Letters / Clinical Oncology 26 (2014) 120e123
reported to the MHRA between 2 May 1999 and 13 September 2012. The haematological ADRs selected were any types of myelosuppression and considered idiosyncratic drug reaction (IDR) if these were associated with bone marrow biopsy-confirmed aplastic anaemia or grade 5 pancytopenia (death) or bone marrow suppression with a slow and incomplete haematological recovery after a temporally related limited exposure to temozolomide; because, normally, temozolomide-related haematological toxicities are reversible [4]. Of a total of 91 unique cases, 31 were reported as myelosuppression; of which nine were excluded due to associated confounders. In 22 cases, the median age (missing in six cases) was 60 years (range 9e66) d14 women (64%), seven men (32%) and one not known. Reported were 14 cases of unresolved profound myelosuppression (possible aplastic anaemia), two deaths and seven cases with features of aplastic anaemia. The IDRs occurred after a median latency (missing in five cases) of 30 days (range 13e76 days) and a median cumulative dose exposure of 4200 mg (range 1500e7800 mg). Fifteen (80%) had a daily schedule with concurrent radiotherapy. Despite few missing values in the MHRA data, the characteristics of haematological IDRs seem to be similar to those observed in the systematic review and Food and Drug Administration MedWatch reporting system (Table 1). Temozolomide seems to be the only non-haematological chemotherapy agent that has been associated with aplastic
121
anaemia. The early onset and lower cumulative dose suggest that these could be IDRs. This report corroborates the prevalence of temozolomide-related aplastic anaemia, although very rare. These haematological IDRs occurred predominantly in females and more often were associated with a daily schedule given concomitant with radiotherapy. To understand the mechanism of such haematological IDRs and to identify an association with any possible genotype, prompt and detailed reporting of such an event to the MHRA is warranted. Presented at British Neuro-Oncology Society Annual Meeting on 11th July 2013, Durham. S. Dixit*, M. Hingorani*, V. Allgary * Hull & East Yorkshire Hospitals NHS Trust, Hull HU16 5JQ, UK y
Hull and York Medical School, University of York, Heslington, York YO10 5DD, UK
References [1] Dixit S, Baker L, Walmsley V, Hingorani M. Temozolomiderelated idiosyncratic and other uncommon toxicities: a systematic review. Anticancer Drugs 2012;23:1099e1106. [2] Villano JL, Letarte N, Yu JM, Abdur S, Bressler LR. Hematologic adverse events associated with temozolomide. Cancer Chemother Pharmacol 2012;69:107e113. [3] http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ ucm115974.htm#TemozolomidemarketedasTemodar: AplasticAnemia. [4] Dario A, Tomei G. The safety of the temozolomide in patients with malignant glioma. Curr Drug Saf 2006;1:205e222.
Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved http://dx.doi.org/10.1016/j.clon.2013.10.003
Intraoperative Radiotherapy for Breast Cancer Deserves a Mention Sir d We read with interest the editorial by Bartlett and colleagues [1] addressing the issue of cardiac toxicity from breast radiotherapy. Although techniques to reduce cardiac dose, including cardiac shielding and breath-holding techniques, are discussed we note that the use of intraoperative radiotherapy techniques are not mentioned. These technologies include the TARGIT system, where a miniature X-ray generator in the operating theatre produces low energy X-rays (50 kV) in an isotropic dose distribution around the tip. The irradiated breast tissue is kept at a fixed distance from the source by a spherical applicator, the size of which is chosen to fit the cavity after the excision of the tumour. Early results of the TARGIT randomised controlled trial suggest that the single dose of radiotherapy delivered at the time of surgery is safe and for selected patients with early breast cancer can be considered an alternative to conventional external beam radiotherapy to the breast [2]. An update of this trial has shown a non-significant trend towards improved overall survival with TARGIT (hazard
ratio ¼ 0.70; 0.46e1.07) due to a reduction in non-breast cancer deaths (17 versus 35, hazard ratio 0.47; 0.26e0.84). Interestingly, cardiovascular deaths were one in the TARGIT arm versus 10 in the external beam arm [3]. Work is ongoing by our team to quantify the difference in cardiac exposure between external beam radiotherapy and intraoperative radiotherapy using a biomarker of radiation exposure: the phosphorylated histone H2AX protein (gH2AX) [4], and will be presented at the San Antonio Breast Cancer Symposium in 2013. Although we believe that external beam radiotherapy in the treatment of early breast cancer remains the gold standard, intraoperative radiotherapy may be a safe alternative, with reduced cardiac dose and toxicity and deserves a mention in the prevention of radiation-induced cardiac late effects. D.K. Woolf, M. Keshtgar Department of Academic Surgery and Oncology, Royal Free Hospital, London, UK
122
Letters / Clinical Oncology 26 (2014) 120e123
References [1] Bartlett FR, Yarnold JR, Kirby AM. Breast radiotherapy and heart disease e where are we now? Clin Oncol 2013. Accessed at: http://dx.doi.org/10.1016/j.clon.2013.08.001. [2] Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376(9735): 91e102.
[3] Vaidya JS, Wenz F, Bulsara M, et al. Targeted intraoperative radiotherapy for early breast cancer: TARGET-A Trial e updated analysis of local recurrence and first analysis of survival. Available at: http://www.abstracts2view.com/sabcs12/ view.php?nu¼SABCS12L_3020. [4] Sak A, Grehl S, Erichsen P, et al. Gamma-H2AX foci formation in peripheral blood lymphocytes of tumor patients after local radiotherapy to different sites of the body: dependence on the dose-distribution, irradiated site and time from start of treatment. Int J Radiat Biol 2007;83(10):639e652.
DOI of original article: http://dx.doi.org/10.1016/j.clon.2013.08.001. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved http://dx.doi.org/10.1016/j.clon.2013.10.004
Research Opportunities for Vascular Endothelial Growth Factor Receptor and Ki67 Relative Percentage Co-reduction in Patients with Locally Advanced Rectal Cancer Treated with Neoadjuvant Therapy Sir e We read with great interest a recent large multicentre collaborative study on Radiogenomics Assessment of Polymorphisms for Predicting the Effects of Radiotherapy (RAPPER) [1]. Successful identification of genetic and/or molecular biomarkers will allow predictive testing for normal tissue radiosensitivity and tumour response and should contribute to better outcomes through biological individualisation of radiotherapy [2]. Several (>35) individual molecular biomarker candidates have been reported. However, molecular overexpression is not consistently associated with survival outcomes [2]. It could be hypothesised that the reason for the inconsistency of reported studies could be that molecular overexpression on its own does not translate into molecular activity [3]. Therefore, we would like to provide a supplementary comparative analysis on this issue. We measured Ki67(DKi67%), vascular endothelial growth factor receptor-2 (VEGFR-2) (DVEGFR-2%), epidermal growth factor receptor (EGFR) (DEGFR%) and cyclooxygenase-2 (COX-2) (DCOX-2%) percentage reduction after preoperative treatment for locally advanced rectal cancer patients (n ¼ 38) and associated molecular response with long-term clinical outcome. VEGFR-2, EGFR and COX-2 were measured using a quantitative and qualitative compound immunohistochemistry analysis (immunoreactive score; IRS) in the pretreatment endoscopic biopsy and definitive surgical specimen [4]. Ki67% activity (median, 80%) was quantified within tumours with molecular overexpression (IRS 3 þ Ki67 80 ¼ nonresponders; IRS 3 þ Ki67 < 80 ¼ responders; IRS < 3 ¼ responders). After immunohistochemical staining, the level of staining of each tissue core was assessed by two pathologists (blind to all patient characteristics and expression of other immunohistochemistry markers) according to the IRS. A re-evaluation of each of the stained cross-sections was carried out at a later date to test reproducibility (all slides matched previous scores).
With a median follow-up of 69.3 months (range 4.5e92), 5-year overall survival and disease-free survival were 78.9 and 72.4%. On multivariate analysis, non-responder DVEGFR-2%/DKi67% (hazard ratio 6.22, P ¼ 0.01) and DCOX-2%/DKi67% (hazard ratio 5.17, P ¼ 0.04) tumours were associated with worse disease-free survival. In relation to overall survival, only DVEGFR-2%/DKi67% non-responder tumours remained statistically significant for overall survival (hazard ratio 5.21, P ¼ 0.04). By contrast, DEGFR %/DKi67% index was not significantly associated with disease-free survival (hazard ratio 2.70, P ¼ 0.39) or overall survival (hazard ratio 3.35, P ¼ 0.41). The emergence of nomograms as new clinical practiceoriented methodologies in the evaluation of locally advanced rectal cancer patients, heralds an era of individualised cancer therapy. The available molecular technology introduces clinical information incorporated as innovative scores for new prognostic/predictive features, that could help to guide treatment recommendations and future randomised trials [5].
Acknowledgements Financed in part by a research grant from Mutua ~ a Biomedical, Foundation Institute Health Madrilen ~ on, study code CMF, FMM 06-02. Research Maran C.V. Sole*yz, F.A. Calvo*yz * Department of Oncology, Hospital General Universitario Gregorio ~o n, Madrid, Spain Maran y z
School of Medicine Complutense University, Madrid, Spain
Institute for Sanitary Research, Hospital General Universitario ~o n, Madrid, Spain Gregorio Maran
reported to the MHRA between 2 May 1999 and 13 September 2012. The haematological ADRs selected were any types of myelosuppression and considered idiosyncratic drug reaction (IDR) if these were associated with bone marrow biopsy-confirmed aplastic anaemia or grade 5 pancytopenia (death) or bone marrow suppression with a slow and incomplete haematological recovery after a temporally related limited exposure to temozolomide; because, normally, temozolomide-related haematological toxicities are reversible [4]. Of a total of 91 unique cases, 31 were reported as myelosuppression; of which nine were excluded due to associated confounders. In 22 cases, the median age (missing in six cases) was 60 years (range 9e66) d14 women (64%), seven men (32%) and one not known. Reported were 14 cases of unresolved profound myelosuppression (possible aplastic anaemia), two deaths and seven cases with features of aplastic anaemia. The IDRs occurred after a median latency (missing in five cases) of 30 days (range 13e76 days) and a median cumulative dose exposure of 4200 mg (range 1500e7800 mg). Fifteen (80%) had a daily schedule with concurrent radiotherapy. Despite few missing values in the MHRA data, the characteristics of haematological IDRs seem to be similar to those observed in the systematic review and Food and Drug Administration MedWatch reporting system (Table 1). Temozolomide seems to be the only non-haematological chemotherapy agent that has been associated with aplastic
121
anaemia. The early onset and lower cumulative dose suggest that these could be IDRs. This report corroborates the prevalence of temozolomide-related aplastic anaemia, although very rare. These haematological IDRs occurred predominantly in females and more often were associated with a daily schedule given concomitant with radiotherapy. To understand the mechanism of such haematological IDRs and to identify an association with any possible genotype, prompt and detailed reporting of such an event to the MHRA is warranted. Presented at British Neuro-Oncology Society Annual Meeting on 11th July 2013, Durham. S. Dixit*, M. Hingorani*, V. Allgary * Hull & East Yorkshire Hospitals NHS Trust, Hull HU16 5JQ, UK y
Hull and York Medical School, University of York, Heslington, York YO10 5DD, UK
References [1] Dixit S, Baker L, Walmsley V, Hingorani M. Temozolomiderelated idiosyncratic and other uncommon toxicities: a systematic review. Anticancer Drugs 2012;23:1099e1106. [2] Villano JL, Letarte N, Yu JM, Abdur S, Bressler LR. Hematologic adverse events associated with temozolomide. Cancer Chemother Pharmacol 2012;69:107e113. [3] http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ ucm115974.htm#TemozolomidemarketedasTemodar: AplasticAnemia. [4] Dario A, Tomei G. The safety of the temozolomide in patients with malignant glioma. Curr Drug Saf 2006;1:205e222.
Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved http://dx.doi.org/10.1016/j.clon.2013.10.003
Intraoperative Radiotherapy for Breast Cancer Deserves a Mention Sir d We read with interest the editorial by Bartlett and colleagues [1] addressing the issue of cardiac toxicity from breast radiotherapy. Although techniques to reduce cardiac dose, including cardiac shielding and breath-holding techniques, are discussed we note that the use of intraoperative radiotherapy techniques are not mentioned. These technologies include the TARGIT system, where a miniature X-ray generator in the operating theatre produces low energy X-rays (50 kV) in an isotropic dose distribution around the tip. The irradiated breast tissue is kept at a fixed distance from the source by a spherical applicator, the size of which is chosen to fit the cavity after the excision of the tumour. Early results of the TARGIT randomised controlled trial suggest that the single dose of radiotherapy delivered at the time of surgery is safe and for selected patients with early breast cancer can be considered an alternative to conventional external beam radiotherapy to the breast [2]. An update of this trial has shown a non-significant trend towards improved overall survival with TARGIT (hazard
ratio ¼ 0.70; 0.46e1.07) due to a reduction in non-breast cancer deaths (17 versus 35, hazard ratio 0.47; 0.26e0.84). Interestingly, cardiovascular deaths were one in the TARGIT arm versus 10 in the external beam arm [3]. Work is ongoing by our team to quantify the difference in cardiac exposure between external beam radiotherapy and intraoperative radiotherapy using a biomarker of radiation exposure: the phosphorylated histone H2AX protein (gH2AX) [4], and will be presented at the San Antonio Breast Cancer Symposium in 2013. Although we believe that external beam radiotherapy in the treatment of early breast cancer remains the gold standard, intraoperative radiotherapy may be a safe alternative, with reduced cardiac dose and toxicity and deserves a mention in the prevention of radiation-induced cardiac late effects. D.K. Woolf, M. Keshtgar Department of Academic Surgery and Oncology, Royal Free Hospital, London, UK
122
Letters / Clinical Oncology 26 (2014) 120e123
References [1] Bartlett FR, Yarnold JR, Kirby AM. Breast radiotherapy and heart disease e where are we now? Clin Oncol 2013. Accessed at: http://dx.doi.org/10.1016/j.clon.2013.08.001. [2] Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376(9735): 91e102.
[3] Vaidya JS, Wenz F, Bulsara M, et al. Targeted intraoperative radiotherapy for early breast cancer: TARGET-A Trial e updated analysis of local recurrence and first analysis of survival. Available at: http://www.abstracts2view.com/sabcs12/ view.php?nu¼SABCS12L_3020. [4] Sak A, Grehl S, Erichsen P, et al. Gamma-H2AX foci formation in peripheral blood lymphocytes of tumor patients after local radiotherapy to different sites of the body: dependence on the dose-distribution, irradiated site and time from start of treatment. Int J Radiat Biol 2007;83(10):639e652.
DOI of original article: http://dx.doi.org/10.1016/j.clon.2013.08.001. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved http://dx.doi.org/10.1016/j.clon.2013.10.004
Research Opportunities for Vascular Endothelial Growth Factor Receptor and Ki67 Relative Percentage Co-reduction in Patients with Locally Advanced Rectal Cancer Treated with Neoadjuvant Therapy Sir e We read with great interest a recent large multicentre collaborative study on Radiogenomics Assessment of Polymorphisms for Predicting the Effects of Radiotherapy (RAPPER) [1]. Successful identification of genetic and/or molecular biomarkers will allow predictive testing for normal tissue radiosensitivity and tumour response and should contribute to better outcomes through biological individualisation of radiotherapy [2]. Several (>35) individual molecular biomarker candidates have been reported. However, molecular overexpression is not consistently associated with survival outcomes [2]. It could be hypothesised that the reason for the inconsistency of reported studies could be that molecular overexpression on its own does not translate into molecular activity [3]. Therefore, we would like to provide a supplementary comparative analysis on this issue. We measured Ki67(DKi67%), vascular endothelial growth factor receptor-2 (VEGFR-2) (DVEGFR-2%), epidermal growth factor receptor (EGFR) (DEGFR%) and cyclooxygenase-2 (COX-2) (DCOX-2%) percentage reduction after preoperative treatment for locally advanced rectal cancer patients (n ¼ 38) and associated molecular response with long-term clinical outcome. VEGFR-2, EGFR and COX-2 were measured using a quantitative and qualitative compound immunohistochemistry analysis (immunoreactive score; IRS) in the pretreatment endoscopic biopsy and definitive surgical specimen [4]. Ki67% activity (median, 80%) was quantified within tumours with molecular overexpression (IRS 3 þ Ki67 80 ¼ nonresponders; IRS 3 þ Ki67 < 80 ¼ responders; IRS < 3 ¼ responders). After immunohistochemical staining, the level of staining of each tissue core was assessed by two pathologists (blind to all patient characteristics and expression of other immunohistochemistry markers) according to the IRS. A re-evaluation of each of the stained cross-sections was carried out at a later date to test reproducibility (all slides matched previous scores).
With a median follow-up of 69.3 months (range 4.5e92), 5-year overall survival and disease-free survival were 78.9 and 72.4%. On multivariate analysis, non-responder DVEGFR-2%/DKi67% (hazard ratio 6.22, P ¼ 0.01) and DCOX-2%/DKi67% (hazard ratio 5.17, P ¼ 0.04) tumours were associated with worse disease-free survival. In relation to overall survival, only DVEGFR-2%/DKi67% non-responder tumours remained statistically significant for overall survival (hazard ratio 5.21, P ¼ 0.04). By contrast, DEGFR %/DKi67% index was not significantly associated with disease-free survival (hazard ratio 2.70, P ¼ 0.39) or overall survival (hazard ratio 3.35, P ¼ 0.41). The emergence of nomograms as new clinical practiceoriented methodologies in the evaluation of locally advanced rectal cancer patients, heralds an era of individualised cancer therapy. The available molecular technology introduces clinical information incorporated as innovative scores for new prognostic/predictive features, that could help to guide treatment recommendations and future randomised trials [5].
Acknowledgements Financed in part by a research grant from Mutua ~ a Biomedical, Foundation Institute Health Madrilen ~ on, study code CMF, FMM 06-02. Research Maran C.V. Sole*yz, F.A. Calvo*yz * Department of Oncology, Hospital General Universitario Gregorio ~o n, Madrid, Spain Maran y z
School of Medicine Complutense University, Madrid, Spain
Institute for Sanitary Research, Hospital General Universitario ~o n, Madrid, Spain Gregorio Maran
