EDITORIAL For reprint orders, please contact: [email protected]
Which therapeutic approach is feasible for elderly people with glioblastoma?
“The presence of comorbidities, and decreased organ functional reserve increases the risk of treatment-related toxicity, especially in elderly patients.”
Alba Fiorentino*1, Mario Balducci2 & Silvia Chiesa2 The incidence of glioblastoma (GBM) is increasing among elderly patients, with a median age at diagnosis of 64 years. Owing to the increase in life expectancy, the age of the GBM population will also continue to grow. The standard treatment approach is still unclear for the elderly population because the effectiveness of adjuvant radiochemotherapy followed by temozolomide (TMZ) was assessed only for patients under 70 years of age in the NCIC trial conducted by Stupp et al. [1,2]. However, despite the benefit of radiochemotherapy especially, in patients with MGMT methylation, survival remains very poor (12–18 months) and improvement has been confined to only younger patients [3]. In neuro-oncology, the therapeutic guidelines for the elderly with GBM are still an unsolved question; and some researchers have reported controversy and difficulties regarding the decision-making process [4–6]. Advanced age is considered a negative prognostic factor for GBM, with a median survival of less than 1 year. Often patients
aged 70 years and over are considered unfit to receive the standard treatment approach owing to the increased risk of toxic effects. However, is this opinion always warranted? Is it possible to define fit or unfit patients in the heterogenic elderly population only using age? Should age be the only factor taken into account when choosing a radical or a palliative treatment? Is a clinical tool necessary? The recently published randomized trials (The Neuro-oncology Working Group of the German Cancer Society, NOA-08 trial, and The Nordic Brain Tumor Study Group, NCBTSG trial), which were conducted to assess the treatment approach for elderly GBM patients, comparing radiotherapy (RT) with TMZ alone, did not evaluate the patients’ geriatric assessment (comorbidity) and enrolled patients only according to age [7,8]. The role of comorbidity in the elderly population with cancer should be evaluated [9–11]. The presence of comorbidities, and decreased organ functional reserve increases the risk of treatment-related toxicity, especially in elderly patients. Organ dysfunction, in fact, may be the
“…patients aged 70 years and over are considered unfit to receive the standard treatment approach owing to the increased risk of toxic effects.”
Radiation Oncology Department, Sacro Cuore-Don Calabria Hospital, Negrar-Verona, Italy Radiation Oncology Department, Catholic University of the Sacred Heart, Rome, Italy *Author for correspondence: Tel.: +39 0972 726480; [email protected] 1 2
10.2217/CNS.13.51 © 2014 Future Medicine Ltd
CNS Oncol. (2014) 3(1), 9–11
part of
ISSN 2045-0907
9
Editorial Fiorentino, Balducci & Chiesa
“At present, age alone should not be the only discriminating factor for choosing or disregarding a treatment modality.”
10
reason for low treatment compliance and the high frequency of treatment side effects (myelosuppression and neurotoxicity, among others). The Charlson Comorbidity index is the only management aid evaluated in GBM. This index, identifying 19 comorbid conditions influencing the 10-year survival rate, has been studied in several tumors and also shows a correlation with survival in GBM patients [9–11]. If other authors can confirm these data, it could be a very useful clinical decision-making tool in the identification of fit or unfit patients. Scott et al. developed a recursive partitioning analysis-derived prognostic model based on age (older or younger than 75.5 years), extent of surgery (complete or partial excision, or biopsy) and Karnofsky performance status for patients older than 70 years of age affected by GBM. The authors observed that this model divided elderly patients into four prognostic subgroups and that “it can be easily implemented in both the patient care and the clinical trial settings” when choosing the correct treatment approach [12]. Thus, those elderly patients with good performance status and without major comorbidities (i.e., fit) should be treated as younger patients [13]. To corroborate this statement, despite the lack of randomized trials, several retrospective, Phase II studies and a recent meta-analysis in patients over 65 years of age showed the tolerability and effectiveness of radiochemotherapy plus TMZ (standard therapy) or radiochemotherapy plus stereotactic RT and TMZ (aggressive treatment) with a median overall survival of 13 months [9,10,13–16]. However, unfit elderly patients (poor performance status and presence of major comorbidities) should receive a therapeutic palliative approach (TMZ or RT alone, or best supportive care). In this setting of patients and treatment, the NOA-08 and the NCBTSG trials [7,8] did not solve the issue of which treatment was preferred because they reported different results, as highlighted by some authors [4,17,18]. In the standard RT arm, the NOA-08 trial showed a median survival of 9.7 months, while the NCBTSG trial reported a survival of only 6 months, these are inferior to the results reported by Stupp et al. [1,2]. Moreover, these trials supported the use of TMZ alone in patients with methylated MGMT status and, in the unmethylated group, the use of RT
CNS Oncol. (2014) 3(1)
(standard or hypofractionated), although TMZ and RT did not differ in terms of outcome. In the NCBTSG trial, median survival in the methylated group was 9.7 and 8.2 months for TMZ and any RT (standard or hypofractionated) arms, respectively, without statistical significance (p = 0.07); while in the NOA-08 trial, methylation status was associated with differences in event-free survival and a trend was observed for overall survival between treatment modalities (TMZ vs RT). The results of these trials were not conclusive, reporting a lower compliance in the chemotherapy group compared with RT, owing to the increased side effects of TMZ, and a higher risk of disease progression during TMZ treatment [7,8]. Despite the fact that TMZ alone, based on MGMT status, can be a valid alternative to RT, it is more expensive and toxic. Other limitations for the comparison of these two trials are: the different cutoff ages (60 vs 70 years old); the NOA-08 trial enrolled patients with a very low performance (Karnofsky performance status: 20) and with grade III and IV histologies; the administration of salvage therapy in both trials, which could have balanced the effects of primary treatments; and the absence of information on the spread of disease/tumor site [17,18]. Sometimes, a limitation for using RT is the potential increased risk of neurotoxicity and mental deterioration, but these toxicities have multifactorial causes, which, in fact, depend more on RT (more frequently by the two-times a day fractionation) than older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, biological agents and progression of disease [19]. Thus, in the palliative setting, especially in elderly patients with poor performance status, other RT or TMZ schedules should be evaluated [20]. In conclusion, the data from the available literature were not sufficient for delineating the correct approach for patients older than 70 years of age affected by GBM. At present, age alone should not be the only discriminating factor for choosing or disregarding a treatment modality. It is still a challenge to determine the correct way to treat elderly patients with GBM in neuro-oncology, and, therefore, trials comparing standard and alternative approaches with the use of a standard nomogram (molecular and clinical findings) to aid the treatment decision-making process, is warranted.
future science group
Which therapeutic approach is feasible for elderly people with glioblastoma? Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
Editorial
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
2
Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987–996 (2005). Stupp R, Hegi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised Phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009).
3
Lawrence YR, Mishra MV, Werner-Wasik M et al. Improving prognosis of glioblastoma in the 21st century: who has benefited most? Cancer 118(17), 4228–4234 (2012).
4
Brandes AA, Bartolotti M. Neuro-oncology: treatment decision in elderly patients with glioblastoma. Nat. Rev. Neurol. 8(12), 664–665 (2012).
5
Nghiemphu PL, Cloughesy T. Glioblastoma therapy in the elderly: one age does not fit all. Lancet Oncol. 13, 857–858 (2012).
6
Fiorentino A, Balducci M, Chiesa S, Fusco V. Elderly people with glioblastoma. Lancet Oncol. 13, e327–e328 (2012).
7
Wick W, Platten M, Meisner C et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, Phase 3 trial. Lancet Oncol. 13, 707–715 (2012).
8
Malmstrom A, Grondberg BH, Marosi C et al. Temozolomide versus standard 6-week
future science group
radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, Phase 3 trial. Lancet Oncol. 13, 916–926 (2012). 9
Fiorentino A, Caivano R, Chiumento C et al. Comorbidity assessment and adjuvant radiochemotherapy in elderly affected by glioblastoma. Med. Oncol. 29(5), 3467–3471 (2012).
10 Balducci M, Fiorentino A, De Bonis P et al.
Impact of age and co-morbidities in patients with newly diagnosed glioblastoma: a pooled data analysis of three prospective monoinstitutional Phase II studies. Med. Oncol. 29(5), 3478–3483 (2012). 11 Fiorentino A, Chiumento C, Fusco V.
Do comorbidity influences acute toxicity and outcome in elderly patients with endometrial cancer treated by adjuvant radiotherapy plus brachytherapy? Clin. Transl. Oncol. 15(8), 665–669 (2013). 12 Scott JG, Bauchet L, Fraum TJ et al.
Recursive partitioning analysis of prognostic factors forglioblastoma patients aged 70 years or older. Cancer 118(22), 5595–5600 (2012). 13 Fiorentino A, Balducci M, De Bonis P et al.
Can elderly patients with newly diagnosed glioblastoma be enrolled in radiochemotherapy trials? Am. J. Clin. Oncol. doi:10.1097/COC.0b013e3182868ea2 (2013) (Epub ahead of print).
14 Floyd SR, Kasper EM, Uhlmann EJ et al.
Hypofractionated radiotherapy and stereotactic boost with concurrent and adjuvant temozolomide for glioblastoma in glioblastoma status elderly patients – early results of a Phase II trial. Front. Oncol. 2, 122 (2012). 15 Yin A, Zhang L, Cheng J et al. Radiotherapy
plus concurrent or sequential Temozolomide for glioblastoma in the elderly: a meta-analysis. PLoS One 8(9), e74242 (2013). 16 Balducci M, Fiorentino A, De Bonis P et al.
Concurrent and adjuvant temozolomide-based chemoradiotherapy schedules for glioblastoma: hypotheses based on two prospective Phase II trials. Strahlenther. Onkol. 189(11), 926–931(2013). 17 De Bonis P, Mangiola A, Pompucci A, Porso
M, Anile C. High-grade glioma: elderly patients, older treatments. Expert Rev. Neurother. 12(11), 1293–1296 (2012). 18 Fiorentino A, De Bonis P, Chiesa S, Balducci
M, Fusco V. Elderly people with glioblastoma: the treatment challenge. Expert Rev. Neurother. 13(10), 1099–1105 (2013). 19 Lawrence YR, Li XA, el Naga I et al.
Radiation dose-volume effects in the brain. Int. J. Radiat. Oncol. Biol. Phys. 76(3 Suppl.), S20–S27 (2010). 20 Balducci M, Chiesa S, Diletto B et al.
Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study. Neuro Oncol. 14(1), 79–86 (2012).
www.futuremedicine.com
11
Which therapeutic approach is feasible for elderly people with glioblastoma?
“The presence of comorbidities, and decreased organ functional reserve increases the risk of treatment-related toxicity, especially in elderly patients.”
Alba Fiorentino*1, Mario Balducci2 & Silvia Chiesa2 The incidence of glioblastoma (GBM) is increasing among elderly patients, with a median age at diagnosis of 64 years. Owing to the increase in life expectancy, the age of the GBM population will also continue to grow. The standard treatment approach is still unclear for the elderly population because the effectiveness of adjuvant radiochemotherapy followed by temozolomide (TMZ) was assessed only for patients under 70 years of age in the NCIC trial conducted by Stupp et al. [1,2]. However, despite the benefit of radiochemotherapy especially, in patients with MGMT methylation, survival remains very poor (12–18 months) and improvement has been confined to only younger patients [3]. In neuro-oncology, the therapeutic guidelines for the elderly with GBM are still an unsolved question; and some researchers have reported controversy and difficulties regarding the decision-making process [4–6]. Advanced age is considered a negative prognostic factor for GBM, with a median survival of less than 1 year. Often patients
aged 70 years and over are considered unfit to receive the standard treatment approach owing to the increased risk of toxic effects. However, is this opinion always warranted? Is it possible to define fit or unfit patients in the heterogenic elderly population only using age? Should age be the only factor taken into account when choosing a radical or a palliative treatment? Is a clinical tool necessary? The recently published randomized trials (The Neuro-oncology Working Group of the German Cancer Society, NOA-08 trial, and The Nordic Brain Tumor Study Group, NCBTSG trial), which were conducted to assess the treatment approach for elderly GBM patients, comparing radiotherapy (RT) with TMZ alone, did not evaluate the patients’ geriatric assessment (comorbidity) and enrolled patients only according to age [7,8]. The role of comorbidity in the elderly population with cancer should be evaluated [9–11]. The presence of comorbidities, and decreased organ functional reserve increases the risk of treatment-related toxicity, especially in elderly patients. Organ dysfunction, in fact, may be the
“…patients aged 70 years and over are considered unfit to receive the standard treatment approach owing to the increased risk of toxic effects.”
Radiation Oncology Department, Sacro Cuore-Don Calabria Hospital, Negrar-Verona, Italy Radiation Oncology Department, Catholic University of the Sacred Heart, Rome, Italy *Author for correspondence: Tel.: +39 0972 726480; [email protected] 1 2
10.2217/CNS.13.51 © 2014 Future Medicine Ltd
CNS Oncol. (2014) 3(1), 9–11
part of
ISSN 2045-0907
9
Editorial Fiorentino, Balducci & Chiesa
“At present, age alone should not be the only discriminating factor for choosing or disregarding a treatment modality.”
10
reason for low treatment compliance and the high frequency of treatment side effects (myelosuppression and neurotoxicity, among others). The Charlson Comorbidity index is the only management aid evaluated in GBM. This index, identifying 19 comorbid conditions influencing the 10-year survival rate, has been studied in several tumors and also shows a correlation with survival in GBM patients [9–11]. If other authors can confirm these data, it could be a very useful clinical decision-making tool in the identification of fit or unfit patients. Scott et al. developed a recursive partitioning analysis-derived prognostic model based on age (older or younger than 75.5 years), extent of surgery (complete or partial excision, or biopsy) and Karnofsky performance status for patients older than 70 years of age affected by GBM. The authors observed that this model divided elderly patients into four prognostic subgroups and that “it can be easily implemented in both the patient care and the clinical trial settings” when choosing the correct treatment approach [12]. Thus, those elderly patients with good performance status and without major comorbidities (i.e., fit) should be treated as younger patients [13]. To corroborate this statement, despite the lack of randomized trials, several retrospective, Phase II studies and a recent meta-analysis in patients over 65 years of age showed the tolerability and effectiveness of radiochemotherapy plus TMZ (standard therapy) or radiochemotherapy plus stereotactic RT and TMZ (aggressive treatment) with a median overall survival of 13 months [9,10,13–16]. However, unfit elderly patients (poor performance status and presence of major comorbidities) should receive a therapeutic palliative approach (TMZ or RT alone, or best supportive care). In this setting of patients and treatment, the NOA-08 and the NCBTSG trials [7,8] did not solve the issue of which treatment was preferred because they reported different results, as highlighted by some authors [4,17,18]. In the standard RT arm, the NOA-08 trial showed a median survival of 9.7 months, while the NCBTSG trial reported a survival of only 6 months, these are inferior to the results reported by Stupp et al. [1,2]. Moreover, these trials supported the use of TMZ alone in patients with methylated MGMT status and, in the unmethylated group, the use of RT
CNS Oncol. (2014) 3(1)
(standard or hypofractionated), although TMZ and RT did not differ in terms of outcome. In the NCBTSG trial, median survival in the methylated group was 9.7 and 8.2 months for TMZ and any RT (standard or hypofractionated) arms, respectively, without statistical significance (p = 0.07); while in the NOA-08 trial, methylation status was associated with differences in event-free survival and a trend was observed for overall survival between treatment modalities (TMZ vs RT). The results of these trials were not conclusive, reporting a lower compliance in the chemotherapy group compared with RT, owing to the increased side effects of TMZ, and a higher risk of disease progression during TMZ treatment [7,8]. Despite the fact that TMZ alone, based on MGMT status, can be a valid alternative to RT, it is more expensive and toxic. Other limitations for the comparison of these two trials are: the different cutoff ages (60 vs 70 years old); the NOA-08 trial enrolled patients with a very low performance (Karnofsky performance status: 20) and with grade III and IV histologies; the administration of salvage therapy in both trials, which could have balanced the effects of primary treatments; and the absence of information on the spread of disease/tumor site [17,18]. Sometimes, a limitation for using RT is the potential increased risk of neurotoxicity and mental deterioration, but these toxicities have multifactorial causes, which, in fact, depend more on RT (more frequently by the two-times a day fractionation) than older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, biological agents and progression of disease [19]. Thus, in the palliative setting, especially in elderly patients with poor performance status, other RT or TMZ schedules should be evaluated [20]. In conclusion, the data from the available literature were not sufficient for delineating the correct approach for patients older than 70 years of age affected by GBM. At present, age alone should not be the only discriminating factor for choosing or disregarding a treatment modality. It is still a challenge to determine the correct way to treat elderly patients with GBM in neuro-oncology, and, therefore, trials comparing standard and alternative approaches with the use of a standard nomogram (molecular and clinical findings) to aid the treatment decision-making process, is warranted.
future science group
Which therapeutic approach is feasible for elderly people with glioblastoma? Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
Editorial
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
2
Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352(10), 987–996 (2005). Stupp R, Hegi ME, Mason WP et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised Phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009).
3
Lawrence YR, Mishra MV, Werner-Wasik M et al. Improving prognosis of glioblastoma in the 21st century: who has benefited most? Cancer 118(17), 4228–4234 (2012).
4
Brandes AA, Bartolotti M. Neuro-oncology: treatment decision in elderly patients with glioblastoma. Nat. Rev. Neurol. 8(12), 664–665 (2012).
5
Nghiemphu PL, Cloughesy T. Glioblastoma therapy in the elderly: one age does not fit all. Lancet Oncol. 13, 857–858 (2012).
6
Fiorentino A, Balducci M, Chiesa S, Fusco V. Elderly people with glioblastoma. Lancet Oncol. 13, e327–e328 (2012).
7
Wick W, Platten M, Meisner C et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, Phase 3 trial. Lancet Oncol. 13, 707–715 (2012).
8
Malmstrom A, Grondberg BH, Marosi C et al. Temozolomide versus standard 6-week
future science group
radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, Phase 3 trial. Lancet Oncol. 13, 916–926 (2012). 9
Fiorentino A, Caivano R, Chiumento C et al. Comorbidity assessment and adjuvant radiochemotherapy in elderly affected by glioblastoma. Med. Oncol. 29(5), 3467–3471 (2012).
10 Balducci M, Fiorentino A, De Bonis P et al.
Impact of age and co-morbidities in patients with newly diagnosed glioblastoma: a pooled data analysis of three prospective monoinstitutional Phase II studies. Med. Oncol. 29(5), 3478–3483 (2012). 11 Fiorentino A, Chiumento C, Fusco V.
Do comorbidity influences acute toxicity and outcome in elderly patients with endometrial cancer treated by adjuvant radiotherapy plus brachytherapy? Clin. Transl. Oncol. 15(8), 665–669 (2013). 12 Scott JG, Bauchet L, Fraum TJ et al.
Recursive partitioning analysis of prognostic factors forglioblastoma patients aged 70 years or older. Cancer 118(22), 5595–5600 (2012). 13 Fiorentino A, Balducci M, De Bonis P et al.
Can elderly patients with newly diagnosed glioblastoma be enrolled in radiochemotherapy trials? Am. J. Clin. Oncol. doi:10.1097/COC.0b013e3182868ea2 (2013) (Epub ahead of print).
14 Floyd SR, Kasper EM, Uhlmann EJ et al.
Hypofractionated radiotherapy and stereotactic boost with concurrent and adjuvant temozolomide for glioblastoma in glioblastoma status elderly patients – early results of a Phase II trial. Front. Oncol. 2, 122 (2012). 15 Yin A, Zhang L, Cheng J et al. Radiotherapy
plus concurrent or sequential Temozolomide for glioblastoma in the elderly: a meta-analysis. PLoS One 8(9), e74242 (2013). 16 Balducci M, Fiorentino A, De Bonis P et al.
Concurrent and adjuvant temozolomide-based chemoradiotherapy schedules for glioblastoma: hypotheses based on two prospective Phase II trials. Strahlenther. Onkol. 189(11), 926–931(2013). 17 De Bonis P, Mangiola A, Pompucci A, Porso
M, Anile C. High-grade glioma: elderly patients, older treatments. Expert Rev. Neurother. 12(11), 1293–1296 (2012). 18 Fiorentino A, De Bonis P, Chiesa S, Balducci
M, Fusco V. Elderly people with glioblastoma: the treatment challenge. Expert Rev. Neurother. 13(10), 1099–1105 (2013). 19 Lawrence YR, Li XA, el Naga I et al.
Radiation dose-volume effects in the brain. Int. J. Radiat. Oncol. Biol. Phys. 76(3 Suppl.), S20–S27 (2010). 20 Balducci M, Chiesa S, Diletto B et al.
Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study. Neuro Oncol. 14(1), 79–86 (2012).
www.futuremedicine.com
11
