- Email: [email protected]
In Reply to Lawrence
Volume 93 Number 1 2015
Comments
small albeit significant subset, while exposing all patients to a high risk of LE. As we seek ways to reduce LE and other complications, radiation dose needs evaluation. Is 50 to 50.4 Gy needed? Given the steepness of the complication rate curve, a drop in dose will have a significant impact. Radiation doses were based on MD Anderson Hospital data published by Gilbert Fletcher in Textbook of Radiotherapy (6). In the 1960s and 1970s, that textbook was the radiation oncology bible. Those data and other studies looking at various doses and tumor control rates used orthovoltage or 60 Co radiation with clinical simulation and setup. The prescribed dose, calculated at some target point, was above the mean dose in target volume and reflected concern for complications. There were significant cold spots in what today is the “target volume,” which determined recurrence rates. There was no relation of prescribed dose to cold spots, which varied from patient to patient. The current practice of computerized conformal 3-dimensional planning using varying beam energies greatly reduced or eliminated cold spots and skin complications. Hence, dose distribution homogeneity in CRT and intensity modulated radiation therapy should permit a reduction in prescribed dose, which will reduce morbidity without compromising tumor control rates. Studies in brain, lung, esophageal, and other cancers have shown that higher doses do not translate into improved tumor control rates. Two other factors in breast cancer have changed since the 1960s. Most patients receiving RLNR receive radiosensitizing systemic therapy. Normal tissue sensitization increases morbidity, and tumor sensitization increases the biological effect of radiation. Additionally, current early presentation of breast cancer reduces the risk and volume of subclinical disease in regional nodes. Sentinel lymph node dissection and completion ALND studies report that the vast majority of patients do not have disease beyond the excised sentinel nodes. Lymphedema is but one complication of RLNR. In some patients LE can be difficult to manage, and long-standing LE has its own complications. The 40% risk of LE (which will likely increase with longer follow-up) is higher than that reported in the past, even after ALND, likely for the reasons discussed. The last decade has seen major advances in radiation treatment planning and treatment delivery technology, which are now standard of care, and we have a better understanding of the biology and behavior of tumors. It is time we revisit radiation dose in a new light, before we read an article saying that postoperative radiation therapy in breast cancer does more harm than good, as reported for lung, uterine, and other cancers.
Faxton Campus Utica, New York
Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology Regional Cancer Center
215
http://dx.doi.org/10.1016/j.ijrobp.2015.03.024
References 1. Chandra RA, Miller CL, Skolny MN, et al. Radiation therapy risk factors for development of lymphedema in patients treated with regional lymph node irradiation for beast cancer. Int J Radiat Oncol Biol Phys 2015;91:760-764. 2. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastases: A randomized clinical trial. JAMA 2011; 305:569-575. 3. Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology Clinical Practice guidelines update. J Clin Oncol 2014;32: 1365-1383. 4. Poortmans PSH, Kirkove C, Budach V, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 year results of the EORTC radiation oncology and breast cancer groups phase III trials 22922/10925. Eur J Cancer 2013; 47(Suppl. 2). 5. Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomized trials. Lancet 2014;383: 2127-2135. 6. G. H. Fletcher, ed. Textbook of Radiotherapy. Philadelphia: Lea and Febiger; 1966.
In Reply to Lawrence We thank Dr Lawrence for his letter regarding our study (1, 2). We agree that prospective investigation of lower radiation doses, particularly in the modern era, is warranted. Progress has been made to reduce fraction number (3); however, recent studies have still relied on robust doses. The MA.20 (4) and European Organization for Research and Treatment of Cancer 22922/10925 (5) studies used 45 Gy (25 fractions) and 50 Gy (25 fractions), respectively. Also the British START-A (6) trial calculated the breast cancer a/b ratio as 4.6, positing a biological basis for higher doses. However, data from dose escalation among 3dimensional conformal external beam partial breast irradiation patients found that local control rates were not improved with increasing doses (7). Another study recently noted low local recurrence with reduced-dose radiation (39.6 Gy plus a 16-Gy boost) and concurrent cyclophosphamide/methotrexate/5-fluorouracil (8). We caution that reducing dose to the breast may not affect lymphedema incidence, because no threshold dose data exist. Lymphedema also has a lower incidence rate in studies in which regional irradiation alone is used instead of an axillary lymph node dissection (<10%) (9).
216
International Journal of Radiation Oncology Biology Physics
Comments Ravi A. Chandra, MD, PhD Harvard Radiation Oncology Program Boston, Massachusetts Alphonse G. Taghian, MD, PhD Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts
http://dx.doi.org/10.1016/j.ijrobp.2015.03.023
References 1. Chandra RA, Miller CL, Skolny MN, et al. Radiation therapy risk factors for development of lymphedema in patients treated with regional lymph node irradiation for breast cancer. Int J Radiat Oncol Biol Phys 2015;91:760-764. 2. Lawrence GA. In regard to Chandra et al. Int J Radiat Oncol Biol Phys 2015;93:213-214. 3. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010; 362:513-520. 4. Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer (abstract LBA1003). Available at: http://meeting.ascopubs.org/cgi/ content/abstract/29/18_suppl/LBA1003. Accessed April 16, 2015. 5. Poortmans PSH, Kirkove C, Budach V, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 year results of the EORTC radiation oncology and breast cancer groups phase III trials 22922/10925. Eur J Cancer 2013; 47(Suppl. 2). 6. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331-341. 7. Pashtan IM, Recht A, Ancukiewicz M, et al. External beam accelerated partial breast irradiation using 32 Gy in 8 twice-daily fractions: 5year results of a prospective study. Int J Radiat Oncol Biol Phys 2012; 84:e271-e277. 8. Bellon JR, Shulman LN, Come SE, et al. A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma. Cancer 2004;100:1358-1364. 9. Warren LE, Miller CL, Horick N, et al. The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: A prospective cohort study. Int J Radiat Oncol Biol Phys 2014;88: 565-571.
Charged particle with helium ion versus iodine-125 plaque therapy In Regard to Mishra et al To the Editor: We read with interest the article presenting long-term results of a randomized trial of charged particle therapy (CPT) versus iodine-125 plaque brachytherapy for uveal melanomas (1). In comparison to treatment with CPT, the authors report rather high rates of treatment failure for plaque patients. We are concerned this may have been because of a suboptimal brachytherapy technique used rather than a failure of brachytherapy.
In Methods, the authors state “a limited margin was used for plaques because it was reasoned that the plaque was sutured into place” and “indirect ophthalmoscopy [was] used to relocalize and confirm.plaque location.” Planning tumor treatment with a limited margin and using only indirect ophthalmoscopy rather than ultrasound guidance likely contributed to the higher-than-expected rate of local treatment failure. We have previously reported the use of ultrasound-guided iodine-125-labeled brachytherapy where no cases of local treatment failure occurred likely because in approximately one-third of cases the plaque needed to be repositioned in order to achieve a margin greater than 1 mm (2). Plaque malposition may be even greater for posterior tumors (3), which indeed was where most of the plaque failures were located in the study by Mishra et al (1). We believe that the authors’ suboptimal technique of brachytherapy biased the data in favor of CPT and did not allow for a valid or generalizable comparison between the 2 modalities. Success rates for treatment of local control with CPT would be higher than those associated with image-guided brachytherapy. The authors’ recommendation to invest in developing more particle therapy centers is unsubstantiated. Mitchell Kamrava, MD Department of Radiation Oncology University of California Los Angeles Los Angeles, California Tara McCannel, MD, PhD Department of Ophthalmology University of California Los Angeles Los Angeles, California http://dx.doi.org/10.1016/j.ijrobp.2015.04.046
References 1. Mishra KK, Quivey JM, Daftari IK, et al. Long-term results of the UCSF-LBNL randomized trial: Charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys 2015;92:376-383. 2. Chang MY, Kamrava M, Demanes D, et al. Intraoperative ultrasonography-guided positioning of iodine 125 plaque brachytherapy in the treatment of choroidal melanoma. Ophthalmology 2012;119: 1073-1077. 3. Tabandeh H, Chaudhry NA, Murray TG, et al. Intraoperative echographic localization of iodine-125 episcleral plaque for brachytherapy of choroidal melanoma. Am J Ophthalmol 2000;129:199-204.
In Reply to Kamrava and McCannel To the Editor: We appreciate the comments on our recent article (1) and agree that current radiation techniques have certainly developed from the time of the original uveal melanoma trial described. Similar to the note by Drs
Comments
small albeit significant subset, while exposing all patients to a high risk of LE. As we seek ways to reduce LE and other complications, radiation dose needs evaluation. Is 50 to 50.4 Gy needed? Given the steepness of the complication rate curve, a drop in dose will have a significant impact. Radiation doses were based on MD Anderson Hospital data published by Gilbert Fletcher in Textbook of Radiotherapy (6). In the 1960s and 1970s, that textbook was the radiation oncology bible. Those data and other studies looking at various doses and tumor control rates used orthovoltage or 60 Co radiation with clinical simulation and setup. The prescribed dose, calculated at some target point, was above the mean dose in target volume and reflected concern for complications. There were significant cold spots in what today is the “target volume,” which determined recurrence rates. There was no relation of prescribed dose to cold spots, which varied from patient to patient. The current practice of computerized conformal 3-dimensional planning using varying beam energies greatly reduced or eliminated cold spots and skin complications. Hence, dose distribution homogeneity in CRT and intensity modulated radiation therapy should permit a reduction in prescribed dose, which will reduce morbidity without compromising tumor control rates. Studies in brain, lung, esophageal, and other cancers have shown that higher doses do not translate into improved tumor control rates. Two other factors in breast cancer have changed since the 1960s. Most patients receiving RLNR receive radiosensitizing systemic therapy. Normal tissue sensitization increases morbidity, and tumor sensitization increases the biological effect of radiation. Additionally, current early presentation of breast cancer reduces the risk and volume of subclinical disease in regional nodes. Sentinel lymph node dissection and completion ALND studies report that the vast majority of patients do not have disease beyond the excised sentinel nodes. Lymphedema is but one complication of RLNR. In some patients LE can be difficult to manage, and long-standing LE has its own complications. The 40% risk of LE (which will likely increase with longer follow-up) is higher than that reported in the past, even after ALND, likely for the reasons discussed. The last decade has seen major advances in radiation treatment planning and treatment delivery technology, which are now standard of care, and we have a better understanding of the biology and behavior of tumors. It is time we revisit radiation dose in a new light, before we read an article saying that postoperative radiation therapy in breast cancer does more harm than good, as reported for lung, uterine, and other cancers.
Faxton Campus Utica, New York
Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology Regional Cancer Center
215
http://dx.doi.org/10.1016/j.ijrobp.2015.03.024
References 1. Chandra RA, Miller CL, Skolny MN, et al. Radiation therapy risk factors for development of lymphedema in patients treated with regional lymph node irradiation for beast cancer. Int J Radiat Oncol Biol Phys 2015;91:760-764. 2. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastases: A randomized clinical trial. JAMA 2011; 305:569-575. 3. Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology Clinical Practice guidelines update. J Clin Oncol 2014;32: 1365-1383. 4. Poortmans PSH, Kirkove C, Budach V, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 year results of the EORTC radiation oncology and breast cancer groups phase III trials 22922/10925. Eur J Cancer 2013; 47(Suppl. 2). 5. Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomized trials. Lancet 2014;383: 2127-2135. 6. G. H. Fletcher, ed. Textbook of Radiotherapy. Philadelphia: Lea and Febiger; 1966.
In Reply to Lawrence We thank Dr Lawrence for his letter regarding our study (1, 2). We agree that prospective investigation of lower radiation doses, particularly in the modern era, is warranted. Progress has been made to reduce fraction number (3); however, recent studies have still relied on robust doses. The MA.20 (4) and European Organization for Research and Treatment of Cancer 22922/10925 (5) studies used 45 Gy (25 fractions) and 50 Gy (25 fractions), respectively. Also the British START-A (6) trial calculated the breast cancer a/b ratio as 4.6, positing a biological basis for higher doses. However, data from dose escalation among 3dimensional conformal external beam partial breast irradiation patients found that local control rates were not improved with increasing doses (7). Another study recently noted low local recurrence with reduced-dose radiation (39.6 Gy plus a 16-Gy boost) and concurrent cyclophosphamide/methotrexate/5-fluorouracil (8). We caution that reducing dose to the breast may not affect lymphedema incidence, because no threshold dose data exist. Lymphedema also has a lower incidence rate in studies in which regional irradiation alone is used instead of an axillary lymph node dissection (<10%) (9).
216
International Journal of Radiation Oncology Biology Physics
Comments Ravi A. Chandra, MD, PhD Harvard Radiation Oncology Program Boston, Massachusetts Alphonse G. Taghian, MD, PhD Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts
http://dx.doi.org/10.1016/j.ijrobp.2015.03.023
References 1. Chandra RA, Miller CL, Skolny MN, et al. Radiation therapy risk factors for development of lymphedema in patients treated with regional lymph node irradiation for breast cancer. Int J Radiat Oncol Biol Phys 2015;91:760-764. 2. Lawrence GA. In regard to Chandra et al. Int J Radiat Oncol Biol Phys 2015;93:213-214. 3. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010; 362:513-520. 4. Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer (abstract LBA1003). Available at: http://meeting.ascopubs.org/cgi/ content/abstract/29/18_suppl/LBA1003. Accessed April 16, 2015. 5. Poortmans PSH, Kirkove C, Budach V, et al. Irradiation of the internal mammary and medial supraclavicular lymph nodes in stage I to III breast cancer: 10 year results of the EORTC radiation oncology and breast cancer groups phase III trials 22922/10925. Eur J Cancer 2013; 47(Suppl. 2). 6. START Trialists’ Group, Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331-341. 7. Pashtan IM, Recht A, Ancukiewicz M, et al. External beam accelerated partial breast irradiation using 32 Gy in 8 twice-daily fractions: 5year results of a prospective study. Int J Radiat Oncol Biol Phys 2012; 84:e271-e277. 8. Bellon JR, Shulman LN, Come SE, et al. A prospective study of concurrent cyclophosphamide/methotrexate/5-fluorouracil and reduced-dose radiotherapy in patients with early-stage breast carcinoma. Cancer 2004;100:1358-1364. 9. Warren LE, Miller CL, Horick N, et al. The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: A prospective cohort study. Int J Radiat Oncol Biol Phys 2014;88: 565-571.
Charged particle with helium ion versus iodine-125 plaque therapy In Regard to Mishra et al To the Editor: We read with interest the article presenting long-term results of a randomized trial of charged particle therapy (CPT) versus iodine-125 plaque brachytherapy for uveal melanomas (1). In comparison to treatment with CPT, the authors report rather high rates of treatment failure for plaque patients. We are concerned this may have been because of a suboptimal brachytherapy technique used rather than a failure of brachytherapy.
In Methods, the authors state “a limited margin was used for plaques because it was reasoned that the plaque was sutured into place” and “indirect ophthalmoscopy [was] used to relocalize and confirm.plaque location.” Planning tumor treatment with a limited margin and using only indirect ophthalmoscopy rather than ultrasound guidance likely contributed to the higher-than-expected rate of local treatment failure. We have previously reported the use of ultrasound-guided iodine-125-labeled brachytherapy where no cases of local treatment failure occurred likely because in approximately one-third of cases the plaque needed to be repositioned in order to achieve a margin greater than 1 mm (2). Plaque malposition may be even greater for posterior tumors (3), which indeed was where most of the plaque failures were located in the study by Mishra et al (1). We believe that the authors’ suboptimal technique of brachytherapy biased the data in favor of CPT and did not allow for a valid or generalizable comparison between the 2 modalities. Success rates for treatment of local control with CPT would be higher than those associated with image-guided brachytherapy. The authors’ recommendation to invest in developing more particle therapy centers is unsubstantiated. Mitchell Kamrava, MD Department of Radiation Oncology University of California Los Angeles Los Angeles, California Tara McCannel, MD, PhD Department of Ophthalmology University of California Los Angeles Los Angeles, California http://dx.doi.org/10.1016/j.ijrobp.2015.04.046
References 1. Mishra KK, Quivey JM, Daftari IK, et al. Long-term results of the UCSF-LBNL randomized trial: Charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int J Radiat Oncol Biol Phys 2015;92:376-383. 2. Chang MY, Kamrava M, Demanes D, et al. Intraoperative ultrasonography-guided positioning of iodine 125 plaque brachytherapy in the treatment of choroidal melanoma. Ophthalmology 2012;119: 1073-1077. 3. Tabandeh H, Chaudhry NA, Murray TG, et al. Intraoperative echographic localization of iodine-125 episcleral plaque for brachytherapy of choroidal melanoma. Am J Ophthalmol 2000;129:199-204.
In Reply to Kamrava and McCannel To the Editor: We appreciate the comments on our recent article (1) and agree that current radiation techniques have certainly developed from the time of the original uveal melanoma trial described. Similar to the note by Drs