant metastases. Local and regional recurrences will often be detected earlier than distant metastases. but are generally only indicators of a high risk to develop distant metastases rather than the cause of them. It should be observed that the main reason for the better relapse-free survival of the patients treated with radiotherapy was their lovver rate of local and regional recurrences. About one-third of the patients who have been treated only surgically and who have had local recurrences are still without any sign of distant disease and the rates of distant metastases of the three treatment groups are much more similar than the rates of all relapses. The belief that a significantly improved relapse-free survival evcntually will improve the longevity. is dangerous since it may lead to a premature acceptance of new treatment modalities. It has recently led to the general acceptance of adjuvant cytotoxic chemotherapy as the routine treatment of breast cancer with nodal involvement. As after radiotherapy, long term survival data show that the survival benefit is much smaller than could have been expected from the benefit in recurrence-free survival. l..\Rb-ERIh
STR~~IX.R.
M.D.
.4KUI WAI I(;Rt h. M.D Radiumhemmet Karolinska Hospital S 104 01 Stockholm
CRITIQUE OF “ADJUVANT RADIOTHERAPY IN OPERABLE BREAST CANCER: CORRELATION BETWEEN DOSE AND INTERNAL MAMMARY NODES AND PROGNOSES” To fhe Editor: The data presented by Strender er al.’ for the Stockholm group on the results of adjuvant radiotherapy in operable breast cancer are of great interest to the radiotherapy community. In this paper, the authors show a statistical improvement in survival for the group of patients receiving preoperative radiation followed by mastectomy, but not for those who were treated with radiotherapy following mastectomy. A rather elaborate explanation is then given, suggesting that the post-mastectomy patients may have received inadequate radiation to the internal mammary lymph nodes. However. both pre-operative and post-operative irradiation resulted in a statistically significant benefit in relapse-free survival. Since virtually all patients who have an initial relapse of their breast cancer following mastectomy will eventually die of metastatic disease, a significant improvement in relapse-free survival is bound to be reflected in the long run by significant improvement in the death rate due to breast cancer as well. Therefore, the premise that only preoperative radiotherapy improves survival will not be the case, given a long enough follow-up, if the relapse-free survival data are correct. The subseauent conclusions about
Strender. L.-E.. Wallgren. A., Arndt. J.. Amer. 0.. Bergstrom, J.. Bjonstedt, B.. Granderg. P.-O., Nitsson. B., Raf. L.. Silfversward. C.: Adjuvant radiotherapy in operable breast cancer: Correlation between dose in internal mammary nodes and prognosis. In, J Radial. Oncol. Biol. Phvs. 7:1319- 1325. 19x1.
INTERSTITIAL
PNEUMONITIS: DOSE-RATE DOSE OF RADIATION
VS TOTAL
To fhe Edifor: Interstitial pneumonitis (IPn). whether idiopathic or virus-associated, is a frequent and usually lethal complication of allogeneic bone marrow transplantation. A recent report by Keane et al.* is valuable in that it calls attention to the possibility that the total radiation dose to lung may correlate directly with fatal idiopathic IPn. Several problems with their data, however, prompted the following comments. Our chief concern has to do with the probit regression analysis which they presented in their Fig. I. The UCLA data. which they showed in
1816
Radiation
Oncology
0 Biology
0 Physics
October
1982, Volume
8, Number
IO
Table 4, were excluded from the probit analysis. A review of the cited UCLA report’ disclosed, and discussion with Dr. Robert P. Gale of UCLA verified, that only 8% (3/39) of their leukemia patients died of idiopathic IPn, although they received a mean absorbed lung dose of Il.7 Gy. Had the UCLA data been included in the probit analysis there would be a different regression line between I I .5 and 12 Gy. It seems unlikely to us, on biological grounds, that the incidence of fatal idiopathic IPn would vary between 8% (UCLA) and 50% (Toronto) in such a narrow (50 cGy) “window”. In a recent report from the International Bone Marrow Transplant Registry, (IMBTR),’ data from 176 patients with acute leukemia treated with allogeneic bone marrow transplantation were entered into multiple logistic function analyses to determine whether there were prognostic factors associated with development of IPn. We found that radiation at a dose-rate 2 5.7 cGy/min was associated with a significantly lower (P < .OOOl) incidence of IPn (6%. 4/69) in comparison with higher (6-30 cGy/min) dose-rates (30%, 32/107), irrespective of the total dose of rota1 body radiation (range 8-14
European Communities, March of Dimes Birth Defects Foundation, Ambrose Monell Foundation, Mount Sinai Medical Center (Milwaukee), Samuel Roberts Noble Foundation, Queen Wilhelmina Fund, Sandoz Limited, Swiss Cancer League and the Upjohn Company, and was conducted under contract NOI-AI-02648 from the National Institute of Allergy and Infectious Diseases and the National Cancer Institute. USDHHS.
GY). If one takes the results of both the IBMTR and Keane analyses into account, one interpretation might be that when the total absorbed lung dose was less than approximately 8 Gy, dose-rate probably did not have an effect; when the total dose was at higher levels, dose-rate probably did make a difference. Unfortunately, the IBMTR data base at the present time is inadequate to test this hypothesis. We also are concerned that they analyzed only fatal cases of IPn rather than total incidence, and they divided the fatal cases into idiopathic and infectious. This fragmentation of their data may not be meaningful. For example, they indicated (Table 4) that the Base1 bone marrow transplant team reported that five of their six cases of fatal IPn were idiopathic, whereas the Seattle team reported that only six of their 22 cases of fatal IPn were idiopathic (X2 = 6.21, P = ,013). This apparent difference in incidence of fatal infectious versus fatal idiopathic IPn could have been related to differences in diagnostic sophistication in the two centers, differences in the virulence of North American versus European cytomegaloviruses, etc. The analyses reported by Keane et a/.* and by the IBMTR’ provide strong evidence that radiation of the lung plays an important role in the pathogenesis of some cases of IPn. Additional studies are required to define the role of total dose and dose-rate of radiation on the development of IPn. More complete understanding of these factors can be expected to lead to changes in radiation protocols with reduced morbidity and higher survival rates for patients treated with bone marrow transplantation. Acknow1edgemenf.s: The research was supported by grants from the Burroughs-Wellcome Fund, Elizabeth Elser Doolittle Charitable Trusts, Carl and Elisabeth Eberbach Foundation, Commission of the
I.
.p 7
1
es
gL
I
1
ProbIt
regresslon
m.
~0
1
error
MORTIMER M. BORTIN, M.D. International Bone Marrow Transplant Mount Sinai Medical Center P.O. Box 342 Milwaukee, WI 53201 ALFRED A. RIMM, PH.D. Section of Biostatistics/Epidemiology The Medical College of Wisconsin Milwaukee, WI 53226
Bortin, M.M., Gale, R.P., Kay, H.E.M., Rimm, A.A.: Factors associated with interstitial pneumonitis following bone marrow Lancer 1: 437-439, 1982. transplantation for acute leukemia. 2. Keane, T.J., Van Dyk, J., Rider, W.D.: Idiopathic interstital pneumonia following following bone marrow transplantation: the relationship with total body irradiation, Inr. J. Radial. Oncol. Biol. Phys. 7: 136551370, 1981. 3. Winston, D.J., Gale, R.P., Meyer, D.V., Young, L.D.: Infectious complications of human bone marrow transplantation. Medicine 48:
l-32,
1979.
REBUTTAL
To rhe Edifoc Bortin and Rimm raise several issues concerning pulmonary complications following bone marrow transplantation. We feel that these issues are very important, requiring further evaluation and discussion. We appreciate the concerns expressed in their letter and we would like to respond to their specific remarks with the following comments. We wish to re-emphasis that the main thesis of our paper2 was, that there is a relationship between idiopathic interstitial pneumonia and absolute absorbed radiation dose to lung, for those patients receiving high single dose total body irradiation (TBI) as part of the preparative regimen prior to bone marrow transplantation. Our evidence was based on our own experience as well as a detailed literature review. In our opinion. this primary thesis needed to be emphasized since many papers discussing the problem of interstitial pneumonitis following TBI do not
I
1
1
I
1
I
estlmotes
$ $ 100 r S z
80-
S .2 S
60-
B 8
40-
s ‘b 2
20-
% S
0 1000
1100
Absolute
Registry
1200 dose Fig.
1300
to lung 1.
1400 (rod
)
1500
600
1700
1800
Correspondence controversial.‘,’ Vereecken cr a/.‘O reported a patient whose therapy failed (local recurrence and distant metastases) despite treatments with radical surgery and pre- and post-operative irradiation. The majority of the reported patients were treated by radical surgery.’ The use of chemotherapy (Cyclophosphamide)“’ has been reported with no prolongation of survival. We realize that it is difficult to draw definite conclusions from Just one reported case. However. our patient had a favorable prognosis and appears to be cured inspite of the limited surgery; this might indicate that a full course of irradiation after a debulking procedure could improve the outcome of this disease. WAGIH M. SHEHATA, M.D.. ABRAHAM A. KERR, M.D. HARRY H. Boss, M.D. THOMAS W. PANKE, M.D. RICHARD L. MEYER, M.D.
Department of Radiation Good Samaritan Hospital Cincinnati. OH 45220
F.F.R.
the adequacy of radiation have to be reconsidered.
to the internal
mammary
lymph nodes will
I.Fo%~RI) R. PROSIT!. M.D. Professor of Therapeutic Radiology Department of Therapeutic Radiology Yale University School of Medicine 333 Cedar Street Yew Haven. CT 06510
I. Strender, L.-E., Wallgren. .4., Arndt, J.. Arner, 0.. Bergstrom. J.. Blomstedt. B.. Granberg. P.-O.. Nilsson. B.. Raf. L... Silfversward. C.: Adjuvant radiotherapy in operable breast cancer: Correlation between dose and internal mammary nodes and propnosrs. Inr J. Radial. Oncol. Biol. Phvs 7: 1319 1325, 1981.
Oncology
I. Attah, E.B.. Powell. M.E.: Atypical stromal hyperplasia of the prostate gland. Am. J. Clin. Pafhol. 61: 324-321. 1971. 2. Chatterjee. A.C.: Leiomyosarcoma of the prostate. Brir. J. Urolog) 47: 577. 1975. 3. Guha, T.: Leiomyosarcoma of the prostate: A case report. Clin. Oncol. 5: 261-265, 1975. 4. Hamman. F.. Bischoff, W.: Histologic changes of a prostatic leiomyosarcoma, case report. Hely. Chir. Acfa 45: 297-300. 1978. 5. MacKenzie. A.R., Sharma. T.C., Whitmore, W.F.. Jr., Melamed. M.R.: Non-extirpative treatment of myosarcomas of the bladder and prostate. Cancer 28: 329-334. I97 I. 6. Mindich, R., Tykoy, H.. Littman. L.. Levowitz, B.S.: Leiomyosarcoma of rectum: report of case. Dis. Colon Recfum l8:233-236. 1975. 7. Mostoh, F.K., Price, E.B.: Tumors of fhe Male Genital Sy.yfem. Fascile 8. Washington, D.C. Armed Forces Institute of Pathology. 1973. pp. 253-356. 8. Schmidt, J.D., Welch, M.J.. Jr.: Sarcoma of the prostate. C‘ancer 37: 1908-1912, 1976. 9. Stallwood, G.. Davidson, J.W.: Leiomyosarcoma of the rectum and prostate. Can. J. Surg. 20:446-9, 1977. IO. Vereecken, R.L.. Lauweryns, J., Droohmano, A., Yan Dijck. M.: Leiomyosarcoma of the prostate: A case report. Europ. J. Ural. 3: 370-2, 1977. I I. Weismann, M.J., Gaeta. J.F., Albert, D.J.: Childhood urogenital sarcoma. J. Surg. Oncol. 4: lO9- I 16, 1972.
REBUTTAL: RELAPSE-FREE SURVIVAL IS NOT A GOOD MEASUREMENT OF SURVIVAL IN BREAST CANCER To the Edifor: Dr. Prosnit supposes that the benetit in relapse-free survival given to the patients of our trial’ by preoperative or postoperative radiotherapy eventually will improve their long run survival. It is true that most patients who have a relapse of breast cancer will die from distant metastases. Local and regional recurrences will often be detected earlier than distant metastases. but are generally only indicators of a high risk to develop distant metastases rather than the cause of them. It should be observed that the main reason for the better relapse-free survival of the patients treated with radiotherapy was their lovver rate of local and regional recurrences. About one-third of the patients who have been treated only surgically and who have had local recurrences are still without any sign of distant disease and the rates of distant metastases of the three treatment groups are much more similar than the rates of all relapses. The belief that a significantly improved relapse-free survival evcntually will improve the longevity. is dangerous since it may lead to a premature acceptance of new treatment modalities. It has recently led to the general acceptance of adjuvant cytotoxic chemotherapy as the routine treatment of breast cancer with nodal involvement. As after radiotherapy, long term survival data show that the survival benefit is much smaller than could have been expected from the benefit in recurrence-free survival. l..\Rb-ERIh
STR~~IX.R.
M.D.
.4KUI WAI I(;Rt h. M.D Radiumhemmet Karolinska Hospital S 104 01 Stockholm
CRITIQUE OF “ADJUVANT RADIOTHERAPY IN OPERABLE BREAST CANCER: CORRELATION BETWEEN DOSE AND INTERNAL MAMMARY NODES AND PROGNOSES” To fhe Editor: The data presented by Strender er al.’ for the Stockholm group on the results of adjuvant radiotherapy in operable breast cancer are of great interest to the radiotherapy community. In this paper, the authors show a statistical improvement in survival for the group of patients receiving preoperative radiation followed by mastectomy, but not for those who were treated with radiotherapy following mastectomy. A rather elaborate explanation is then given, suggesting that the post-mastectomy patients may have received inadequate radiation to the internal mammary lymph nodes. However. both pre-operative and post-operative irradiation resulted in a statistically significant benefit in relapse-free survival. Since virtually all patients who have an initial relapse of their breast cancer following mastectomy will eventually die of metastatic disease, a significant improvement in relapse-free survival is bound to be reflected in the long run by significant improvement in the death rate due to breast cancer as well. Therefore, the premise that only preoperative radiotherapy improves survival will not be the case, given a long enough follow-up, if the relapse-free survival data are correct. The subseauent conclusions about
Strender. L.-E.. Wallgren. A., Arndt. J.. Amer. 0.. Bergstrom, J.. Bjonstedt, B.. Granderg. P.-O., Nitsson. B., Raf. L.. Silfversward. C.: Adjuvant radiotherapy in operable breast cancer: Correlation between dose in internal mammary nodes and prognosis. In, J Radial. Oncol. Biol. Phvs. 7:1319- 1325. 19x1.
INTERSTITIAL
PNEUMONITIS: DOSE-RATE DOSE OF RADIATION
VS TOTAL
To fhe Edifor: Interstitial pneumonitis (IPn). whether idiopathic or virus-associated, is a frequent and usually lethal complication of allogeneic bone marrow transplantation. A recent report by Keane et al.* is valuable in that it calls attention to the possibility that the total radiation dose to lung may correlate directly with fatal idiopathic IPn. Several problems with their data, however, prompted the following comments. Our chief concern has to do with the probit regression analysis which they presented in their Fig. I. The UCLA data. which they showed in
1816
Radiation
Oncology
0 Biology
0 Physics
October
1982, Volume
8, Number
IO
Table 4, were excluded from the probit analysis. A review of the cited UCLA report’ disclosed, and discussion with Dr. Robert P. Gale of UCLA verified, that only 8% (3/39) of their leukemia patients died of idiopathic IPn, although they received a mean absorbed lung dose of Il.7 Gy. Had the UCLA data been included in the probit analysis there would be a different regression line between I I .5 and 12 Gy. It seems unlikely to us, on biological grounds, that the incidence of fatal idiopathic IPn would vary between 8% (UCLA) and 50% (Toronto) in such a narrow (50 cGy) “window”. In a recent report from the International Bone Marrow Transplant Registry, (IMBTR),’ data from 176 patients with acute leukemia treated with allogeneic bone marrow transplantation were entered into multiple logistic function analyses to determine whether there were prognostic factors associated with development of IPn. We found that radiation at a dose-rate 2 5.7 cGy/min was associated with a significantly lower (P < .OOOl) incidence of IPn (6%. 4/69) in comparison with higher (6-30 cGy/min) dose-rates (30%, 32/107), irrespective of the total dose of rota1 body radiation (range 8-14
European Communities, March of Dimes Birth Defects Foundation, Ambrose Monell Foundation, Mount Sinai Medical Center (Milwaukee), Samuel Roberts Noble Foundation, Queen Wilhelmina Fund, Sandoz Limited, Swiss Cancer League and the Upjohn Company, and was conducted under contract NOI-AI-02648 from the National Institute of Allergy and Infectious Diseases and the National Cancer Institute. USDHHS.
GY). If one takes the results of both the IBMTR and Keane analyses into account, one interpretation might be that when the total absorbed lung dose was less than approximately 8 Gy, dose-rate probably did not have an effect; when the total dose was at higher levels, dose-rate probably did make a difference. Unfortunately, the IBMTR data base at the present time is inadequate to test this hypothesis. We also are concerned that they analyzed only fatal cases of IPn rather than total incidence, and they divided the fatal cases into idiopathic and infectious. This fragmentation of their data may not be meaningful. For example, they indicated (Table 4) that the Base1 bone marrow transplant team reported that five of their six cases of fatal IPn were idiopathic, whereas the Seattle team reported that only six of their 22 cases of fatal IPn were idiopathic (X2 = 6.21, P = ,013). This apparent difference in incidence of fatal infectious versus fatal idiopathic IPn could have been related to differences in diagnostic sophistication in the two centers, differences in the virulence of North American versus European cytomegaloviruses, etc. The analyses reported by Keane et a/.* and by the IBMTR’ provide strong evidence that radiation of the lung plays an important role in the pathogenesis of some cases of IPn. Additional studies are required to define the role of total dose and dose-rate of radiation on the development of IPn. More complete understanding of these factors can be expected to lead to changes in radiation protocols with reduced morbidity and higher survival rates for patients treated with bone marrow transplantation. Acknow1edgemenf.s: The research was supported by grants from the Burroughs-Wellcome Fund, Elizabeth Elser Doolittle Charitable Trusts, Carl and Elisabeth Eberbach Foundation, Commission of the
I.
.p 7
1
es
gL
I
1
ProbIt
regresslon
m.
~0
1
error
MORTIMER M. BORTIN, M.D. International Bone Marrow Transplant Mount Sinai Medical Center P.O. Box 342 Milwaukee, WI 53201 ALFRED A. RIMM, PH.D. Section of Biostatistics/Epidemiology The Medical College of Wisconsin Milwaukee, WI 53226
Bortin, M.M., Gale, R.P., Kay, H.E.M., Rimm, A.A.: Factors associated with interstitial pneumonitis following bone marrow Lancer 1: 437-439, 1982. transplantation for acute leukemia. 2. Keane, T.J., Van Dyk, J., Rider, W.D.: Idiopathic interstital pneumonia following following bone marrow transplantation: the relationship with total body irradiation, Inr. J. Radial. Oncol. Biol. Phys. 7: 136551370, 1981. 3. Winston, D.J., Gale, R.P., Meyer, D.V., Young, L.D.: Infectious complications of human bone marrow transplantation. Medicine 48:
l-32,
1979.
REBUTTAL
To rhe Edifoc Bortin and Rimm raise several issues concerning pulmonary complications following bone marrow transplantation. We feel that these issues are very important, requiring further evaluation and discussion. We appreciate the concerns expressed in their letter and we would like to respond to their specific remarks with the following comments. We wish to re-emphasis that the main thesis of our paper2 was, that there is a relationship between idiopathic interstitial pneumonia and absolute absorbed radiation dose to lung, for those patients receiving high single dose total body irradiation (TBI) as part of the preparative regimen prior to bone marrow transplantation. Our evidence was based on our own experience as well as a detailed literature review. In our opinion. this primary thesis needed to be emphasized since many papers discussing the problem of interstitial pneumonitis following TBI do not
I
1
1
I
1
I
estlmotes
$ $ 100 r S z
80-
S .2 S
60-
B 8
40-
s ‘b 2
20-
% S
0 1000
1100
Absolute
Registry
1200 dose Fig.
1300
to lung 1.
1400 (rod
)
1500
600
1700
1800