- Email: [email protected]
Interstitial fluid pressure of tumors as a function of parameters derived by dynamic contrast-enhanced magnetic resonance imaging: Response to letter by Farace and Boschi
Letters to the Editor / Radiotherapy and Oncology 94 (2010) 384–390
The above equation seems to be the function which Gulliksrud et al. are looking for; mapping this function could produce relative maps of IFP. The parameters Kin and Kep are commonly used in the Tofts pharmacokinetic model [5] and are related to the parameters of the modified Kety equation applied in [1]. In both the bolus and slow infusion methods, a term Kout = Kepve is defined as the out-flux volume transfer constant, where ve depicts EES fractional volume. It has been suggested [4,6] that Kout and ve cannot be determined independently, being K in –K out , due to convective pressure gradients. If a unique transfer constant (i.e. Kin = Kout in each voxel) is assumed, it would result that IFP / ve, but the above distinction (i.e. K in –K out ), taking convective pressure gradients into account, has to be preferred. References [1] Gulliksrud K, Brurberg KG, Rofstad EK. Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure. Radiother Oncol 2009;91:107–13. [2] Rofstad EK, Gaustad JV, Brurberg KG, Mathiesen B, Galappathi K, Simonsen TG. Radiocurability is associated with interstitial fluid pressure in human tumor xenografts. Neoplasia. 2009;11:1243–51. [3] Hassid Y, Furman-Haran E, Margalit R, Eilam R, Degani H. Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors. Cancer Res 2006;66:4159–66. [4] Hassid Y, Eyal E, Margalit R, Furman-Haran E, Degani H. Non-invasive imaging of barriers to drug delivery in tumors. Microvasc Res 2008;76:94–103. [5] Tofts PS, Berkowitz BA. Measurement of capillary permeability from the Gd enhancement curve: a comparison of bolus and constant infusion injection methods. Magn Reson Imaging 1994;12:81–91. [6] Dadiani M, Margalit R, Sela N, Degani H. High-resolution magnetic resonance imaging of disparities in the transcapillary transfer rates in orthotopically inoculated invasive breast tumors. Cancer Res 2004;64:3155–61.
Paolo Farace Federico Boschi Department of Morphological-Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Verona (VR), Italy E-mail address: [email protected] (P. Farace). Received 27 November 2009 Accepted 23 December 2009
385
entire tumor volume except close to the surface, where it drops precipitously to normal tissue values. High central tumor IFP is associated with high incidence of metastases [2], radiation resistance [3], and poor outcome of treatment [4]. A noninvasive method for assessing the IFP of tumors is therefore needed. To be useful, the method should determine accurately the IFP in the central regions of tumors, but does not necessarily need to map the steep IFP gradient in the tumor periphery. By using a slow gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) infusion method, Hassid et al. [5] showed that parametric images of the steady-state concentration of Gd-DTPA reflected the spatial distribution of IFP in human tumor xenografts. However, this method did not provide accurate absolute values of the IFP in the tumor center. Based on the method of Hassid et al. [5], Farace and Boschi [1] suggest that relative maps of IFP can be produced from DCE-MRIderived pharmacokinetic parameters obtained by bolus injection of Gd-DTPA using the relation
IFP /
K in kep
where Kin is the influx volume transfer constant of Gd-DTPA from blood plasma to extravascular extracellular space (EES) and kep is the efflux rate of Gd-DTPA from EES to blood plasma. This is exactly one of the possibilities that were investigated in our study [6]. We determined two parameters (Kin and kep) and produced parametric images of E F and k, where E F / Kin and k / Kin/kep = (Kin/Kout) ve, where ve represents the EES fractional volume and can be calculated by assuming isodirectional permeability (Kout = Kin). A weak but statistically significant inverse correlation was found between k and central tumor IFP for A-07 tumors, but no correlation was found for R-18 tumors. Furthermore, particularly high k values could not be detected in the tumor periphery in regions corresponding to the steep IFP gradient. Most likely, k maps (i.e., Kin/kep maps) obtained after bolus injection of Gd-DTPA do not reflect IFP well because these maps are determined primarily by the EES fractional volume and not by the main determinant of the IFP, the microvascular hydrostatic pressure. In line with this suggestion, weak but statistically significant inverse correlations were found between E F and IFP for both A-07 and R18 tumors [6].
0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.12.026
References Interstitial fluid pressure of tumors as a function of parameters derived by dynamic contrast-enhanced magnetic resonance imaging: Response to letter by Farace and Boschi We read with interest the letter by Farace and Boschi [1] sharing their thoughts on strategies for assessing the interstitial fluid pressure (IFP) of tumors by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Tumors show high resistance to capillary blood flow, low resistance to transcapillary fluid flow, and impaired lymphatic drainage. The microvascular hydrostatic pressure forces fluid from the microvasculature into the interstitium where it accumulates and causes an elevation of the IFP. The IFP forces interstitial fluid from the tumor periphery into adjacent normal tissues where it is collected by lymphatics. Because the resistance to fluid flow in the interstitium greatly exceeds the resistance to transcapillary fluid flow, a pseudostable state is established where the central tumor IFP is nearly equal to the microvascular hydrostatic pressure. In this pseudostable state, the IFP is nearly uniform throughout the
[1] Farace P, Boschi F. IFP as a function of DCE-MRI derived parameters. Radiother Oncol 2010;94:384–5. [2] Rofstad EK, Tunheim SH, Mathiesen B, et al. Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Res 2002;62:661–4. [3] Rofstad EK, Gaustad JV, Brurberg KG, Mathiesen B, Galappathi K, Simonsen TG. Radiocurability is associated with interstitial fluid pressure in human tumor xenografts. Neoplasia 2009;11:1243–51. [4] Fyles A, Milosevic M, Pintilie M, et al. Long-term performance of interstitial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006;80:132–7. [5] Hassid Y, Furman-Haran E, Margalit R, Eilam R, Degani H. Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors. Cancer Res 2006;66:4159–66. [6] Gulliksrud K, Brurberg KG, Rofstad EK. Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure. Radiother Oncol 2009;91:107–13.
Kristine Gulliksrud Tormod A.M. Egeland Jon-Vidar Gaustad Einar K. Rofstad
386
Letters to the Editor / Radiotherapy and Oncology 94 (2010) 384–390
Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway E-mail address: [email protected] (E.K. Rofstad). Received 15 December 2009 Accepted 23 December 2009 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.12.025
In response to the ‘‘Letter to the editor’’ by Al-Qaisieh et al.: Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: Comparison between loose and stranded seed implants
We have read with interest the comments of Al-Qaisieh et al. on our study concerning the decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy [1]. Their first remark concerns reporting only D90. However, the results section also gives the values of the parameters VT,100, VT,150 and VT,200 and explains why we chose to perform the analysis on D90 only. The second remark concerns patient selection and number of patients in different groups. As mentioned in the material and methods section the patients were arbitrarily selected for either a stranded seed implant or a loose seed implant, which makes this study a retrospective study and not a randomized one. Therefore, a statistical analysis was performed taking possibly influencing factors like prostate volume or physician preference into account (see also Table 2). Differences in group size are taken into account in standard statistical testing procedures. The third remark concerns experience and robustness of technique. As described in the discussion and conclusion section, we expect other differences in technique, apart from different seed types, not to be confounders in this comparison study. We have a large experience in using both implant techniques (loose and stranded). Both techniques are the same (template, US guidance, planning system, dose criteria), except for type of seeds (loose or stranded) and insertion (manually for stranded seeds or automatically with seedloader for loose selectSeeds). In both techniques needle position and seed delivery is verified on the live US image. We see no reason why one technique is more robust or reproducible than the other. And if experience plays a role, the strand technique is used since 1996, while the loose seed technique with the seedloader is routinely used since 2000. The 4th remark concerns the use of the 1D dose calculation formalism in this study. We agree that the use of a 3D dose calculation algorithm would give more accurate dosimetry results. However, for this study the use of the 1D dose formalism as described in the AAPM TG43 update report [2] is not a limiting factor to make judgments on implant quality for three reasons. Firstly, in current practice most institutes use the 1D formalism and reported results are generally based on the 1D calculations. Therefore the D90 values in our manuscript can be compared with reported values from literature. Secondly, due to the large amount of seeds of an implant D90 differences between the 1D and 2D calculations are small. Thirdly, the decline in D90 between post implant dosimetry and intraoperative plan stems from superior/inferior shifts of the seeds/strands irrespective of dose calculation formalism. The 5th remark concerns the impact of different prostate volumes resulting in different number of needles and sources when
using seeds of a certain air kerma strength. It might also influence the dynamic of prostate swelling. As shown in Table 2, decline of D90 between post implant and intraoperative dosimetry hardly changed if adjusted for intraoperative prostate volume and ratio of post implant and intraoperative prostate volume. The 6th remark concerns the definition of base and apex and D90 values of these regions. As described in the material and methods section, two or three contours were extracted from the delineated prostate to get base and apex prostate volumes of 2 cm3 on average and for these volumes D90 values were calculated as a measure for post implant apex dose and base dose. Finally, Al-Qaisieh et al. state that that loose seeds are more likely to experience migration, movement and loss affecting post implant dosimetry. In this study, any seed loss within 4 weeks post implant was taken into account, since dosimetry was based on CT and MRI acquired 4 weeks after the implant. Nevertheless, dosimetry results (D90) were better for the loose seed implants indicating that loss of loose seeds plays a minor role in this study. References [1] Moerland MA, van Deursen MJH, Elias SG, van Vulpen M, Jürgenliemk-Schulz IM, Battermann JJ. Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: comparison between loose and stranded seed implants. Radiother Oncol 2009;91:202–6. [2] Rivard MJ, Coursey BM, DeWerd LA, et al. Update of AAPM Task Group No. 43 Report: a revised AAPM protocol for brachytherapy dose calculations. Med Phys 2004;31:633–74.
M.A. Moerland a,* M.J.H. van Deursen a S.G. Elias b M. van Vulpen a I.M. Jürgenliemk-Schulz a J.J. Battermann a a Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands b Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands * Tel.: +31 887557158; fax: +31 887555850. E-mail address: [email protected] (M.A. Moerland). Received 25 January 2010 Accepted 29 January 2010 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.01.018
Comment on Moerland et al. study of decline of dose coverage between different implant techniques for I125 prostate brachytherapy
This paper describes a retrospective comparison of the dose coverage between loose and stranded seeds implants. The goal of the study is to investigate which implant technique gives the best agreement between planned and achieved prostate dosimetry. The main conclusions are that the dose coverage expressed as D90 in the post planning is lower than the intra-operative value, and more importantly that this decline is more obvious when using a stranded implant technique. The authors have vast experience in prostate brachytherapy and the paper is certainly of importance. However, in our opinion there are important aspects that have not been considered in the paper. In particular, further calcification of the results and the hypotheses generated would be helpful. We feel the following issues should be addressed.
The above equation seems to be the function which Gulliksrud et al. are looking for; mapping this function could produce relative maps of IFP. The parameters Kin and Kep are commonly used in the Tofts pharmacokinetic model [5] and are related to the parameters of the modified Kety equation applied in [1]. In both the bolus and slow infusion methods, a term Kout = Kepve is defined as the out-flux volume transfer constant, where ve depicts EES fractional volume. It has been suggested [4,6] that Kout and ve cannot be determined independently, being K in –K out , due to convective pressure gradients. If a unique transfer constant (i.e. Kin = Kout in each voxel) is assumed, it would result that IFP / ve, but the above distinction (i.e. K in –K out ), taking convective pressure gradients into account, has to be preferred. References [1] Gulliksrud K, Brurberg KG, Rofstad EK. Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure. Radiother Oncol 2009;91:107–13. [2] Rofstad EK, Gaustad JV, Brurberg KG, Mathiesen B, Galappathi K, Simonsen TG. Radiocurability is associated with interstitial fluid pressure in human tumor xenografts. Neoplasia. 2009;11:1243–51. [3] Hassid Y, Furman-Haran E, Margalit R, Eilam R, Degani H. Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors. Cancer Res 2006;66:4159–66. [4] Hassid Y, Eyal E, Margalit R, Furman-Haran E, Degani H. Non-invasive imaging of barriers to drug delivery in tumors. Microvasc Res 2008;76:94–103. [5] Tofts PS, Berkowitz BA. Measurement of capillary permeability from the Gd enhancement curve: a comparison of bolus and constant infusion injection methods. Magn Reson Imaging 1994;12:81–91. [6] Dadiani M, Margalit R, Sela N, Degani H. High-resolution magnetic resonance imaging of disparities in the transcapillary transfer rates in orthotopically inoculated invasive breast tumors. Cancer Res 2004;64:3155–61.
Paolo Farace Federico Boschi Department of Morphological-Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Verona (VR), Italy E-mail address: [email protected] (P. Farace). Received 27 November 2009 Accepted 23 December 2009
385
entire tumor volume except close to the surface, where it drops precipitously to normal tissue values. High central tumor IFP is associated with high incidence of metastases [2], radiation resistance [3], and poor outcome of treatment [4]. A noninvasive method for assessing the IFP of tumors is therefore needed. To be useful, the method should determine accurately the IFP in the central regions of tumors, but does not necessarily need to map the steep IFP gradient in the tumor periphery. By using a slow gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) infusion method, Hassid et al. [5] showed that parametric images of the steady-state concentration of Gd-DTPA reflected the spatial distribution of IFP in human tumor xenografts. However, this method did not provide accurate absolute values of the IFP in the tumor center. Based on the method of Hassid et al. [5], Farace and Boschi [1] suggest that relative maps of IFP can be produced from DCE-MRIderived pharmacokinetic parameters obtained by bolus injection of Gd-DTPA using the relation
IFP /
K in kep
where Kin is the influx volume transfer constant of Gd-DTPA from blood plasma to extravascular extracellular space (EES) and kep is the efflux rate of Gd-DTPA from EES to blood plasma. This is exactly one of the possibilities that were investigated in our study [6]. We determined two parameters (Kin and kep) and produced parametric images of E F and k, where E F / Kin and k / Kin/kep = (Kin/Kout) ve, where ve represents the EES fractional volume and can be calculated by assuming isodirectional permeability (Kout = Kin). A weak but statistically significant inverse correlation was found between k and central tumor IFP for A-07 tumors, but no correlation was found for R-18 tumors. Furthermore, particularly high k values could not be detected in the tumor periphery in regions corresponding to the steep IFP gradient. Most likely, k maps (i.e., Kin/kep maps) obtained after bolus injection of Gd-DTPA do not reflect IFP well because these maps are determined primarily by the EES fractional volume and not by the main determinant of the IFP, the microvascular hydrostatic pressure. In line with this suggestion, weak but statistically significant inverse correlations were found between E F and IFP for both A-07 and R18 tumors [6].
0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.12.026
References Interstitial fluid pressure of tumors as a function of parameters derived by dynamic contrast-enhanced magnetic resonance imaging: Response to letter by Farace and Boschi We read with interest the letter by Farace and Boschi [1] sharing their thoughts on strategies for assessing the interstitial fluid pressure (IFP) of tumors by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Tumors show high resistance to capillary blood flow, low resistance to transcapillary fluid flow, and impaired lymphatic drainage. The microvascular hydrostatic pressure forces fluid from the microvasculature into the interstitium where it accumulates and causes an elevation of the IFP. The IFP forces interstitial fluid from the tumor periphery into adjacent normal tissues where it is collected by lymphatics. Because the resistance to fluid flow in the interstitium greatly exceeds the resistance to transcapillary fluid flow, a pseudostable state is established where the central tumor IFP is nearly equal to the microvascular hydrostatic pressure. In this pseudostable state, the IFP is nearly uniform throughout the
[1] Farace P, Boschi F. IFP as a function of DCE-MRI derived parameters. Radiother Oncol 2010;94:384–5. [2] Rofstad EK, Tunheim SH, Mathiesen B, et al. Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Res 2002;62:661–4. [3] Rofstad EK, Gaustad JV, Brurberg KG, Mathiesen B, Galappathi K, Simonsen TG. Radiocurability is associated with interstitial fluid pressure in human tumor xenografts. Neoplasia 2009;11:1243–51. [4] Fyles A, Milosevic M, Pintilie M, et al. Long-term performance of interstitial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006;80:132–7. [5] Hassid Y, Furman-Haran E, Margalit R, Eilam R, Degani H. Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors. Cancer Res 2006;66:4159–66. [6] Gulliksrud K, Brurberg KG, Rofstad EK. Dynamic contrast-enhanced magnetic resonance imaging of tumor interstitial fluid pressure. Radiother Oncol 2009;91:107–13.
Kristine Gulliksrud Tormod A.M. Egeland Jon-Vidar Gaustad Einar K. Rofstad
386
Letters to the Editor / Radiotherapy and Oncology 94 (2010) 384–390
Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway E-mail address: [email protected] (E.K. Rofstad). Received 15 December 2009 Accepted 23 December 2009 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2009.12.025
In response to the ‘‘Letter to the editor’’ by Al-Qaisieh et al.: Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: Comparison between loose and stranded seed implants
We have read with interest the comments of Al-Qaisieh et al. on our study concerning the decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy [1]. Their first remark concerns reporting only D90. However, the results section also gives the values of the parameters VT,100, VT,150 and VT,200 and explains why we chose to perform the analysis on D90 only. The second remark concerns patient selection and number of patients in different groups. As mentioned in the material and methods section the patients were arbitrarily selected for either a stranded seed implant or a loose seed implant, which makes this study a retrospective study and not a randomized one. Therefore, a statistical analysis was performed taking possibly influencing factors like prostate volume or physician preference into account (see also Table 2). Differences in group size are taken into account in standard statistical testing procedures. The third remark concerns experience and robustness of technique. As described in the discussion and conclusion section, we expect other differences in technique, apart from different seed types, not to be confounders in this comparison study. We have a large experience in using both implant techniques (loose and stranded). Both techniques are the same (template, US guidance, planning system, dose criteria), except for type of seeds (loose or stranded) and insertion (manually for stranded seeds or automatically with seedloader for loose selectSeeds). In both techniques needle position and seed delivery is verified on the live US image. We see no reason why one technique is more robust or reproducible than the other. And if experience plays a role, the strand technique is used since 1996, while the loose seed technique with the seedloader is routinely used since 2000. The 4th remark concerns the use of the 1D dose calculation formalism in this study. We agree that the use of a 3D dose calculation algorithm would give more accurate dosimetry results. However, for this study the use of the 1D dose formalism as described in the AAPM TG43 update report [2] is not a limiting factor to make judgments on implant quality for three reasons. Firstly, in current practice most institutes use the 1D formalism and reported results are generally based on the 1D calculations. Therefore the D90 values in our manuscript can be compared with reported values from literature. Secondly, due to the large amount of seeds of an implant D90 differences between the 1D and 2D calculations are small. Thirdly, the decline in D90 between post implant dosimetry and intraoperative plan stems from superior/inferior shifts of the seeds/strands irrespective of dose calculation formalism. The 5th remark concerns the impact of different prostate volumes resulting in different number of needles and sources when
using seeds of a certain air kerma strength. It might also influence the dynamic of prostate swelling. As shown in Table 2, decline of D90 between post implant and intraoperative dosimetry hardly changed if adjusted for intraoperative prostate volume and ratio of post implant and intraoperative prostate volume. The 6th remark concerns the definition of base and apex and D90 values of these regions. As described in the material and methods section, two or three contours were extracted from the delineated prostate to get base and apex prostate volumes of 2 cm3 on average and for these volumes D90 values were calculated as a measure for post implant apex dose and base dose. Finally, Al-Qaisieh et al. state that that loose seeds are more likely to experience migration, movement and loss affecting post implant dosimetry. In this study, any seed loss within 4 weeks post implant was taken into account, since dosimetry was based on CT and MRI acquired 4 weeks after the implant. Nevertheless, dosimetry results (D90) were better for the loose seed implants indicating that loss of loose seeds plays a minor role in this study. References [1] Moerland MA, van Deursen MJH, Elias SG, van Vulpen M, Jürgenliemk-Schulz IM, Battermann JJ. Decline of dose coverage between intraoperative planning and post implant dosimetry for I-125 permanent prostate brachytherapy: comparison between loose and stranded seed implants. Radiother Oncol 2009;91:202–6. [2] Rivard MJ, Coursey BM, DeWerd LA, et al. Update of AAPM Task Group No. 43 Report: a revised AAPM protocol for brachytherapy dose calculations. Med Phys 2004;31:633–74.
M.A. Moerland a,* M.J.H. van Deursen a S.G. Elias b M. van Vulpen a I.M. Jürgenliemk-Schulz a J.J. Battermann a a Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands b Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands * Tel.: +31 887557158; fax: +31 887555850. E-mail address: [email protected] (M.A. Moerland). Received 25 January 2010 Accepted 29 January 2010 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.01.018
Comment on Moerland et al. study of decline of dose coverage between different implant techniques for I125 prostate brachytherapy
This paper describes a retrospective comparison of the dose coverage between loose and stranded seeds implants. The goal of the study is to investigate which implant technique gives the best agreement between planned and achieved prostate dosimetry. The main conclusions are that the dose coverage expressed as D90 in the post planning is lower than the intra-operative value, and more importantly that this decline is more obvious when using a stranded implant technique. The authors have vast experience in prostate brachytherapy and the paper is certainly of importance. However, in our opinion there are important aspects that have not been considered in the paper. In particular, further calcification of the results and the hypotheses generated would be helpful. We feel the following issues should be addressed.