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Comparison of three accelerated partial breast irradiation techniques: Treatment effectiveness based upon biological models
beyond the central question of which patients after a successful lumpectomy can attain appropriate local control with APBI versus standard WBI. This central question of efficacy in comparison to WBI is being addressed by accrual following lumpectomy to 3 large randomized trials for fractionated APBI: (1) NSABP B-39, RTOG 0413, which is accruing 4,300 breast cancer patients to WBI versus APBI with either multicatheter brachytherapy, MamoSite balloon brachytherapy, or external-beam 3-dimensional conformal radiation therapy (3DCRT); (2) the GEC-ESTRO trial randomizing 1,170 patients to APBI with mulitcatheter brachytherapy versus WBI; and (3) the OCOG RAPID trial, which is randomizing 2,128 women to APBI with 3DCRT versus standard WBI. Two trials are evaluating intraoperative APBI: (1)
the ELIOT trial randomized approximately 1,000 patients to a single fraction of intraoperative electrons at the time of lumpectomy versus standard WBI after surgery and (2) the TARGIT trial is randomizing 2,232 women to IORT using an applicator and low-energy x-rays at the time of lumpectomy versus WBI after surgery. Altogether these trials will accrue more than 10 000 women and will provide data to answer the central question regarding APBI: does APBI yield local control comparable to standard WBI following lumpectomy? However, the final outcomes from these trials will not be available for a decade or longer. It is unrealistic to expect that APBI will not be used in clinical practice in the interim. This calls for some guidelines regarding how to use APBI once these clinical trials complete accrual and the local
control outcomes remain years away. Perhaps even as equally compelling a reason for a guideline is the technical sophistication required to deliver the various APBI methods. For instance, what should be the minimal quality assurance procedure or expertise an institution should have for each method? The ‘‘easy’’ answer to all of these questions for the time being may be to do just what this consensus statement has done— support the use of APBI only on a clinical trial and ‘‘explicitly discouraged the use of APBI in any other setting.’’ However, a more explicit guideline for the use and technical execution of APBI may be in order soon as we await the outcome of the randomized trials.
Comparison of three accelerated partial breast irradiation techniques: Treatment effectiveness based upon biological models
evaluated the anticipated efficacy among the APBI methods for equivalent uniform dose (EUD), Tumor Control Probability (TCP), and Normal Tissue Complication Probability (NTCP). Materials and Methods.—Treatment plans from five patients treated by each APBI modality were retrospectively selected. Dose-volume-histograms (DVH) for planning target volume (PTV), breast, and lung were generated. The LQ parameters a ¼ 0.3 Gy1 and a/b ¼ 10 Gy were used for calculations. The values of EUD, TCP, and NTCP were calculated based on DVHs. Results.—The average EUD (normalized to 3.4 Gy BID) for the MCT, MST, and 3DCRT APBI was 35, 37.2, and 37.6 Gy. When normalized to 2 Gy fractionation these become, 42.2, 46.4, and 46.9 Gy.
Average TCP for MCT, MST, and 3DCRT PBI was 94.8%, 99.1%, and 99.2%. The NTCP values for breast and lung were low for all three methods. Conclusions.—The EUD for PTV and TCP were most similar in MST and 3DCRT APBI and were lower in MCT APBI. This questions the equivalence of the three APBI modalities that are currently being evaluated in the NSABP-B39/RTOG 0413 protocol.
Bovi J, Qi XS, White J, et al (Med College of Wisconsin, Milwaukee) Radiother Oncol 84:226-232, 2007
Background and Purpose.—Accelerated partial breast irradiation (APBI) is being studied in a phase III randomized trial as an alternative to whole breast irradiation (WBI) for early stage breast cancer patients. There are three methods for APBI: multi-catheter brachytherapy (MCT), MammoSiteÒ brachytherapy (MST), or 3D conformal (3DCRT). There is a paucity of data comparing among methods. Using a linear–quadratic (LQ) model, we
J. White, MD
In the NSABP-B39/RTOG 0413 phase III trial investigating APBI, treatment was delivered via any of the 3 ‘‘classic’’ APBI techniques: MCT, MST, or 3DCRT. In the design of the protocol, these 3 treatment techniques were assumed to be equivalent, and quality assurance guidelines were designed to best equate dose delivery. However, it is recognized that
Breast Diseases: A Year BookÒ Quarterly Vol 19 No 3 2008
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unavoidable dosimetric differences between the techniques do exist. This sophisticated investigation by Bovi and colleagues of the expected biological effectiveness of these classic methods of APBI delivery is one of the most comprehensive analyses to date of the radiobiologic aspects of APBI. This study attempted to provide insight into how the dosimetric differences of these techniques may be related to outcome. In review of this investigation, the conclusions made by the authors serve as motivation for further investigation and raise 3 important issues. Using the concept of EUD, the authors concluded that there were identifiable differences in TCP between the 3 treatment techniques. Because the authors did not conduct a statistical evaluation, the first issue focuses on whether the calculated differences were statistically significant. Without this statistical information, it is unclear whether the findings can be translated into clinically significant findings. The second issue focuses on the a/b ratio. The authors acknowledged that recent clinical data from a randomized trial conducted at the Royal Marsden Hospital1 had sug-
260
gested that the value of a/b is close to 4 Gy; however, for their comparison of these techniques, Bovi and colleagues used the standard a/b value of 10 Gy. The use of an a/b value of 4 Gy would result in an increased EUD for all modalities because of the hypofractionation inherent in APBI; however, these results were not presented because the authors were interested in the relative values for the different modalities. The third issue involves the authors’ conclusions. In this study, multicatheter APBI was associated with a lower EUD, which led the authors to conclude that this technique might be biologically inferior to the others and that an adjustment in prescription dose might be needed to ensure comparable results. However, it should be noted that MCT is the original method for delivering APBI; has resulted in excellent, mature follow-up data; and is the technique upon which the foundation of APBI has been built. Intermediate follow-up data are only now emerging from the use of the MammoSite device, and follow-up data from treatment with 3DCRT are limited at best. With MCT arguably representing the gold standard method of APBI
Breast Diseases: A Year BookÒ Quarterly Vol 19 No 3 2008
delivery, the authors have generated an interesting hypothesis: if the current dose for multicatheter APBI produces excellent clinical outcomes but is associated with a lower EUD, it may be more correct to suggest that the doses presently used for MST and 3DCRT delivery of APBI are actually too high. It is difficult to make definitive treatment recommendations on the basis of radiobiologic modeling without confirmatory clinical outcome; however, this work generates some interesting questions that may generate insight about this topic and enable us to properly interpret results from ongoing randomized trials as long-term follow-up data become available. L. W. Cuttino, MD D. W. Arthur, MD
Reference 1. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with earlystage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006;7:467-471.
the ELIOT trial randomized approximately 1,000 patients to a single fraction of intraoperative electrons at the time of lumpectomy versus standard WBI after surgery and (2) the TARGIT trial is randomizing 2,232 women to IORT using an applicator and low-energy x-rays at the time of lumpectomy versus WBI after surgery. Altogether these trials will accrue more than 10 000 women and will provide data to answer the central question regarding APBI: does APBI yield local control comparable to standard WBI following lumpectomy? However, the final outcomes from these trials will not be available for a decade or longer. It is unrealistic to expect that APBI will not be used in clinical practice in the interim. This calls for some guidelines regarding how to use APBI once these clinical trials complete accrual and the local
control outcomes remain years away. Perhaps even as equally compelling a reason for a guideline is the technical sophistication required to deliver the various APBI methods. For instance, what should be the minimal quality assurance procedure or expertise an institution should have for each method? The ‘‘easy’’ answer to all of these questions for the time being may be to do just what this consensus statement has done— support the use of APBI only on a clinical trial and ‘‘explicitly discouraged the use of APBI in any other setting.’’ However, a more explicit guideline for the use and technical execution of APBI may be in order soon as we await the outcome of the randomized trials.
Comparison of three accelerated partial breast irradiation techniques: Treatment effectiveness based upon biological models
evaluated the anticipated efficacy among the APBI methods for equivalent uniform dose (EUD), Tumor Control Probability (TCP), and Normal Tissue Complication Probability (NTCP). Materials and Methods.—Treatment plans from five patients treated by each APBI modality were retrospectively selected. Dose-volume-histograms (DVH) for planning target volume (PTV), breast, and lung were generated. The LQ parameters a ¼ 0.3 Gy1 and a/b ¼ 10 Gy were used for calculations. The values of EUD, TCP, and NTCP were calculated based on DVHs. Results.—The average EUD (normalized to 3.4 Gy BID) for the MCT, MST, and 3DCRT APBI was 35, 37.2, and 37.6 Gy. When normalized to 2 Gy fractionation these become, 42.2, 46.4, and 46.9 Gy.
Average TCP for MCT, MST, and 3DCRT PBI was 94.8%, 99.1%, and 99.2%. The NTCP values for breast and lung were low for all three methods. Conclusions.—The EUD for PTV and TCP were most similar in MST and 3DCRT APBI and were lower in MCT APBI. This questions the equivalence of the three APBI modalities that are currently being evaluated in the NSABP-B39/RTOG 0413 protocol.
Bovi J, Qi XS, White J, et al (Med College of Wisconsin, Milwaukee) Radiother Oncol 84:226-232, 2007
Background and Purpose.—Accelerated partial breast irradiation (APBI) is being studied in a phase III randomized trial as an alternative to whole breast irradiation (WBI) for early stage breast cancer patients. There are three methods for APBI: multi-catheter brachytherapy (MCT), MammoSiteÒ brachytherapy (MST), or 3D conformal (3DCRT). There is a paucity of data comparing among methods. Using a linear–quadratic (LQ) model, we
J. White, MD
In the NSABP-B39/RTOG 0413 phase III trial investigating APBI, treatment was delivered via any of the 3 ‘‘classic’’ APBI techniques: MCT, MST, or 3DCRT. In the design of the protocol, these 3 treatment techniques were assumed to be equivalent, and quality assurance guidelines were designed to best equate dose delivery. However, it is recognized that
Breast Diseases: A Year BookÒ Quarterly Vol 19 No 3 2008
259
unavoidable dosimetric differences between the techniques do exist. This sophisticated investigation by Bovi and colleagues of the expected biological effectiveness of these classic methods of APBI delivery is one of the most comprehensive analyses to date of the radiobiologic aspects of APBI. This study attempted to provide insight into how the dosimetric differences of these techniques may be related to outcome. In review of this investigation, the conclusions made by the authors serve as motivation for further investigation and raise 3 important issues. Using the concept of EUD, the authors concluded that there were identifiable differences in TCP between the 3 treatment techniques. Because the authors did not conduct a statistical evaluation, the first issue focuses on whether the calculated differences were statistically significant. Without this statistical information, it is unclear whether the findings can be translated into clinically significant findings. The second issue focuses on the a/b ratio. The authors acknowledged that recent clinical data from a randomized trial conducted at the Royal Marsden Hospital1 had sug-
260
gested that the value of a/b is close to 4 Gy; however, for their comparison of these techniques, Bovi and colleagues used the standard a/b value of 10 Gy. The use of an a/b value of 4 Gy would result in an increased EUD for all modalities because of the hypofractionation inherent in APBI; however, these results were not presented because the authors were interested in the relative values for the different modalities. The third issue involves the authors’ conclusions. In this study, multicatheter APBI was associated with a lower EUD, which led the authors to conclude that this technique might be biologically inferior to the others and that an adjustment in prescription dose might be needed to ensure comparable results. However, it should be noted that MCT is the original method for delivering APBI; has resulted in excellent, mature follow-up data; and is the technique upon which the foundation of APBI has been built. Intermediate follow-up data are only now emerging from the use of the MammoSite device, and follow-up data from treatment with 3DCRT are limited at best. With MCT arguably representing the gold standard method of APBI
Breast Diseases: A Year BookÒ Quarterly Vol 19 No 3 2008
delivery, the authors have generated an interesting hypothesis: if the current dose for multicatheter APBI produces excellent clinical outcomes but is associated with a lower EUD, it may be more correct to suggest that the doses presently used for MST and 3DCRT delivery of APBI are actually too high. It is difficult to make definitive treatment recommendations on the basis of radiobiologic modeling without confirmatory clinical outcome; however, this work generates some interesting questions that may generate insight about this topic and enable us to properly interpret results from ongoing randomized trials as long-term follow-up data become available. L. W. Cuttino, MD D. W. Arthur, MD
Reference 1. Owen JR, Ashton A, Bliss JM, et al. Effect of radiotherapy fraction size on tumour control in patients with earlystage breast cancer after local tumour excision: long-term results of a randomised trial. Lancet Oncol. 2006;7:467-471.