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Efficacy, toxicity, and cost-effectiveness of single-dose versus fractionated hemibody irradiation (HBI)
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I. J. Radiation Oncology
● Biology ● Physics
therapy (HFX RT) followed by multiagent chemotherapy (CHT) in patients with malignant glioma: A phase II study. Int J Radiat Oncol Biol Phys 1994;30:1179 –1185. Jeremic B, Shibamoto Y. Effect of interfraction interval in hyperfractionated radiotherapy with or without concurrent chemotherapy for stage III nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 1996;34:303–308. Shibamoto Y, Jeremic B, Acimovic LJ, et al. Influence of interfraction interval on the efficacy and toxicity of hyperfractionated radiotherapy in combination with concurrent daily chemotherapy in stage III nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 2001;50:295–300. Werner-Wasik M, Scott C, Graham ML, et al. Interfraction interval does not affect survival of patients with non–small cell lung cancer treated with chemotherapy and/or hyperfractionated radiotherapy: A multivariate analysis of 1076 RTOG patients. Int J Radiat Oncol Biol Phys 1999;44:327–331. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis-chloroethyl nitrosourea in the treatment of malignant glioma—Possible advantage observed at 72.0 Gy in 1.2 Gy b.i.d. fractions: Report of the Radiation Therapy Oncology Group protocol 8302. Int J Radiat Oncol Biol Phys 1993;25:191–207. Cox JD, Pajak TF, Marcial VA, et al. ASTRO prenary: Interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from Radiation Therapy Oncology Group protocol 8313. Int J Radiat Oncol Biol Phys 1991;20:1191–1195. Jeremic B, Shibamoto Y, Milicic B, et al. Absence of thoracic radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for stage III non–small-cell lung cancer. Int J Radiat Oncol Biol Phys 1998;40:343–346.
EFFICACY, TOXICITY, AND COST-EFFECTIVENESS OF SINGLE-DOSE VERSUS FRACTIONATED HEMIBODY IRRADIATION (HBI) To the Editor: There is now unequivocal evidence that patients with widespread bone metastasis achieve excellent pain relief with HBI. In the recent International Atomic Energy Agency (IAEA) randomized trial reported by Salazar et al. (1), the objective was to identify the best schedule for economically delivering HBI, especially in the developing countries. In this 3-arm trial, Arm A (15 Gy/5 fractions/5 days) and Arm C (12 Gy/4 fractions/2 days) were equivalent in terms of pain relief and both were better than Arm B (8 Gy/2 fractions/1 day). Thus they recommend Arm C as the most convenient schedule with equivalent efficacy. However, to recommend this as the best schedule for economically delivering HBI without a direct comparison with the most widely used and perhaps the most cost-effective single-dose schedule of HBI should be questioned. Not surprisingly, the 1-day schedule used in this trial (Arm B: 8 Gy in 2 fractions) was inferior, since it delivered much lower biological dose. The reason for excluding the single-dose HBI arm from this trial may be the author’s previous experience (2) wherein fractionation of HBI without premedication, achieved pain relief and toxicity comparable to 7–10 Gy single dose with premedication and superior pain relief than ⬍7 Gy single dose. If indeed, the reason for excluding single-dose HBI was the apprehension about premedication and monitoring, it is misplaced, because their experience of single dose was gained during 1981 to 1985, much before the advent of highly effective ondansetron/granisetron. At our institution, we routinely use intravenous bolus of 8 –16 mg of ondansetron and dexamethasone before 6 – 8 Gy single-dose HBI and if required oral steroids, antiemetics, and loperamide/codeine after HBI. This pre- and post-HBI medication allows the procedure to be given on an outpatient basis for the vast majority of our patients. For the fractionated HBI schedule recommended in this study, most patients with widely disseminated painful cancer and their physicians would prefer a few days of hospitalization for reasons of logistics and comfort, even though not necessary for medical intervention. The authors have not provided any information about the premedication and need for hospitalization in this trial. Even if these patients did not request or were not offered hospitalizations, they would certainly be more uncomfortable and exhausted due to an extra day of traveling, sometimes by public transport in the peak traffic hours and spending two full days in a busy outpatient department. The saving in the cost of this pre- and postmedication (approximately US$3 in India but possibly higher in some developing countries) by fractionating the HBI is likely to be far less than the actual
Volume 52, Number 4, 2002 cost of a few days of hospitalization (which may be partly borne by the state) or additional transportation cost. Thus a detailed cost analysis of hospitalization, transport, radiotherapy machine time, and drugs is likely to show that single-dose HBI with modern premedication is not only more cost-effective as compared to the recommended fractionated HBI but also more appealing to the patients, their families and institutions. The sole evidence suggesting a favorable response with fractionated HBI is from a small nonrandomized study of 29 prostate cancer patients (3) and insufficient to change practice. Fractionated HBI should be largely reserved for protocols aiming to improve tumor cell kill by dose escalation, and not when the aim is pain relief for which there is no dose–response effect beyond 6 – 8 Gy single dose (4, 5). The RTOG study found that 6 Gy for upper and 8 Gy for lower HBI were the most effective and safe single doses and further dose escalation only increased toxicity but not pain relief (4). We have also reported an analysis of all prospective studies of localized single-fraction radiotherapy for bone metastasis and found no improvement in pain relief with doses beyond 6 – 8 Gy (5). It seems that the unfounded reluctance of American oncologists to use single-fraction localized radiotherapy for bone metastasis (5, 6) is now being applied to HBI, which started and gained acceptance worldwide as a single-dose, simple, very effective, and safe treatment. While this recommendation of fractionated HBI for pain relief comes from Salazar, a pioneer in this field, on the basis of available evidence, 6 – 8 Gy single dose with modern premedication and not the fractionated HBI schedule should be the standard of care anywhere in the world. RAJIV SARIN, M.D., D.N.B., F.R.C.R. ASHWINI BUDRUKKAR, M.D., D.N.B Department of Radiation Oncology Tata Memorial Hospital, Parel Mumbai, India
PII S0360-3016(01)02706-7 1. Salazar OM, Sandhu T, da Motta NW, et al. Fractionated half body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: A randomized phase III trial of the International Atomic Energy Agency (IAEA). Int J Radiat Oncol Biol Phys 2001;50:765–775. 2. Salazar OM, da Motta NW, Bridgman SM, et al. Fractionated half body irradiation for pain palliation in widely metastatic cancers: Comparison with single dose. Int J Radiat Oncol Biol Phys 1996;36:49 – 60. 3. Zelefsky MJ, Scher HI, Forman JD, et al. Palliative hemiskeletal irradiation for widely metastatic prostate cancer: A comparison of single dose and fractionated regimens. Int J Radiat Oncol Biol Phys 1989;17: 1281–1285. 4. Salazar OM, Rubin P, Hendrickson F, et al. Single dose half body irradiation for palliation of multiple bone metastases from solid tumors: Final Radiation Therapy Oncology Group Report. Cancer 1986;58:29–36. 5. Chander S, Sarin R. Single fraction radiotherapy for bone metastasis: Are all questions answered? Radiother Oncol 1999;52:191–193. 6. Rose CM, Kagan R. The final report of the expert panel for the Radiation Oncology Bone Metastases Work Group of the American College of Radiology. Int J Radiat Oncol Biol Phys 1998;40:1117–1124.
IN RESPONSE TO DRS. SARIN AND BUDRUKKAR It has been the intention of the International Atomic Energy Agency (IAEA) to explore the usefulness of half-body irradiation (HBI) against widespread symptomatic bone metastases to the best of its abilities. The axioms under which studies similar to this HBI trial were sponsored by the IAEA for Third World countries have been based on “feasibility (simplicity), economics and quality control.” The final decision on which studies were going to be implemented, in particular this HBI study, were based on the recommendations of several IAEA consultants. The HBI study in question was primarily designed to benefit Third World countries. The involvement of “American oncologists” was mainly a coordinating effort and in no way represents an imposition of any philosophical “unfounded reluctance from American oncologists” with whom the authors of such letter seem to tag the design of this particular HBI study. Equally, it does not represent an extrapolation from any sentiment harbored or practiced in America for the radiation treatment of isolated bone metastases.
3.
4.
5.
6.
7.
8.
I. J. Radiation Oncology
● Biology ● Physics
therapy (HFX RT) followed by multiagent chemotherapy (CHT) in patients with malignant glioma: A phase II study. Int J Radiat Oncol Biol Phys 1994;30:1179 –1185. Jeremic B, Shibamoto Y. Effect of interfraction interval in hyperfractionated radiotherapy with or without concurrent chemotherapy for stage III nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 1996;34:303–308. Shibamoto Y, Jeremic B, Acimovic LJ, et al. Influence of interfraction interval on the efficacy and toxicity of hyperfractionated radiotherapy in combination with concurrent daily chemotherapy in stage III nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys 2001;50:295–300. Werner-Wasik M, Scott C, Graham ML, et al. Interfraction interval does not affect survival of patients with non–small cell lung cancer treated with chemotherapy and/or hyperfractionated radiotherapy: A multivariate analysis of 1076 RTOG patients. Int J Radiat Oncol Biol Phys 1999;44:327–331. Nelson DF, Curran WJ, Scott C, et al. Hyperfractionated radiation therapy and bis-chloroethyl nitrosourea in the treatment of malignant glioma—Possible advantage observed at 72.0 Gy in 1.2 Gy b.i.d. fractions: Report of the Radiation Therapy Oncology Group protocol 8302. Int J Radiat Oncol Biol Phys 1993;25:191–207. Cox JD, Pajak TF, Marcial VA, et al. ASTRO prenary: Interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from Radiation Therapy Oncology Group protocol 8313. Int J Radiat Oncol Biol Phys 1991;20:1191–1195. Jeremic B, Shibamoto Y, Milicic B, et al. Absence of thoracic radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for stage III non–small-cell lung cancer. Int J Radiat Oncol Biol Phys 1998;40:343–346.
EFFICACY, TOXICITY, AND COST-EFFECTIVENESS OF SINGLE-DOSE VERSUS FRACTIONATED HEMIBODY IRRADIATION (HBI) To the Editor: There is now unequivocal evidence that patients with widespread bone metastasis achieve excellent pain relief with HBI. In the recent International Atomic Energy Agency (IAEA) randomized trial reported by Salazar et al. (1), the objective was to identify the best schedule for economically delivering HBI, especially in the developing countries. In this 3-arm trial, Arm A (15 Gy/5 fractions/5 days) and Arm C (12 Gy/4 fractions/2 days) were equivalent in terms of pain relief and both were better than Arm B (8 Gy/2 fractions/1 day). Thus they recommend Arm C as the most convenient schedule with equivalent efficacy. However, to recommend this as the best schedule for economically delivering HBI without a direct comparison with the most widely used and perhaps the most cost-effective single-dose schedule of HBI should be questioned. Not surprisingly, the 1-day schedule used in this trial (Arm B: 8 Gy in 2 fractions) was inferior, since it delivered much lower biological dose. The reason for excluding the single-dose HBI arm from this trial may be the author’s previous experience (2) wherein fractionation of HBI without premedication, achieved pain relief and toxicity comparable to 7–10 Gy single dose with premedication and superior pain relief than ⬍7 Gy single dose. If indeed, the reason for excluding single-dose HBI was the apprehension about premedication and monitoring, it is misplaced, because their experience of single dose was gained during 1981 to 1985, much before the advent of highly effective ondansetron/granisetron. At our institution, we routinely use intravenous bolus of 8 –16 mg of ondansetron and dexamethasone before 6 – 8 Gy single-dose HBI and if required oral steroids, antiemetics, and loperamide/codeine after HBI. This pre- and post-HBI medication allows the procedure to be given on an outpatient basis for the vast majority of our patients. For the fractionated HBI schedule recommended in this study, most patients with widely disseminated painful cancer and their physicians would prefer a few days of hospitalization for reasons of logistics and comfort, even though not necessary for medical intervention. The authors have not provided any information about the premedication and need for hospitalization in this trial. Even if these patients did not request or were not offered hospitalizations, they would certainly be more uncomfortable and exhausted due to an extra day of traveling, sometimes by public transport in the peak traffic hours and spending two full days in a busy outpatient department. The saving in the cost of this pre- and postmedication (approximately US$3 in India but possibly higher in some developing countries) by fractionating the HBI is likely to be far less than the actual
Volume 52, Number 4, 2002 cost of a few days of hospitalization (which may be partly borne by the state) or additional transportation cost. Thus a detailed cost analysis of hospitalization, transport, radiotherapy machine time, and drugs is likely to show that single-dose HBI with modern premedication is not only more cost-effective as compared to the recommended fractionated HBI but also more appealing to the patients, their families and institutions. The sole evidence suggesting a favorable response with fractionated HBI is from a small nonrandomized study of 29 prostate cancer patients (3) and insufficient to change practice. Fractionated HBI should be largely reserved for protocols aiming to improve tumor cell kill by dose escalation, and not when the aim is pain relief for which there is no dose–response effect beyond 6 – 8 Gy single dose (4, 5). The RTOG study found that 6 Gy for upper and 8 Gy for lower HBI were the most effective and safe single doses and further dose escalation only increased toxicity but not pain relief (4). We have also reported an analysis of all prospective studies of localized single-fraction radiotherapy for bone metastasis and found no improvement in pain relief with doses beyond 6 – 8 Gy (5). It seems that the unfounded reluctance of American oncologists to use single-fraction localized radiotherapy for bone metastasis (5, 6) is now being applied to HBI, which started and gained acceptance worldwide as a single-dose, simple, very effective, and safe treatment. While this recommendation of fractionated HBI for pain relief comes from Salazar, a pioneer in this field, on the basis of available evidence, 6 – 8 Gy single dose with modern premedication and not the fractionated HBI schedule should be the standard of care anywhere in the world. RAJIV SARIN, M.D., D.N.B., F.R.C.R. ASHWINI BUDRUKKAR, M.D., D.N.B Department of Radiation Oncology Tata Memorial Hospital, Parel Mumbai, India
PII S0360-3016(01)02706-7 1. Salazar OM, Sandhu T, da Motta NW, et al. Fractionated half body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: A randomized phase III trial of the International Atomic Energy Agency (IAEA). Int J Radiat Oncol Biol Phys 2001;50:765–775. 2. Salazar OM, da Motta NW, Bridgman SM, et al. Fractionated half body irradiation for pain palliation in widely metastatic cancers: Comparison with single dose. Int J Radiat Oncol Biol Phys 1996;36:49 – 60. 3. Zelefsky MJ, Scher HI, Forman JD, et al. Palliative hemiskeletal irradiation for widely metastatic prostate cancer: A comparison of single dose and fractionated regimens. Int J Radiat Oncol Biol Phys 1989;17: 1281–1285. 4. Salazar OM, Rubin P, Hendrickson F, et al. Single dose half body irradiation for palliation of multiple bone metastases from solid tumors: Final Radiation Therapy Oncology Group Report. Cancer 1986;58:29–36. 5. Chander S, Sarin R. Single fraction radiotherapy for bone metastasis: Are all questions answered? Radiother Oncol 1999;52:191–193. 6. Rose CM, Kagan R. The final report of the expert panel for the Radiation Oncology Bone Metastases Work Group of the American College of Radiology. Int J Radiat Oncol Biol Phys 1998;40:1117–1124.
IN RESPONSE TO DRS. SARIN AND BUDRUKKAR It has been the intention of the International Atomic Energy Agency (IAEA) to explore the usefulness of half-body irradiation (HBI) against widespread symptomatic bone metastases to the best of its abilities. The axioms under which studies similar to this HBI trial were sponsored by the IAEA for Third World countries have been based on “feasibility (simplicity), economics and quality control.” The final decision on which studies were going to be implemented, in particular this HBI study, were based on the recommendations of several IAEA consultants. The HBI study in question was primarily designed to benefit Third World countries. The involvement of “American oncologists” was mainly a coordinating effort and in no way represents an imposition of any philosophical “unfounded reluctance from American oncologists” with whom the authors of such letter seem to tag the design of this particular HBI study. Equally, it does not represent an extrapolation from any sentiment harbored or practiced in America for the radiation treatment of isolated bone metastases.