- Email: [email protected]
Prophets that don't predict
I. J. Radiation
212
Oncology
0 Biology 0 Physics
therapy and so a discordance between the surfactant assay and pulmonary complications will be amplified in the clinical situation where single radiation doses are rarely given. We feel that the radiation-induced changes in alveolar surfactant represents an intriguing observation and serves to expand our understanding of phospholipid regulation in this tissue. Nevertheless, it appears to be of very doubtful significance in the generation of true radiation toxicity. We would therefore conclude that measuring broncho-alveolar Iavage surfactant in patients, as recommended by Rubin and associates, will not provide a predictive marker for the clinical syndrome of radiation pneumonitis. JULIAN D. DOWN, PH.D. Joint Center for Radiation Harvard Medical School 50 Binney Street Boston, MA 02 115
Therapy
PETER G. COULTAS, PH.D. STANLEY B. FIELD, PH.D. MRC Cyclotron Unit Hammersmith Hospital Ducane Road London W 12 OHS UK 1. Ahier, R.G., Anderson, R.L., Coultas, P.G.: Response of mouse lung to irradiation. 1. Alterations in alveolar surfactant after neutrons and X-rays. Radiother. Oncol. 3: 6 l-68, 1985. J.F., Parkins, C.S., Denekamp, J., Terry, N.H.A., 2. Fowler, Maughan, R.L., Travis, E.L.: Early and late effects in mouse lung and rectum. ht. J. Radiat. Oncol. Biol. Phvs. 8: 2089-2093. 1982. K.D., Chistensen; G.M., Parker, R.G., 3. Geraci, J.P., Jackson, Thrower, P.D., Fox, M.: Single dose fast neutron RBE for pulmonary and esophageal damage in mice. Radiology 120:701-703, 1976. Y., Field, S.B.: Damage to mouse lung 4. Hornsey, S., Kutsutani, with fractionated neutron and X-rays. Radiology 116:171-174, 1975. of RBE 5. Phillips, T.L., Barchall, H.H., Goldberg, E.,: Comparison valves of I5 MeV neutrons for damage to an experimental tumor and some normal tissue. Eur. J. Can& 10:287-292, 1974. 6. Rubin. P.: The Franz Buschke lecture: Late effects of chemotherapy and radiation therapy: A new hypothesis. ht. J. Radiat. Oncol. Biol. Phys. 10:5-34, 1984. J.N., Siemann, D.W., Shapiro, D.L., Van 7. Rubin, P., Finkelstein, Houtte, P., Penney, D.P.: Predictive biochemical assays for late radiation effects. Int. J. Radiat. Oncol. Biol. Phys. 12: 469-476,
1986. J.N., Penney, D.P.: The 8. Rubin, P., Shapiro, D.L., Finklestein, early release of surfactant following lung irradiation of alveolar type II cells. Int. J. Radiat. Oncol. Biol. Phys. 6: 75-77, 1980. 9. Rubin, P., Siemann, D.W., Shapiro, D.L., Finkelstein, J.N., Penney, D.P.: Surfactant release as an early measure ofradiation pneumonitis. Int. J. Radiat. Oncol. Biol. Phys. 9: 1669-1673, 1983. J.N., Penney, D.P., Siemann, D.W., 10. Shapiro, D.L., Finkelstein, Rubin, P.: Sequential effects of irradiation on the pulmonary surfactant system. Int. J. Radiat. Oncol. Biol. Phys. 8: 879-882, 1982. PROPHETS
THAT
DON’T
PREDICT
To the Editor: We share some of the concerns expressed by Drs. Down, Coultas and Field’ as to the reliability of alveolar surfactant release as a predictor for later pneumonitis. With the development of a radioimmunoassay specific for the apoprotein of surfactant, the broncho-alveolar lavage (BAL) assays have become more reproducible and accurate than with the original phospholipid assays based upon detection of the disaturated phosphatidylcholine. Our laboratory evidence continues to show a strong correlation with surfactant release at 7 and/ or 28 days in vivo with later pulmonary lethality at 4 months. As additional rabbit data become available, the results are more consistent with the mouse dose response curves in which the surfactant threshold more closely precedes the lethality. The variability in alveolar surfactant level is due to a number of factors and may not be due to an excessive release of surfactant per se. For example, the macrophage which is responsible for phagocytosing surfactant is dramatically reduced in number after irradiation and the level of alveolar surfactant is inversely related to the alveolar macrophage in our rabbit studies. Although the genetic diversity of human populations is sited as a negative factor for reducing reliability and increasing variability, this would apply to any laboratory
January
1988, Volume
14, Number
1
animal model extrapolated to man and would invalidate even the excellent experimentation of criticizers of our work. Surfactant release is physiologic and there are many agents that are not cytoxic that can induce Type II cells to release surfactant. Surfactant secretion is controlled by a beta-adrenergic mechanism and such agents asterbutaline can evoke this response. We agree that the mechanism for surfactant release may be separate from the mechanism for alveolar type II cell death. We have found no indication of a rapid cell death after irradiation, otherwise surfactant release is not a predictor, but an indicator of immediate alveolar type II cell pulmonary lethality which clearly does not occur in our ultrastructural studies. We do not agree that the two mechanisms (surfactant release and cell death) need to be the same for surfactant to be a useful predictor. In an analogous fashion to weather prediction, the usefulness of satellite photographs of cloud movements, barometric pressure, jet stream behavior, and wind direction and strength, allow for reasonably accurate weather forecasts, but they do not provide a mechanistic basis for weather behavior. We agree that “radiation-induced change in alveolar surfactant is an intriguing observation and serves to expand our observation of phospholipid regulation. .“I We believe that we will be able to demonstrate that a dramatic decrease in alveolar Type II cell numbers occurs prior to the onset of lethal pneumonitis with the development of quantitative assays using enzymatic washing to lavage out Type II cells and cell sorting and elutriation techniques. Furthermore, we are cautious in its applicability to man, but we are proceeding with protocols since whole lung irradiation is occurring with increasing frequency as a by-product ofTB1 and bone marrow transplant and the increasing use of hemibody (HBI) irradiation for palliation of metastases. We respect the doubts expressed by Down, Coultas, and Field as to measuring surfactant levels as predictors, but we realize the radiobiological proof of the pudding is in the clinical eating-not in the words of radiobiologic prophets who say that a potential biochemical predictor will not predict. PHILIP RUBIN* JACOB N. FINKELSTEINt * Cancer Center and Department of Radiation Oncology t Department of Pediatrics and Division of Toxicology University of Rochester School of Medicine and Dentistry Rochester, NY 14642 1. Down, J.D., Cot&as, P.G., Field, S.B.: Is surfactant release a reliable predictor of radiation pneumonitis? Int. J. Radiat. Oncol. Biol. Phys. 14: 000-000, 1988. REBUTTAL
To the Editor: Our experience with accelerated and hyperfractionated radiotherapy in advanced head and neck tumors started in 1976 and lasted until 198 1, when no more patients were treated in this way. In 1978-1979, the study was prolonged only because the acute reactions that were noted after the first schedule of irradiation were reduced to an acceptable rate. At this time, no data on late complications were available.* By definition, these injuries need many years to occur and happen progressively. In our series, more than one third of severe complications were noted 30 months after the full completion of radiotherapy. Therefore, any present study using unusual fractionation schemes and daily doses larger than 2 Gy requires a large follow-up to establish that the late complication rate will not exceed the rate observed in conventional series. Even though we agree that the short interval between two fractions in our series isprobabIy mainly responsible for the severity of late injuries. it is still debatable. as mentioned bv Dr. C. C. Wang. that a 4-hour interval is sufficient to allow for complete repair of sub-lethal damages, especially in late reacting tissues. Moreover, sub-lethal damages are not the only parameter which modifies the response of tissues to multiple daily fractionation.’ Therefore, in spite of considerable cooperative efforts of radiobiologists and radiotherapists, the inaccuracy ofanticipating some important side effects may preclude the strict clinical application of fundamental radiobiological findings. TAN D. NGUYEN, M.D. Department of Radiotherapy Institut Jean-Godinot, BP 17 1 5 1100 Reims, France 1. Kotalik,
J.F.:
Multiple
daily
fractions
in radiotherapy.
Cancer
Treat. Rev. 8: 127-146, 1981. 2. Nguyen, T.D., Panis, X., Legros, M., Froissart, D.: Hyperfractionated radiotherapy in advanced squamous cell carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 9: 393-395, 1983.
212
Oncology
0 Biology 0 Physics
therapy and so a discordance between the surfactant assay and pulmonary complications will be amplified in the clinical situation where single radiation doses are rarely given. We feel that the radiation-induced changes in alveolar surfactant represents an intriguing observation and serves to expand our understanding of phospholipid regulation in this tissue. Nevertheless, it appears to be of very doubtful significance in the generation of true radiation toxicity. We would therefore conclude that measuring broncho-alveolar Iavage surfactant in patients, as recommended by Rubin and associates, will not provide a predictive marker for the clinical syndrome of radiation pneumonitis. JULIAN D. DOWN, PH.D. Joint Center for Radiation Harvard Medical School 50 Binney Street Boston, MA 02 115
Therapy
PETER G. COULTAS, PH.D. STANLEY B. FIELD, PH.D. MRC Cyclotron Unit Hammersmith Hospital Ducane Road London W 12 OHS UK 1. Ahier, R.G., Anderson, R.L., Coultas, P.G.: Response of mouse lung to irradiation. 1. Alterations in alveolar surfactant after neutrons and X-rays. Radiother. Oncol. 3: 6 l-68, 1985. J.F., Parkins, C.S., Denekamp, J., Terry, N.H.A., 2. Fowler, Maughan, R.L., Travis, E.L.: Early and late effects in mouse lung and rectum. ht. J. Radiat. Oncol. Biol. Phvs. 8: 2089-2093. 1982. K.D., Chistensen; G.M., Parker, R.G., 3. Geraci, J.P., Jackson, Thrower, P.D., Fox, M.: Single dose fast neutron RBE for pulmonary and esophageal damage in mice. Radiology 120:701-703, 1976. Y., Field, S.B.: Damage to mouse lung 4. Hornsey, S., Kutsutani, with fractionated neutron and X-rays. Radiology 116:171-174, 1975. of RBE 5. Phillips, T.L., Barchall, H.H., Goldberg, E.,: Comparison valves of I5 MeV neutrons for damage to an experimental tumor and some normal tissue. Eur. J. Can& 10:287-292, 1974. 6. Rubin. P.: The Franz Buschke lecture: Late effects of chemotherapy and radiation therapy: A new hypothesis. ht. J. Radiat. Oncol. Biol. Phys. 10:5-34, 1984. J.N., Siemann, D.W., Shapiro, D.L., Van 7. Rubin, P., Finkelstein, Houtte, P., Penney, D.P.: Predictive biochemical assays for late radiation effects. Int. J. Radiat. Oncol. Biol. Phys. 12: 469-476,
1986. J.N., Penney, D.P.: The 8. Rubin, P., Shapiro, D.L., Finklestein, early release of surfactant following lung irradiation of alveolar type II cells. Int. J. Radiat. Oncol. Biol. Phys. 6: 75-77, 1980. 9. Rubin, P., Siemann, D.W., Shapiro, D.L., Finkelstein, J.N., Penney, D.P.: Surfactant release as an early measure ofradiation pneumonitis. Int. J. Radiat. Oncol. Biol. Phys. 9: 1669-1673, 1983. J.N., Penney, D.P., Siemann, D.W., 10. Shapiro, D.L., Finkelstein, Rubin, P.: Sequential effects of irradiation on the pulmonary surfactant system. Int. J. Radiat. Oncol. Biol. Phys. 8: 879-882, 1982. PROPHETS
THAT
DON’T
PREDICT
To the Editor: We share some of the concerns expressed by Drs. Down, Coultas and Field’ as to the reliability of alveolar surfactant release as a predictor for later pneumonitis. With the development of a radioimmunoassay specific for the apoprotein of surfactant, the broncho-alveolar lavage (BAL) assays have become more reproducible and accurate than with the original phospholipid assays based upon detection of the disaturated phosphatidylcholine. Our laboratory evidence continues to show a strong correlation with surfactant release at 7 and/ or 28 days in vivo with later pulmonary lethality at 4 months. As additional rabbit data become available, the results are more consistent with the mouse dose response curves in which the surfactant threshold more closely precedes the lethality. The variability in alveolar surfactant level is due to a number of factors and may not be due to an excessive release of surfactant per se. For example, the macrophage which is responsible for phagocytosing surfactant is dramatically reduced in number after irradiation and the level of alveolar surfactant is inversely related to the alveolar macrophage in our rabbit studies. Although the genetic diversity of human populations is sited as a negative factor for reducing reliability and increasing variability, this would apply to any laboratory
January
1988, Volume
14, Number
1
animal model extrapolated to man and would invalidate even the excellent experimentation of criticizers of our work. Surfactant release is physiologic and there are many agents that are not cytoxic that can induce Type II cells to release surfactant. Surfactant secretion is controlled by a beta-adrenergic mechanism and such agents asterbutaline can evoke this response. We agree that the mechanism for surfactant release may be separate from the mechanism for alveolar type II cell death. We have found no indication of a rapid cell death after irradiation, otherwise surfactant release is not a predictor, but an indicator of immediate alveolar type II cell pulmonary lethality which clearly does not occur in our ultrastructural studies. We do not agree that the two mechanisms (surfactant release and cell death) need to be the same for surfactant to be a useful predictor. In an analogous fashion to weather prediction, the usefulness of satellite photographs of cloud movements, barometric pressure, jet stream behavior, and wind direction and strength, allow for reasonably accurate weather forecasts, but they do not provide a mechanistic basis for weather behavior. We agree that “radiation-induced change in alveolar surfactant is an intriguing observation and serves to expand our observation of phospholipid regulation. .“I We believe that we will be able to demonstrate that a dramatic decrease in alveolar Type II cell numbers occurs prior to the onset of lethal pneumonitis with the development of quantitative assays using enzymatic washing to lavage out Type II cells and cell sorting and elutriation techniques. Furthermore, we are cautious in its applicability to man, but we are proceeding with protocols since whole lung irradiation is occurring with increasing frequency as a by-product ofTB1 and bone marrow transplant and the increasing use of hemibody (HBI) irradiation for palliation of metastases. We respect the doubts expressed by Down, Coultas, and Field as to measuring surfactant levels as predictors, but we realize the radiobiological proof of the pudding is in the clinical eating-not in the words of radiobiologic prophets who say that a potential biochemical predictor will not predict. PHILIP RUBIN* JACOB N. FINKELSTEINt * Cancer Center and Department of Radiation Oncology t Department of Pediatrics and Division of Toxicology University of Rochester School of Medicine and Dentistry Rochester, NY 14642 1. Down, J.D., Cot&as, P.G., Field, S.B.: Is surfactant release a reliable predictor of radiation pneumonitis? Int. J. Radiat. Oncol. Biol. Phys. 14: 000-000, 1988. REBUTTAL
To the Editor: Our experience with accelerated and hyperfractionated radiotherapy in advanced head and neck tumors started in 1976 and lasted until 198 1, when no more patients were treated in this way. In 1978-1979, the study was prolonged only because the acute reactions that were noted after the first schedule of irradiation were reduced to an acceptable rate. At this time, no data on late complications were available.* By definition, these injuries need many years to occur and happen progressively. In our series, more than one third of severe complications were noted 30 months after the full completion of radiotherapy. Therefore, any present study using unusual fractionation schemes and daily doses larger than 2 Gy requires a large follow-up to establish that the late complication rate will not exceed the rate observed in conventional series. Even though we agree that the short interval between two fractions in our series isprobabIy mainly responsible for the severity of late injuries. it is still debatable. as mentioned bv Dr. C. C. Wang. that a 4-hour interval is sufficient to allow for complete repair of sub-lethal damages, especially in late reacting tissues. Moreover, sub-lethal damages are not the only parameter which modifies the response of tissues to multiple daily fractionation.’ Therefore, in spite of considerable cooperative efforts of radiobiologists and radiotherapists, the inaccuracy ofanticipating some important side effects may preclude the strict clinical application of fundamental radiobiological findings. TAN D. NGUYEN, M.D. Department of Radiotherapy Institut Jean-Godinot, BP 17 1 5 1100 Reims, France 1. Kotalik,
J.F.:
Multiple
daily
fractions
in radiotherapy.
Cancer
Treat. Rev. 8: 127-146, 1981. 2. Nguyen, T.D., Panis, X., Legros, M., Froissart, D.: Hyperfractionated radiotherapy in advanced squamous cell carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 9: 393-395, 1983.