- Email: [email protected]
In Reply to Dr. Hartley
Int. J. Radiation Oncology Biol. Phys., Vol. 75, No. 1, pp. 315–319, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
LETTERS TO THE EDITOR MODELING THE CONTRIBUTION OF SYNCHRONOUS CHEMOTHERAPY TO THE RATE OF GRADE 3 AND 4 MUCOSITIS IN LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
4. Bentzen S, Ruifrok A, Thames H. Repair capacity and kinetics for human mucosa and epithelial tumors in the head and neck: Clinical data on the effect of changing the interval between multiple fractions per day in radiotherapy. Radiother Oncol 1996;38:89–101. 5. Fu K, Pajak T, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48: 7–16. 6. Overgaard J, Hansen H, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial. Lancet 2003;362:933–940. 7. Poulsen MG, Denham JW, Peters LJ, et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: A Trans-Tasman Radiation Oncology Group Study. Radiother Oncol 2001;60:113. 8. Bentzen S, Saunders M, Dische S, et al. Radiotherapy-related early morbidity in head and neck cancer: Quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 2001;60: 123–135. 9. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992;25:231–241. 10. Bourrhis J, Lapeyre M, Tortochaux J, et al. Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: A GORTEC trial. J Clin Oncol 2006;24:2873–2878.
To the Editor: Lee and Eisbruch have attempted to model the contribution of chemotherapy to the incidence of Grade 3 and 4 mucositis in locally advanced squamous cell carcinoma (1). Their methodology is based on the Kasibhatla et al. model of the contribution of chemotherapy to local control, subsequently corrected by Fowler (2, 3). The conclusion by Lee and Eisbruch that chemotherapy improves the therapeutic ratio in head-and-neck cancer cannot be supported by their results. Using a value of Sm (ratio of absolute increase in percentage of patients having at least Grade 3 mucositis to the percentage increase in mucosal BED [mBED]) of 1, they found only a 0.8 Gy10 difference between the contribution of chemotherapy to local control and its contribution to ‘‘at least Grade 3 mucositis.’’ They speculate that this difference might be as large as 8 Gy10 if a value of Sm of 7 is used. This latter value is based on the work of Bentzen et al., who estimated Sm using data from two studies (4). The first study scored ‘‘mucositis’’ not otherwise graded and the second Grade 4 mucositis. This value of Sm is clearly not relevant to the current analysis of ‘‘at least Grade 3 mucositis.’’ Using the same radiobiologic parameters as Lee and Eisbruch (except a =0.3Gy 1 [not 0.35Gy 1] to be consistent with Kasibhatla et al. and Fowler, whose estimates for local control were later used in the Lee and Eisbruch analysis), we analyzed six trials of altered fractionation without synchronous chemotherapy to calculate a more evidence based value for Sm (4–10). The value of Sm from each study was weighted by the number of patients, giving a weighted mean value for Sm of 1.36 (95% confidence interval, 1.18–1.54). Applying this value to the seven trials of synchronous chemotherapy added to conventionally fractionated radiation used by Lee gave a weighted mean additional BED from chemotherapy of 6.42 Gy10 (95% confidence interval, 3.19–9.66). Using Fowler’s estimate of the same parameter for local control (8.8 Gy10) gives an absolute difference of 2.38 Gy10 or 1.98 Gy2. In summary, the addition of synchronous chemotherapy to radiotherapy results in approximately one 2-Gy fraction of sparing of the mucosal reaction when compared with use of a higher dose of radiation to achieve the same increment in local control. Although we agree that chemotherapy may ‘‘widen the therapeutic window for late effects,’’ there is little evidence that current agents, with the possible exceptions of mitomycin and cetuximab, achieve this acutely.
IN REPLY TO DR. HARTLEY To the Editor: We thank Dr. Hartley for his interest in our study (1). He has claimed to have developed a ‘‘more evidence-based’’ value of Sm, which he has estimated to be 1.36. In asserting this level of precision, one encounters some of the very pitfalls against which we have warned in our discussion. In particular, the lack of reliable scoring of mucositis in trials of irradiation (with or without chemotherapy) of head-and-neck cancer undoubtedly adds far more uncertainty to any estimate of Sm than is suggested by their confidence intervals. In addition, to claim any meaningful difference between their final estimate of 1.98 Gy10 and our estimate of 0.8 Gy10 for the difference in mucositis and tumor biologic effective dose ignores the limits of the model we used, which we also acknowledged in our paper. Until more reliable toxicity data are available, which might allow for a more sophisticated model, neither our results nor Hartley’s can be regarded as strongly evidence-based. At present, they merely serve to help generate hypotheses that must be tested with carefully conducted and scored clinical trials.
ANDREW HARTLEY, MRCP., FRCR. PAUL SANGHERA, MRCP., FRCR. JOHN GLAHOLM, FRCP., FRCR. Cancer Centre, Queen Elizabeth Hospital Birmingham, United Kingdom JACK F. FOWLER, DSC., PHD., FRCR., FACRO. Departments of Human Oncology and Medical Physics University of Wisconsin, Madison, WI doi:10.1016/j.ijrobp.2009.05.007
IRWIN H. LEE, M.D., PH.D. Rohnert Park Cancer Center Rohnert Park, CA
1. Lee IH, Eisbruch A. Mucositis versus tumor control: The therapeutic index of adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys. Epub ahead of print March 2009. 2. Kasibhatla M, Kirkpatrick J, Brizel D. How much radiation is the chemotherapy worth in advanced head and neck cancer? Int J Radiat Oncol Biol Phys 2007;68:1491–1495. 3. Fowler J. Correction to Kasibhatla, et-al. How much radiation is the chemotherapy worth in advanced head and neck cancer? (Int J Radiat Oncol Biol Phys 2007;68:1491–1495). Int J Radiat Oncol Biol Phys 2008;71: 326–329.
AVRAHAM EISBRUCH, M.D. University of Michigan Ann Arbor, MI doi:10.1016/j.ijrobp.2009.04.076 1. Lee IH, Eisbruch A. Mucositis vs tumor control: The therapeutic index of adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys. Epub ahead of print March 2009. 315
LETTERS TO THE EDITOR MODELING THE CONTRIBUTION OF SYNCHRONOUS CHEMOTHERAPY TO THE RATE OF GRADE 3 AND 4 MUCOSITIS IN LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK
4. Bentzen S, Ruifrok A, Thames H. Repair capacity and kinetics for human mucosa and epithelial tumors in the head and neck: Clinical data on the effect of changing the interval between multiple fractions per day in radiotherapy. Radiother Oncol 1996;38:89–101. 5. Fu K, Pajak T, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000;48: 7–16. 6. Overgaard J, Hansen H, Specht L, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial. Lancet 2003;362:933–940. 7. Poulsen MG, Denham JW, Peters LJ, et al. A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: A Trans-Tasman Radiation Oncology Group Study. Radiother Oncol 2001;60:113. 8. Bentzen S, Saunders M, Dische S, et al. Radiotherapy-related early morbidity in head and neck cancer: Quantitative clinical radiobiology as deduced from the CHART trial. Radiother Oncol 2001;60: 123–135. 9. Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992;25:231–241. 10. Bourrhis J, Lapeyre M, Tortochaux J, et al. Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: A GORTEC trial. J Clin Oncol 2006;24:2873–2878.
To the Editor: Lee and Eisbruch have attempted to model the contribution of chemotherapy to the incidence of Grade 3 and 4 mucositis in locally advanced squamous cell carcinoma (1). Their methodology is based on the Kasibhatla et al. model of the contribution of chemotherapy to local control, subsequently corrected by Fowler (2, 3). The conclusion by Lee and Eisbruch that chemotherapy improves the therapeutic ratio in head-and-neck cancer cannot be supported by their results. Using a value of Sm (ratio of absolute increase in percentage of patients having at least Grade 3 mucositis to the percentage increase in mucosal BED [mBED]) of 1, they found only a 0.8 Gy10 difference between the contribution of chemotherapy to local control and its contribution to ‘‘at least Grade 3 mucositis.’’ They speculate that this difference might be as large as 8 Gy10 if a value of Sm of 7 is used. This latter value is based on the work of Bentzen et al., who estimated Sm using data from two studies (4). The first study scored ‘‘mucositis’’ not otherwise graded and the second Grade 4 mucositis. This value of Sm is clearly not relevant to the current analysis of ‘‘at least Grade 3 mucositis.’’ Using the same radiobiologic parameters as Lee and Eisbruch (except a =0.3Gy 1 [not 0.35Gy 1] to be consistent with Kasibhatla et al. and Fowler, whose estimates for local control were later used in the Lee and Eisbruch analysis), we analyzed six trials of altered fractionation without synchronous chemotherapy to calculate a more evidence based value for Sm (4–10). The value of Sm from each study was weighted by the number of patients, giving a weighted mean value for Sm of 1.36 (95% confidence interval, 1.18–1.54). Applying this value to the seven trials of synchronous chemotherapy added to conventionally fractionated radiation used by Lee gave a weighted mean additional BED from chemotherapy of 6.42 Gy10 (95% confidence interval, 3.19–9.66). Using Fowler’s estimate of the same parameter for local control (8.8 Gy10) gives an absolute difference of 2.38 Gy10 or 1.98 Gy2. In summary, the addition of synchronous chemotherapy to radiotherapy results in approximately one 2-Gy fraction of sparing of the mucosal reaction when compared with use of a higher dose of radiation to achieve the same increment in local control. Although we agree that chemotherapy may ‘‘widen the therapeutic window for late effects,’’ there is little evidence that current agents, with the possible exceptions of mitomycin and cetuximab, achieve this acutely.
IN REPLY TO DR. HARTLEY To the Editor: We thank Dr. Hartley for his interest in our study (1). He has claimed to have developed a ‘‘more evidence-based’’ value of Sm, which he has estimated to be 1.36. In asserting this level of precision, one encounters some of the very pitfalls against which we have warned in our discussion. In particular, the lack of reliable scoring of mucositis in trials of irradiation (with or without chemotherapy) of head-and-neck cancer undoubtedly adds far more uncertainty to any estimate of Sm than is suggested by their confidence intervals. In addition, to claim any meaningful difference between their final estimate of 1.98 Gy10 and our estimate of 0.8 Gy10 for the difference in mucositis and tumor biologic effective dose ignores the limits of the model we used, which we also acknowledged in our paper. Until more reliable toxicity data are available, which might allow for a more sophisticated model, neither our results nor Hartley’s can be regarded as strongly evidence-based. At present, they merely serve to help generate hypotheses that must be tested with carefully conducted and scored clinical trials.
ANDREW HARTLEY, MRCP., FRCR. PAUL SANGHERA, MRCP., FRCR. JOHN GLAHOLM, FRCP., FRCR. Cancer Centre, Queen Elizabeth Hospital Birmingham, United Kingdom JACK F. FOWLER, DSC., PHD., FRCR., FACRO. Departments of Human Oncology and Medical Physics University of Wisconsin, Madison, WI doi:10.1016/j.ijrobp.2009.05.007
IRWIN H. LEE, M.D., PH.D. Rohnert Park Cancer Center Rohnert Park, CA
1. Lee IH, Eisbruch A. Mucositis versus tumor control: The therapeutic index of adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys. Epub ahead of print March 2009. 2. Kasibhatla M, Kirkpatrick J, Brizel D. How much radiation is the chemotherapy worth in advanced head and neck cancer? Int J Radiat Oncol Biol Phys 2007;68:1491–1495. 3. Fowler J. Correction to Kasibhatla, et-al. How much radiation is the chemotherapy worth in advanced head and neck cancer? (Int J Radiat Oncol Biol Phys 2007;68:1491–1495). Int J Radiat Oncol Biol Phys 2008;71: 326–329.
AVRAHAM EISBRUCH, M.D. University of Michigan Ann Arbor, MI doi:10.1016/j.ijrobp.2009.04.076 1. Lee IH, Eisbruch A. Mucositis vs tumor control: The therapeutic index of adding chemotherapy to irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys. Epub ahead of print March 2009. 315