Radiotherapy and Oncology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Low incidence of melanoma brain metastasis in the hippocampus Angela M. Hong a,b,c,d,⇑, Chao Suo e, Michael Valenzuela e, Lauren E. Haydu a,b, Kari D. Jacobsen d,f, Claudius H. Reisse d,g, Gerald Fogarty a,d,h a Melanoma Institute Australia, Poche Centre, North Sydney; b Department of Medicine, Central Clinical School, The University of Sydney; c Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney; d Australia and New Zealand Melanoma Trials Group, North Sydney; e Regenerative Neuroscience Group, Brain & Mind Research Institute, The University of Sydney, Australia; f Department of Medical Oncology; g Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo, Norway; h Genesis Cancer Care, Mater Hospital, North Sydney, Australia
a r t i c l e
i n f o
Article history: Received 7 October 2013 Received in revised form 19 January 2014 Accepted 19 January 2014 Available online xxxx Keywords: Brain metastasis Melanoma Whole brain Hippocampal sparing Radiotherapy
a b s t r a c t Aims: ANZMTG 01.07 WBRTMel is a phase 3 randomized trial to address the role of whole brain radiation therapy (WBRT) after local treatment of 1–3 melanoma brain metastases. Modern radiation therapy technologies can now conformally spare the hippocampus during WBRT and therefore potentially reduce the risk of neurocognitive deficit. The aims of this study were to report the prevalence of melanoma metastases within the hippocampal sparing region and to identify variables that correlate with the presence of metastases within the hippocampal sparing region. Methods: The pre-local treatment MRI scans of 77 eligible WBRTMel patients were used to contour the individual metastasis and the hippocampus. The volume, location and closest distance of each metastasis to the hippocampus were recorded. Binary logistic regression was performed to assess the influence of factors on the location of a metastasis within 5 mm of the hippocampus. Results: The median age was 61 and 66% were male. The distribution of the 115 metastases was frontal (50, 43.5%), parietal (23, 20.0%), temporal (13, 11.2%), occipital (18, 15.7%), cerebellum (10, 8.6%) and pineal gland (1, 1.0%). The median aggregate volume of the metastasis was 3516 mm3. None of the metastases were within the hippocampus. Four patients (5.2%) had metastases within 5 mm of the hippocampus. The median distance from metastasis to the nearest hippocampus was 37.2 mm. Only the total volume of metastases was a significant predictor for the risk of a metastasis within the hippocampal sparing region (OR 1.071, 95% CI: 1.003–1.144, p = 0.040). Conclusions: This study confirmed a low incidence of melanoma metastasis in the hippocampal sparing region at diagnosis. Given the lack of randomized data on the safety and benefit of hippocampal sparing WBRT, the current WBRTMel trial provides the opportunity to explore the feasibility of this technique. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2014) xxx–xxx
The incidence of brain metastases in patients with metastatic melanoma ranges from 10% to 40% in clinical studies [1,2] and is even higher in autopsy series with as many as 75% of patients demonstrating cerebral involvement [3,4]. Metastatic melanoma to the brain is a serious event because of the poor prognosis [5] and potential impact on quality of life. Patients with a limited number of lesions and controlled or minimal extracranial disease could benefit from more aggressive treatments such as surgery or stereotactic radiosurgery. The role of whole brain radiation therapy (WBRT) after surgery or stereotactic radiosurgery of the single or oligo melanoma metastases is controversial with no level 1 evidence at this time. The rationale of WBRT is to treat microscopic ⇑ Corresponding author at: Melanoma Institute Australia, Poche Centre, 40 Rocklands Road, North Sydney, NSW 2060, Australia. E-mail address: [email protected] (A.M. Hong).
disease with the aim to maintain long term cerebral control based on randomised studies including mostly non-melanoma histology [6–8]. The Australia and New Zealand Melanoma Trials Group (ANZMTG) and Trans-Tasman Radiation Oncology Group (TROG) are currently conducting a phase 3 randomized trial (WBRTMel) to address the role of whole brain radiation therapy after local treatment of 1–3 melanoma metastases [9]. One concern when delivering WBRT after local treatment of single or oligometastases is the potential for neurological deficit after irradiation. Preclinical and early clinical evidences suggest that damage to neural stem cell compartment in the hippocampus is central to the pathogenesis of neurocognitive deficits after cerebral irradiation [10–12]. Modern radiation therapy technologies, such as volumetric modulated arc therapy and helical tomotherapy can conformally spare the hippocampus during WBRT [8,13] and therefore potentially reduce the risk of neurocognitive deficit
http://dx.doi.org/10.1016/j.radonc.2014.01.012 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Hong AM et al. Low incidence of melanoma brain metastasis in the hippocampus. Radiother Oncol (2014), http:// dx.doi.org/10.1016/j.radonc.2014.01.012
2
Incidence of hippocampal metastasis in melanoma
[14]. Such hippocampal sparing WBRT typically delivers a subtherapeutic dose of radiation to hippocampal sparing region (i.e. both hippocampi and a surrounding 5 mm boundary volume). The aims of this study were to report the prevalence of melanoma metastasis within the hippocampal sparing region, characterize the distribution of metastatic location in relation to hippocampus and to identify clinical and radiographic variables that correlate with the presence of metastasis within the hippocampal sparing region in eligible patients in the WBRTMel trial.
Distance ¼
pffiffiffi fðxi xj Þ2 þ ðyi yj Þ2 þ ðzi zj Þ2 g
Methods and material
where (xi, yi, zi) indicating the coordinate of the ith voxel of VOIHP, and (xj, yj, zj) indicating the coordinate of the jth voxel of VOImet. Since the scale of voxel was resampled as 1 mm by 1 mm by 1 mm, the distances were calculated in mm as well. Finally the shortest distance was calculated between each metastasis and the nearest hippocampus for each individual. This distance was later categorized into the following intervals: 0 (i.e. within or abutting the hippocampus),
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Low incidence of melanoma brain metastasis in the hippocampus Angela M. Hong a,b,c,d,⇑, Chao Suo e, Michael Valenzuela e, Lauren E. Haydu a,b, Kari D. Jacobsen d,f, Claudius H. Reisse d,g, Gerald Fogarty a,d,h a Melanoma Institute Australia, Poche Centre, North Sydney; b Department of Medicine, Central Clinical School, The University of Sydney; c Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney; d Australia and New Zealand Melanoma Trials Group, North Sydney; e Regenerative Neuroscience Group, Brain & Mind Research Institute, The University of Sydney, Australia; f Department of Medical Oncology; g Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo, Norway; h Genesis Cancer Care, Mater Hospital, North Sydney, Australia
a r t i c l e
i n f o
Article history: Received 7 October 2013 Received in revised form 19 January 2014 Accepted 19 January 2014 Available online xxxx Keywords: Brain metastasis Melanoma Whole brain Hippocampal sparing Radiotherapy
a b s t r a c t Aims: ANZMTG 01.07 WBRTMel is a phase 3 randomized trial to address the role of whole brain radiation therapy (WBRT) after local treatment of 1–3 melanoma brain metastases. Modern radiation therapy technologies can now conformally spare the hippocampus during WBRT and therefore potentially reduce the risk of neurocognitive deficit. The aims of this study were to report the prevalence of melanoma metastases within the hippocampal sparing region and to identify variables that correlate with the presence of metastases within the hippocampal sparing region. Methods: The pre-local treatment MRI scans of 77 eligible WBRTMel patients were used to contour the individual metastasis and the hippocampus. The volume, location and closest distance of each metastasis to the hippocampus were recorded. Binary logistic regression was performed to assess the influence of factors on the location of a metastasis within 5 mm of the hippocampus. Results: The median age was 61 and 66% were male. The distribution of the 115 metastases was frontal (50, 43.5%), parietal (23, 20.0%), temporal (13, 11.2%), occipital (18, 15.7%), cerebellum (10, 8.6%) and pineal gland (1, 1.0%). The median aggregate volume of the metastasis was 3516 mm3. None of the metastases were within the hippocampus. Four patients (5.2%) had metastases within 5 mm of the hippocampus. The median distance from metastasis to the nearest hippocampus was 37.2 mm. Only the total volume of metastases was a significant predictor for the risk of a metastasis within the hippocampal sparing region (OR 1.071, 95% CI: 1.003–1.144, p = 0.040). Conclusions: This study confirmed a low incidence of melanoma metastasis in the hippocampal sparing region at diagnosis. Given the lack of randomized data on the safety and benefit of hippocampal sparing WBRT, the current WBRTMel trial provides the opportunity to explore the feasibility of this technique. Ó 2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology xxx (2014) xxx–xxx
The incidence of brain metastases in patients with metastatic melanoma ranges from 10% to 40% in clinical studies [1,2] and is even higher in autopsy series with as many as 75% of patients demonstrating cerebral involvement [3,4]. Metastatic melanoma to the brain is a serious event because of the poor prognosis [5] and potential impact on quality of life. Patients with a limited number of lesions and controlled or minimal extracranial disease could benefit from more aggressive treatments such as surgery or stereotactic radiosurgery. The role of whole brain radiation therapy (WBRT) after surgery or stereotactic radiosurgery of the single or oligo melanoma metastases is controversial with no level 1 evidence at this time. The rationale of WBRT is to treat microscopic ⇑ Corresponding author at: Melanoma Institute Australia, Poche Centre, 40 Rocklands Road, North Sydney, NSW 2060, Australia. E-mail address: [email protected] (A.M. Hong).
disease with the aim to maintain long term cerebral control based on randomised studies including mostly non-melanoma histology [6–8]. The Australia and New Zealand Melanoma Trials Group (ANZMTG) and Trans-Tasman Radiation Oncology Group (TROG) are currently conducting a phase 3 randomized trial (WBRTMel) to address the role of whole brain radiation therapy after local treatment of 1–3 melanoma metastases [9]. One concern when delivering WBRT after local treatment of single or oligometastases is the potential for neurological deficit after irradiation. Preclinical and early clinical evidences suggest that damage to neural stem cell compartment in the hippocampus is central to the pathogenesis of neurocognitive deficits after cerebral irradiation [10–12]. Modern radiation therapy technologies, such as volumetric modulated arc therapy and helical tomotherapy can conformally spare the hippocampus during WBRT [8,13] and therefore potentially reduce the risk of neurocognitive deficit
http://dx.doi.org/10.1016/j.radonc.2014.01.012 0167-8140/Ó 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: Hong AM et al. Low incidence of melanoma brain metastasis in the hippocampus. Radiother Oncol (2014), http:// dx.doi.org/10.1016/j.radonc.2014.01.012
2
Incidence of hippocampal metastasis in melanoma
[14]. Such hippocampal sparing WBRT typically delivers a subtherapeutic dose of radiation to hippocampal sparing region (i.e. both hippocampi and a surrounding 5 mm boundary volume). The aims of this study were to report the prevalence of melanoma metastasis within the hippocampal sparing region, characterize the distribution of metastatic location in relation to hippocampus and to identify clinical and radiographic variables that correlate with the presence of metastasis within the hippocampal sparing region in eligible patients in the WBRTMel trial.
Distance ¼
pffiffiffi fðxi xj Þ2 þ ðyi yj Þ2 þ ðzi zj Þ2 g
Methods and material
where (xi, yi, zi) indicating the coordinate of the ith voxel of VOIHP, and (xj, yj, zj) indicating the coordinate of the jth voxel of VOImet. Since the scale of voxel was resampled as 1 mm by 1 mm by 1 mm, the distances were calculated in mm as well. Finally the shortest distance was calculated between each metastasis and the nearest hippocampus for each individual. This distance was later categorized into the following intervals: 0 (i.e. within or abutting the hippocampus),
