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Rebuttal
292
Radiation Oncology 0 Biology 0 Physics
and maximal preservation of soft tissue tolerance is clearly a desired objective. Dose rates in the range of 180 to 200 rad per day will best accomplish soft tissue preservation in the brain, as elsewhere. in most patients with metastatic cancer. Certainly the physician must accommodate patients with extensive dissemination in a manner which does not use up an exorbitant amount of their probable remaining lifetime in obtaining a probable duration of CNS control which is not needed for their expected lifetime. I do not. however, think that one can say generally that the short treatment/large fraction schedules studied in this paper are justified in routine clinical practice based on data presented in this paper. The conclusion which one should reach based on the number of patients dying of CNS disease is quite to the contrary. R. ARNOLD SMITH. M.D. Department of Radiation Therapy Mississippi Baptist Med. Center I225 North State Street Jackson, Mississippi 39201 I. Borgelt, B, Gelber, R., Kramer, S.. Brady, L.W., Chang. C.H., Davis, L.W. Perez, C.A., Hendrickson, F.R.: The palliation of brain metastasa: final results of the first two studies by the Radiation Therapy Oncology Group. Inr. J. Radial. Oncol. Biol. Phys. 6: 1-9. 1980.
February 198 1, Volume 7, Number 2
curve. Figure 4 of the communication cited and interpreted by the investigators as the initial slope of the radiation response of human epithelial cells, may represent. simply, the terminal slope, at high doses, of a resistant fraction (4 - 490 z I50 rad, the authors’derived value) of cells. What actually is observed in the study reported is not the responseto a small dose but the response to a high cumulative dose and the response.itself, is not cehular survival per cm* but colonies observed per cm* and the figure, Figure 4, might more aptly have been labeled as such. The authors are correct in indicating that the consequencesof the repair of radiation injury between fractional doses, the influence of redistribution and the efkct of repopulation cannot specifically bc evaluated. What is certain. only, is that the denuding effect observed (the authors’ Patient A) lies somewhere between the greater denuding effect that would have been observed had the total doses, 6300, 6850, and 7150 rad. been delivered as single large dosesrather than as closely spaced small doses and the absence of a denuding effect when similar total doses were administered as widely spaced small doses in the same patient, Patient A. With such an endpoint,-the denuding effect,-at such high doses it seems tenable only to infer that the absence of a denuding effect in Patient B is the consequence of the difference of the fractionation pattern, -Patient A: 250+ 150+ 150 and Patient B: 150+ 150+150+150 rad per day .-and of such other and unaccountable differences as are due to subject, Patient A compared with Patient B. differences.
REBUTTAL To the Editor: In his recent letter to the editor, Dr. Smith expressed concern regarding our conclusion that shorter treatment regimens are as efficacious as longer, higher dose regimens in palliating patients with brain metastases. I do not wish to reiterate the data which was clearly presented in the paper. However, when one conducts a controlled study which prospectively compares two or more treatment regimens and finds the results to be insignificantly different, one can only conclude that ail treatments have comparable efficacy. This is not to say that they represent the most efficacious treatments for that particular problem. Certainly, when 30 to 50% of patients irradiated for brain metastases eventually die of intracranial disease, there is room for improvement. This is a situation however, where higher radiation doses do not appear to be the answer. In patients with favorable survival prognosis,the one-year neurologic function control rates range from 10% to 25% depending upon the primary site (Gelber et al.. submitted to Cancer). Again, 30 to 50% of these patients die without evidence of neurologic progression and the protracted higher dose regimens are no more effective than the shorter time-dose fractionation schemes. I agree with Dr. Smith that the issue of retreating patients with recurrent brain me&stases is an important one with respect to both efficacy and potential complications. Unfortunately, the scope of the paper did not permit discussion of all the information gathered in the two studies. As was indicated in the discussion, an analysis of retreated patients is being undertaken. BRUCE B. B~RGELT. M.D., PH.D. Assist. Professor of Radiotherapy Department of Radiotherapy The University of Texas-System Cancer Center M.D. Anderson Hospital and Tumor institute 6723 Bertner Avenue Houston. TX 77030
CRITIQUE OF “DOSE-SURVIVAL RELATIONSHIP FOR EPITHELIAL CELLS OF HUMAN SKIN AFTER MULTIFRACTION IRRADIATION: EVALUATION BY A QUANTITATIVE METHOD /IY FIFO,” G. ARCANGELI et al., In& J. Radiat. Oncol. Biol. Phys. 6:841-844,1980
To the Editor: In the communication by Arcangeli er al.’ the authors have made some interesting speculations. However. there is another interpretation that may be put on the findings reported: their derived
J. ROBERT ANDREWS Department of Radiation Oncology Georgetown University Hospital 3800 Reservoir Road, NW Washington, DC 20007, USA I. Arcangeii. G., Mauro, F., Newi. C., Withers. H.R.: Dose-survival relationship for epithelial ceils of human skin after multifraction irradiation: Evaluation by a quantitative method in viva. Inr. J. 1980. Radial. Oncol. Biol. Phys. 6: 84 I-844,
REBU’ITAL To rhc Editor: Dr. Andrew’s letter draws attention to two points worth further explanation. Firstly, the nodules were what was observed, but it is unlikely that hypothesesother than a single cell origin could be consistant with random survival and the survival curves parameters measured.’ The second point is that the & value measured may have been the terminal slope of a radioresistant subpopulation surviving high cumulative doses. While it is possible that there had been progressive synchronization of surviving cells during the fractionated dose regimens, the responseto the final dose of 250 rad could still be defined by the “initial” slope of the survival curve for that subpopulation, the only requirement being that sublethal injury had been repaired during the preceeding fractionation interval.
GIORGIO ARCANGELI, M.D. CARLO NERVI,M.D. lstituto Medico e di Ricerca Scientifica Via Bodio 58,00191 Rome. ltalv FRANCESCOMAURO, D.S& CSN Casaccia CNEN. Rome. ltalv H.R. WI~HERS,.M.D. Dept. of Radiation Oncology University of California Los Angeles. CA 90024, U.S.A. I. Withers. H.R.: The dose-survival relationship for irradiation of epithelial cells of mouse skin. Br. J. Radio/. 40: 187-l 94. 1967.
Radiation Oncology 0 Biology 0 Physics
and maximal preservation of soft tissue tolerance is clearly a desired objective. Dose rates in the range of 180 to 200 rad per day will best accomplish soft tissue preservation in the brain, as elsewhere. in most patients with metastatic cancer. Certainly the physician must accommodate patients with extensive dissemination in a manner which does not use up an exorbitant amount of their probable remaining lifetime in obtaining a probable duration of CNS control which is not needed for their expected lifetime. I do not. however, think that one can say generally that the short treatment/large fraction schedules studied in this paper are justified in routine clinical practice based on data presented in this paper. The conclusion which one should reach based on the number of patients dying of CNS disease is quite to the contrary. R. ARNOLD SMITH. M.D. Department of Radiation Therapy Mississippi Baptist Med. Center I225 North State Street Jackson, Mississippi 39201 I. Borgelt, B, Gelber, R., Kramer, S.. Brady, L.W., Chang. C.H., Davis, L.W. Perez, C.A., Hendrickson, F.R.: The palliation of brain metastasa: final results of the first two studies by the Radiation Therapy Oncology Group. Inr. J. Radial. Oncol. Biol. Phys. 6: 1-9. 1980.
February 198 1, Volume 7, Number 2
curve. Figure 4 of the communication cited and interpreted by the investigators as the initial slope of the radiation response of human epithelial cells, may represent. simply, the terminal slope, at high doses, of a resistant fraction (4 - 490 z I50 rad, the authors’derived value) of cells. What actually is observed in the study reported is not the responseto a small dose but the response to a high cumulative dose and the response.itself, is not cehular survival per cm* but colonies observed per cm* and the figure, Figure 4, might more aptly have been labeled as such. The authors are correct in indicating that the consequencesof the repair of radiation injury between fractional doses, the influence of redistribution and the efkct of repopulation cannot specifically bc evaluated. What is certain. only, is that the denuding effect observed (the authors’ Patient A) lies somewhere between the greater denuding effect that would have been observed had the total doses, 6300, 6850, and 7150 rad. been delivered as single large dosesrather than as closely spaced small doses and the absence of a denuding effect when similar total doses were administered as widely spaced small doses in the same patient, Patient A. With such an endpoint,-the denuding effect,-at such high doses it seems tenable only to infer that the absence of a denuding effect in Patient B is the consequence of the difference of the fractionation pattern, -Patient A: 250+ 150+ 150 and Patient B: 150+ 150+150+150 rad per day .-and of such other and unaccountable differences as are due to subject, Patient A compared with Patient B. differences.
REBUTTAL To the Editor: In his recent letter to the editor, Dr. Smith expressed concern regarding our conclusion that shorter treatment regimens are as efficacious as longer, higher dose regimens in palliating patients with brain metastases. I do not wish to reiterate the data which was clearly presented in the paper. However, when one conducts a controlled study which prospectively compares two or more treatment regimens and finds the results to be insignificantly different, one can only conclude that ail treatments have comparable efficacy. This is not to say that they represent the most efficacious treatments for that particular problem. Certainly, when 30 to 50% of patients irradiated for brain metastases eventually die of intracranial disease, there is room for improvement. This is a situation however, where higher radiation doses do not appear to be the answer. In patients with favorable survival prognosis,the one-year neurologic function control rates range from 10% to 25% depending upon the primary site (Gelber et al.. submitted to Cancer). Again, 30 to 50% of these patients die without evidence of neurologic progression and the protracted higher dose regimens are no more effective than the shorter time-dose fractionation schemes. I agree with Dr. Smith that the issue of retreating patients with recurrent brain me&stases is an important one with respect to both efficacy and potential complications. Unfortunately, the scope of the paper did not permit discussion of all the information gathered in the two studies. As was indicated in the discussion, an analysis of retreated patients is being undertaken. BRUCE B. B~RGELT. M.D., PH.D. Assist. Professor of Radiotherapy Department of Radiotherapy The University of Texas-System Cancer Center M.D. Anderson Hospital and Tumor institute 6723 Bertner Avenue Houston. TX 77030
CRITIQUE OF “DOSE-SURVIVAL RELATIONSHIP FOR EPITHELIAL CELLS OF HUMAN SKIN AFTER MULTIFRACTION IRRADIATION: EVALUATION BY A QUANTITATIVE METHOD /IY FIFO,” G. ARCANGELI et al., In& J. Radiat. Oncol. Biol. Phys. 6:841-844,1980
To the Editor: In the communication by Arcangeli er al.’ the authors have made some interesting speculations. However. there is another interpretation that may be put on the findings reported: their derived
J. ROBERT ANDREWS Department of Radiation Oncology Georgetown University Hospital 3800 Reservoir Road, NW Washington, DC 20007, USA I. Arcangeii. G., Mauro, F., Newi. C., Withers. H.R.: Dose-survival relationship for epithelial ceils of human skin after multifraction irradiation: Evaluation by a quantitative method in viva. Inr. J. 1980. Radial. Oncol. Biol. Phys. 6: 84 I-844,
REBU’ITAL To rhc Editor: Dr. Andrew’s letter draws attention to two points worth further explanation. Firstly, the nodules were what was observed, but it is unlikely that hypothesesother than a single cell origin could be consistant with random survival and the survival curves parameters measured.’ The second point is that the & value measured may have been the terminal slope of a radioresistant subpopulation surviving high cumulative doses. While it is possible that there had been progressive synchronization of surviving cells during the fractionated dose regimens, the responseto the final dose of 250 rad could still be defined by the “initial” slope of the survival curve for that subpopulation, the only requirement being that sublethal injury had been repaired during the preceeding fractionation interval.
GIORGIO ARCANGELI, M.D. CARLO NERVI,M.D. lstituto Medico e di Ricerca Scientifica Via Bodio 58,00191 Rome. ltalv FRANCESCOMAURO, D.S& CSN Casaccia CNEN. Rome. ltalv H.R. WI~HERS,.M.D. Dept. of Radiation Oncology University of California Los Angeles. CA 90024, U.S.A. I. Withers. H.R.: The dose-survival relationship for irradiation of epithelial cells of mouse skin. Br. J. Radio/. 40: 187-l 94. 1967.