- Email: [email protected]
Comments to article: Henriksson R et al., Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA) Radiother Oncol (2008)
Letters to the Editor / Radiotherapy and Oncology 88 (2008) 285–288
References [1] De Crevoisier R, Sanfilippo N, Gerbaulet A, Morice P, Pomel C, Castaigne D, et al. Exclusive radiotherapy for primary squamous cell carcinoma of the vagina. Radiother Oncol 2007;85: 362–70. [2] Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, et al. Hyperthermia in combined treatment of cancer. Lancet Oncol 2002;3:487–97. [3] J van der Zee. Review. Heating the patient: a promising approach? Annals of Oncology 2002;13:1173–84. [4] Aktas M, De Jong D, Nuyttens JJ, Van der Zee J, Wielheesen DHM, Batman E, et al. Concomitant radiotherapy and hyperthermia for primary carcinoma of the vagina: a cohort study. Eur J Obstet Gynecol Reprod Biol 2007;133:100–4. [5] Creasman WT, Phillips JL, Menck HR. The national cancer data base report on cancer of the vagina. Cancer 1998;83:1033–40. [6] Samant R, Lau B, Choan E, Le T, Tam T. Primary vaginal cancer treated with concurrent chemoradiation using cis-platin. Int J Radiat Oncol Biol Phys 2007;69:746–50. [7] Van der Zee J, Van Rhoon GC. Cervical cancer: radiotherapy and hyperthermia. Int J Hyperthermia 2006;22:229–34.
Jacoba Van der Zee* Erasmus MC – Daniel den Hoed Cancer Centre, Radiotherapy – Hyperthermia Unit, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands E-mail address: [email protected] Catharina E. Kleynen Joost J. Nuyttens Dept Radiation Oncology, Erasmus MC – Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands Anca C. Ansink Gynaecologic Oncology, Erasmus MC – Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands
*
Corresponding author.
Received 23 January 2008; accepted 29 January 2008; Available online 4 March 2008
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.01.020
Comments to article: Henriksson R et al., Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA) Radiother Oncol (2008) The study [1] is based on treatments done at the BNCT facility operated by Studsvik Medical AB at Studsvik, Sweden. My role was that of the physician responsible for the treatments, including physical examination and other medical procedures prior to BNCT, neutron irradiations at Studsvik and patient care during the observation period after
287
BNCT. I was also a co-investigator and responsible for the follow-up of 5 of the 30 patients in the study. I do not concur with many of the conclusions in the article by Henriksson et al. and I therefore decided to withdraw my name from the list of authors. Some of the conclusions which in my opinion have serious consequences for a proper understanding of the clinical results of the study are discussed below. An extensive and misleading account of medication with temozolomide leaves the reader with the impression that this was a major reason for the long survival. The presumed survival advantage is reported in the abstract, despite the fact that this medication was not even part of the study. Also, the difference in survival is actually only as should be expected from the much lower age of patients offered temozolomide, which is the most obvious of several selection biases involved. The median age and the average age of patients offered temozolomide were 13 and 14 years lower, respectively, than that of patients not offered temozolomide. The incorrect value of the median survival in the VTTstudy reported in an earlier version of the study report has been corrected (Table 3), which is important as the true value highlights the advantage of the novel infusion protocol used in the present study. However, while the correct value for the median survival in the BNL-study was quoted in the earlier report, in the present report a range of median survivals is listed. Whatever the reason for this is, the result is that the obvious advantage of prolonged infusion for the efficacy of BNCT is obscured. Unsubstantiated and incorrect statements are made regarding the pre-treatment performance status of the patients and the side effects of the treatment. The true situation is easily verified by comparing the WHO performance status and the frequency of grade 3–4 adverse events, respectively, in the present study to those reported by Stupp et al. (ref. 23 in the article). The remark in the abstract regarding ‘‘the requirement of complex infrastructure and higher resources’’ is appropriate for an initial trial with few patients at a reactor facility but not for the situation in the future, when large volumes of patients will be treated at accelerator based facilities at hospitals. I am personally convinced that, if correctly evaluated, the results of this study would represent a major step forward in the development of BNCT. The unfortunate consequence of the present article, published more than four years after conclusion of the study, is that the development of a promising radiotherapy for a life threatening disease will be seriously compromised.
References [1] Henriksson R, Capala J, Michanek A, et al. Boron neutron capture therapy (BNCT) for glioblastoma multiforme: a phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA). Radiother Oncol 2008;88:183–91.
Britta H-Stenstam Landstinget Sormland, Skogvaktarvagen 22, Eskilstuna, Sweden E-mail address: [email protected]
288
Letters to the Editor / Radiotherapy and Oncology 88 (2008) 285–288
Received 19 March 2008; received in revised form 28 May 2008; accepted 29 May 2008; Available online 9 July 2008
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi: 10.1016/j.radonc.2008.05.026
Boron neutron capture therapy (BNCT) for glioblastoma 4 multiforme: A phase II study evaluating a prolonged highdose of 5 boronophenylalanine (BPA) at the Studsvik facility in Sweden
reason for this was mainly due to the different opinion in evaluation of the results expressed by Dr. Stenstam and by official representatives for the former Studsvik Company. We still believe that the concept of BNCT is most interesting and a challenge to further evaluate. Development of more efficient boron carriers is needed and, by studying the pharmacokinetics of BPA, it has been demonstrated that the timing of neutron irradiation may not have been optimal [1]. The potential efficacy of BNCT has also been indicated in a recent study in the head and neck cancer [3]. However, even the greatest enthusiast must accept a thorough scientific and clinical evaluation.
References Dear Editor We, the authors of the publication of the Swedish BNCTphase II study, as well as Britta Stenstam, former co-author and responsible physician employed to run the BNCT treatment of glioblastoma at the Studsvik BNCT facility, were disappointed when the results of our study were delivered by the independent CRO (clinical trial research organisation)/statistician engaged. Nevertheless, as scientists and clinicians we have to face the hard fact that time-to-tumour progression was only 5.8 months following treatment. This is very similar to what recently has been reported from another Swedish multicenter study in a similar study population, where the time to progress after conventional radiotherapy in glioblastoma was 5.1 months [2]. Therefore, it is our strong opinion that the conclusion ‘‘the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy’’ is correct. As stated in the study protocol, and clearly reported in the present paper, the treatment at relapse was to the discretion of each responsible physician. When retrospectively reviewing the information on the treatment at relapse, it was found that the patients had been given additional treatments. Among those, 13 patients (45%) had been treated with temozolomide and they had a substantial longer survival than those that did not receive temozolomide (17.7 vs. 11.5 months). Despite the fact that the groups were not comparable we believe that it should be misleading not to report this circumstance that, if not reported, could lead to the false impression that BNCT alone was the reason for the overall survival of 14.2 months from treatment. However, as we stated in the discussion ‘‘our results must be evaluated cautiously due to the risk of selections bias’’. We also regret that we have not been able to publish the results from the Swedish BNCT study earlier. However, the
[1] Bergenheim AT, Capala J, Roslin M, Henriksson R. Distribution of P-BPA and metabolic assessment in glioblastoma. A microdialysis study in patients during BNCT treatment. J NeuroOncology 2005;71:287–93. [2] Henriksson R, Malmstro ¨m A, Bergh G, Trojanowsky T, Andreasson L, Blomquist E, et al. Highgrade astrocytoma concomitantly treated with estramustine and radiotherapy. J Neuro-Oncology 2006;78:321–6. [3] Kankaanranta L, Seppa ¨la ¨ T, Koivunoro H, Saarilahti K, Atula T, Collan J, et al. Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69:475–82.
Roger Henriksson* Jacek Capala Annika Michanek ˚ ke Lindahl Sten-A Leif G. Salford Lars Franze ´n Erik Blomquist Jan-Erik Westlin Tommy Bergenheim University Hospital, Department of Radiation Sciences, Umea, Sweden E-mail address: [email protected]
*
Corresponding author.
Received 18 May 2008; accepted 18 May 2008; Available online 14 June 2008
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi: 10.1016/j.radonc.2008.05.024
References [1] De Crevoisier R, Sanfilippo N, Gerbaulet A, Morice P, Pomel C, Castaigne D, et al. Exclusive radiotherapy for primary squamous cell carcinoma of the vagina. Radiother Oncol 2007;85: 362–70. [2] Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, et al. Hyperthermia in combined treatment of cancer. Lancet Oncol 2002;3:487–97. [3] J van der Zee. Review. Heating the patient: a promising approach? Annals of Oncology 2002;13:1173–84. [4] Aktas M, De Jong D, Nuyttens JJ, Van der Zee J, Wielheesen DHM, Batman E, et al. Concomitant radiotherapy and hyperthermia for primary carcinoma of the vagina: a cohort study. Eur J Obstet Gynecol Reprod Biol 2007;133:100–4. [5] Creasman WT, Phillips JL, Menck HR. The national cancer data base report on cancer of the vagina. Cancer 1998;83:1033–40. [6] Samant R, Lau B, Choan E, Le T, Tam T. Primary vaginal cancer treated with concurrent chemoradiation using cis-platin. Int J Radiat Oncol Biol Phys 2007;69:746–50. [7] Van der Zee J, Van Rhoon GC. Cervical cancer: radiotherapy and hyperthermia. Int J Hyperthermia 2006;22:229–34.
Jacoba Van der Zee* Erasmus MC – Daniel den Hoed Cancer Centre, Radiotherapy – Hyperthermia Unit, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands E-mail address: [email protected] Catharina E. Kleynen Joost J. Nuyttens Dept Radiation Oncology, Erasmus MC – Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands Anca C. Ansink Gynaecologic Oncology, Erasmus MC – Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands
*
Corresponding author.
Received 23 January 2008; accepted 29 January 2008; Available online 4 March 2008
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2008.01.020
Comments to article: Henriksson R et al., Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA) Radiother Oncol (2008) The study [1] is based on treatments done at the BNCT facility operated by Studsvik Medical AB at Studsvik, Sweden. My role was that of the physician responsible for the treatments, including physical examination and other medical procedures prior to BNCT, neutron irradiations at Studsvik and patient care during the observation period after
287
BNCT. I was also a co-investigator and responsible for the follow-up of 5 of the 30 patients in the study. I do not concur with many of the conclusions in the article by Henriksson et al. and I therefore decided to withdraw my name from the list of authors. Some of the conclusions which in my opinion have serious consequences for a proper understanding of the clinical results of the study are discussed below. An extensive and misleading account of medication with temozolomide leaves the reader with the impression that this was a major reason for the long survival. The presumed survival advantage is reported in the abstract, despite the fact that this medication was not even part of the study. Also, the difference in survival is actually only as should be expected from the much lower age of patients offered temozolomide, which is the most obvious of several selection biases involved. The median age and the average age of patients offered temozolomide were 13 and 14 years lower, respectively, than that of patients not offered temozolomide. The incorrect value of the median survival in the VTTstudy reported in an earlier version of the study report has been corrected (Table 3), which is important as the true value highlights the advantage of the novel infusion protocol used in the present study. However, while the correct value for the median survival in the BNL-study was quoted in the earlier report, in the present report a range of median survivals is listed. Whatever the reason for this is, the result is that the obvious advantage of prolonged infusion for the efficacy of BNCT is obscured. Unsubstantiated and incorrect statements are made regarding the pre-treatment performance status of the patients and the side effects of the treatment. The true situation is easily verified by comparing the WHO performance status and the frequency of grade 3–4 adverse events, respectively, in the present study to those reported by Stupp et al. (ref. 23 in the article). The remark in the abstract regarding ‘‘the requirement of complex infrastructure and higher resources’’ is appropriate for an initial trial with few patients at a reactor facility but not for the situation in the future, when large volumes of patients will be treated at accelerator based facilities at hospitals. I am personally convinced that, if correctly evaluated, the results of this study would represent a major step forward in the development of BNCT. The unfortunate consequence of the present article, published more than four years after conclusion of the study, is that the development of a promising radiotherapy for a life threatening disease will be seriously compromised.
References [1] Henriksson R, Capala J, Michanek A, et al. Boron neutron capture therapy (BNCT) for glioblastoma multiforme: a phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA). Radiother Oncol 2008;88:183–91.
Britta H-Stenstam Landstinget Sormland, Skogvaktarvagen 22, Eskilstuna, Sweden E-mail address: [email protected]
288
Letters to the Editor / Radiotherapy and Oncology 88 (2008) 285–288
Received 19 March 2008; received in revised form 28 May 2008; accepted 29 May 2008; Available online 9 July 2008
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi: 10.1016/j.radonc.2008.05.026
Boron neutron capture therapy (BNCT) for glioblastoma 4 multiforme: A phase II study evaluating a prolonged highdose of 5 boronophenylalanine (BPA) at the Studsvik facility in Sweden
reason for this was mainly due to the different opinion in evaluation of the results expressed by Dr. Stenstam and by official representatives for the former Studsvik Company. We still believe that the concept of BNCT is most interesting and a challenge to further evaluate. Development of more efficient boron carriers is needed and, by studying the pharmacokinetics of BPA, it has been demonstrated that the timing of neutron irradiation may not have been optimal [1]. The potential efficacy of BNCT has also been indicated in a recent study in the head and neck cancer [3]. However, even the greatest enthusiast must accept a thorough scientific and clinical evaluation.
References Dear Editor We, the authors of the publication of the Swedish BNCTphase II study, as well as Britta Stenstam, former co-author and responsible physician employed to run the BNCT treatment of glioblastoma at the Studsvik BNCT facility, were disappointed when the results of our study were delivered by the independent CRO (clinical trial research organisation)/statistician engaged. Nevertheless, as scientists and clinicians we have to face the hard fact that time-to-tumour progression was only 5.8 months following treatment. This is very similar to what recently has been reported from another Swedish multicenter study in a similar study population, where the time to progress after conventional radiotherapy in glioblastoma was 5.1 months [2]. Therefore, it is our strong opinion that the conclusion ‘‘the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy’’ is correct. As stated in the study protocol, and clearly reported in the present paper, the treatment at relapse was to the discretion of each responsible physician. When retrospectively reviewing the information on the treatment at relapse, it was found that the patients had been given additional treatments. Among those, 13 patients (45%) had been treated with temozolomide and they had a substantial longer survival than those that did not receive temozolomide (17.7 vs. 11.5 months). Despite the fact that the groups were not comparable we believe that it should be misleading not to report this circumstance that, if not reported, could lead to the false impression that BNCT alone was the reason for the overall survival of 14.2 months from treatment. However, as we stated in the discussion ‘‘our results must be evaluated cautiously due to the risk of selections bias’’. We also regret that we have not been able to publish the results from the Swedish BNCT study earlier. However, the
[1] Bergenheim AT, Capala J, Roslin M, Henriksson R. Distribution of P-BPA and metabolic assessment in glioblastoma. A microdialysis study in patients during BNCT treatment. J NeuroOncology 2005;71:287–93. [2] Henriksson R, Malmstro ¨m A, Bergh G, Trojanowsky T, Andreasson L, Blomquist E, et al. Highgrade astrocytoma concomitantly treated with estramustine and radiotherapy. J Neuro-Oncology 2006;78:321–6. [3] Kankaanranta L, Seppa ¨la ¨ T, Koivunoro H, Saarilahti K, Atula T, Collan J, et al. Boron neutron capture therapy in the treatment of locally recurred head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69:475–82.
Roger Henriksson* Jacek Capala Annika Michanek ˚ ke Lindahl Sten-A Leif G. Salford Lars Franze ´n Erik Blomquist Jan-Erik Westlin Tommy Bergenheim University Hospital, Department of Radiation Sciences, Umea, Sweden E-mail address: [email protected]
*
Corresponding author.
Received 18 May 2008; accepted 18 May 2008; Available online 14 June 2008
0167-8140/$ - see front matter c 2008 Elsevier Ireland Ltd. All rights reserved. doi: 10.1016/j.radonc.2008.05.024