Original Article
Feasibility of the EORTC/NCIC Trial Protocol in a Neurosurgical Outpatient Unit: The Case for Neurosurgical Neuro-Oncology Marion Rapp1 Hosai Sadat1 Michael Sabel1
Philipp Joerg Slotty1
1 Department of Neurosurgery, Heinrich Heine Medical Centre,
Düsseldorf, Germany 2 Neurochirurgische Klinik, Universitätsklinik Düsseldorf, Düsseldorf, Germany 3 Department of Radiation Oncology, Heinrich Heine Medical Centre, Düsseldorf, Germany
Hans Jakob Steiger2
Wilfried Budach3
Address for correspondence Marion Rapp, MD, Department of Neurosurgery, Heinrich Heine Medical Centre, Moorenstr. 5, Düsseldorf 40225, Germany (e-mail: [email protected]).
J Neurol Surg A 2015;76:298–302.
Abstract
Keywords
► glioblastoma ► temozolomide ► concomitant radio chemotherapy
received March 7, 2014 accepted after revision September 15, 2014 published online April 27, 2015
Objective With the publication of the European Organization for Research and Treatment of Cancer/National Cancer Information Center (EORTC/NCIC) trial, concomitant radiochemotherapy followed by intermittent chemotherapy became the new treatment standard for patients with primary glioblastoma. Eight years after widespread introduction of this protocol, it is of interest to investigate whether this new standard has been established in daily neuro-oncologic practice. We were particularly interested in its practicality within a neurosurgical neuro-oncologic setting. Patients and Methods We analyzed primary glioblastoma patients diagnosed between 2005 and 2013 treated at our center according to the EORTC/NCIC trial. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were retrospectively analyzed and compared with the available data from the EORTC/NCIC trial. Results In this single-center retrospective study, we identified 189 patients (116 men, 73 women; median age: 62 years) who were treated according to the EORTC/NCIC trial protocol. A total of 176 patients received cytoreductive surgery; 13 patients had stereotactic biopsy only (EORTC/NCIC trial: 239 patients and 48 patients, respectively). Radiotherapy had to be interrupted in 9 patients (5%) (EORTC/NCIC trial: 15 patients [5%]) and concomitant chemotherapy in 26 patients (14%) (EORTC/NCIC trial: 37 patients [13%]). In 156 patients (83%), adjuvant TMZ chemotherapy was initiated (6 median temozolomide [TMZ] cycles; range: 1–30). In the EORTC/NCIC trial, 223 patients (47%) received the intermittent chemotherapy protocol (median: 3 cycles; range: 1–7). Overall, 97 patients (62%) completed 6 TMZ cycles (EORTC/NCIC-trial: 105 patients [47%]); dose escalation to 200 mg/qm at the second cycle was performed in 91 patients (58%) (versus 149 patients [67%]). Intermittent TMZ therapy was discontinued in 59 patients (38%) (versus 118 patients [53%]). Median overall survival in our patient
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1396437. ISSN 2193-6315.
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Feasibility of the EORTC/NCIC Trial Protocol
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Introduction In one of the most important studies on adjuvant treatment for glioblastoma (GBM), the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) prospective clinical trial 26981–22981/CE.3 (EORTC protocol) demonstrated that the combination of conformal radiotherapy with daily (concomitant) temozolomide (TMZ) followed by six cycles of (intermittent) TMZ increased median survival (14.6 versus 12.1 months) and the 2-year survival rate (26.5% versus 10.4%) compared with radiation therapy alone.1 Since the trial defined the new standard for adjuvant treatment, the vast majority of patients with newly diagnosed GBM are now subject to concomitant radiochemotherapy. As yet, little is known about the feasibility of this treatment protocol outside the setting of a prospective randomized study, that is, in a patient population not subject to rigid inclusion criteria and controls of treatment performance and complications. Furthermore, transfer of the new treatment protocol into common neuro-oncologic practice might be hampered by insufficient logistics and the competence of the individual treatment centers, resulting in a lack of compliance with the treatment protocol and insufficient management of complications. Moreover, we were interested in the practicability of the protocol within the setting of a neurosurgical neuro-oncologic unit.
Patients and Methods In this retrospective single-center study, a database search identified patients treated for primary GBM at our center. Adjuvant treatment was performed according to the EORTC/NCIC protocol. Concomitant radiochemotherapy was performed at our center or elsewhere (three-dimensional [3D] conformal or intensity-modulated radiation therapy [IMRT] technique; the clinical target volume encompassed the contrast enhancement in T1-weighted magnetic resonance imaging [MR]) with a 1.5 cm anatomically adapted safety margin; 2 Gy per fraction, for a total dose of 60 Gy; concomitant TMZ chemotherapy at a dose of 75 mg/m2). Upon completion of the concomitant part, after a 4-week interval, our neurosurgical neuro-oncologic outpatient unit initiated the intermittent part of therapy. Patients received six cycles of intermittent TMZ therapy according to the 5-day schedule every 28 days (first cycle 150 mg/m2 following by 200 mg/m2). Hematologic controls were routinely performed at the expected nadir (21 days after the first dose). Patients
presented for a prescription of the subsequent cycle in our neurosurgical neuro-oncologic outpatient clinic, consisting of two consultant neurosurgeons specialized in neuro-oncology and one study nurse. Here patient evaluation (neurologic status by National Institutes of Health Stroke Scale score, Karnofsky performance status [KPS]) was performed every month with a cranial MRI every 3 months. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were prospectively entered in a dedicated database and retrospectively analyzed. Data were compared with data derived from the original publication by Stupp et al.1
Patients Inclusion criteria for this retrospective single-center study were as follows: 1. Histopathology confirmed newly diagnosed GBM (World Health Organization [WHO] class IV) 2. Postoperative combined radiotherapy with concomitant TMZ according to the EORTC protocol 3. Following intermittent TMZ therapy The university ethics committee approved the study (no. 4202). ►Table 1 summarizes the patient characteristics.
Evaluation of Treatment Side Effects Toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria, with a score 3 indicating severe adverse effects (thrombocytopenia < 50,000/µL; neutropenia < 1.0 109/dm3). According to the criteria suggested by the EORTC/NCIC protocol, therapy was postponed until recovery if the patient presented with a thrombocytopenia < 100,000/µL or leukocytopenia < 3,000/µL. A dose reduction in the subsequent cycle was induced by thrombocytopenia < 25,000/µL or a leukocytopenia < 1,000/µL. Continuous myelosuppression > 4 weeks resulted in a discontinuation of treatment.
Results Patients Between January 2005 and January 2013, our department treated 430 patients with newly diagnosed GBM. Due to incomplete data or inclusion into different therapy protocols, Journal of Neurological Surgery—Part A
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cohort was 19 months (versus 14.6 months); median time to progression was 9 months (versus 6.9 months). Conclusion Comparison between the feasibility of the treatment protocol established by the EORTC/NCIC trial (performed within the setting of a prospective randomized trial) and the daily routine in a dedicated neurosurgical neuro-oncologic department demonstrates that the protocol is suitable for daily practice within a neurosurgical unit.
Feasibility of the EORTC/NCIC Trial Protocol
Rapp et al.
Table 1 Patient characteristics Patients, n (%)
Characteristics Age, y Median
61
Range
24–85
< 50 y
31 (16)
> 50 y
158 (84)
Sex Male
116 (62)
Female
73 (38)
KPS pretreatment < 70
8 (4)
> 70
170 (90)
KPS posttreatment < 70
6 (3)
> 70
175 (93)
Extent of surgery Biopsy
13 (7)
Complete resection
116 (62)
Partial resection
60 (31)
Time to progression Median, mo
9
Overall survival Median, mo
19
Abbreviation: KPS, Karnofsky performance status.
241 patients were not eligible for this analysis. Therefore, 189 newly diagnosed GBM patients (116 men, 73 women; median age: 61 years) were available for analysis. Cytoreductive surgery was performed in 176 patients (116 gross total [66%], 60 incomplete resection [34%]). In 13 patients a diagnostic stereotactic biopsy was performed. Median overall survival (OS) was 19 months; median time to progression (TTP) was 9 months. At the time of final data analyses, 131 patients were dead due to tumor progression. In 143 patients a progression was diagnosed; 33 patients were lost to follow-up.
Radiotherapy Plus Concomitant Temozolomide Therapy The median time from diagnosis to radiation therapy was 4 weeks (range: 1–12 weeks). A total of 161 patients (85%) completed the combined therapy as planned without further side effects. A discontinuation of radiotherapy occurred in 10 patients (5%); one of these patients (0.5%) was able to resume therapy without further events. Radiotherapy was stopped in nine patients (5%) due to clinical deterioration (2%), tumor progression (0.5%), or patient’s decision (2%). Interruption of concomitant TMZ therapy was observed in 27 patients (14%); 6 patients (3%) could continue therapy after recovery. In 21 patients (11%), TMZ therapy had to be stopped because of (1) hematotoxic side effects in 13 patients Journal of Neurological Surgery—Part A
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(6.9%), thrombocytopenia in 11 patients (6%), leukocytopenia in 5 patients (3%), and anemia in 1 patient (0.5%); (2) infections in two patients (1.1%); (3) clinical deterioration in six patients (3.2%); and (4) hepatotoxicity in 3 patients (1.5%). Ten of these patients did not receive any further adjuvant therapy; one patient whose chemotherapy had to be stopped because of hematotoxic events was able to continue intermittent chemotherapy without further complications. Side effects and toxicity during the combined radio/chemotherapy are summarized in ►Table 2.
Intermittent Temozolomide Therapy In 156 patients (83%), intermittent TMZ chemotherapy was initiated (median: 6 cycles, range: 1–40). Overall, 95 patients (61%) completed six TMZ cycles without further adverse events; dose escalation to 200 mg/qm was performed in 105 patients (67%). Intermittent TMZ therapy was interrupted in 61 patients (39%) due to (1) tumor progression in 41 patients (26%), (2) hematotoxic side effects in 8 patients (5%), and (3) clinical deterioration in 8 patients (5%). After therapy interruption in 25 patients (16%), TMZ therapy could be continued after recovery; in 11 patients (7%) the adjuvant therapy scheme was changed; in 25 patients (16%) no further therapy was initiated. Side effects and toxicity during intermittent chemotherapy are summarized in ►Table 2; hematotoxic grade III and IV events are shown in ►Table 3.
Comparison with the EORTC/NCIC Data In the EORTC/NCIC study, 287 patients (median age: 56 years; 185 men and 102 women) were randomized for the concomitant therapy arm. In our analyses we reviewed 189 patients (median age: 62 years; 116 men and 73 women). Most of the EORTC/NCIC study patients (83%) were subject to open resection. A complete resection was performed in 113 patients (39%), partial resection in 126 patients (44%), whereas in 48 patients (17%) a stereotactic biopsy was performed. In our patient cohort, in 13 patients (7%) a stereotactic biopsy was performed, a complete resection in 116 (61.4%), and a partial resection in 60 (31.7%). For further clinical characterization of
Table 2 Reasons for therapy interruption during combined radio/chemotherapy and intermittent TMZ therapy in our patient cohort Concomitant TMZ therapy, patients, n (%)
Intermittent TMZ therapy, patients, n (%)
Tumor progression
2 (1.1)
41 (26.3)
Hematotoxic events
13 (6.9)
8 (5.1)
Infection
2 (1.1)
Clinical deterioration
11 (5.8)
8 (5.1)
Others
9 (4.7)
4 (2.6)
Abbreviation: TMZ, temozolomide.
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Table 3 Grade III and IV hematotoxic events in our patient cohort compared with the EORTC study Hematotoxic events, n (%)
Our patient cohort (n ¼ 189)
EORTC study (n ¼ 284)
Leukopenia
14 (7.4)
20 (7)
Thrombocytopenia
24 (12.7)
33 (12)
Neutropenia
4 (2.1)
21 (7)
Lymphocytopenia
13 (6.9)
Anemia
4 (2.1)
4 (1)
WHO performance status, the EORTC quality-of-life questionnaire and the Mini Mental State Examination score were evaluated during the EORTC study, reflecting 249 patients with a WHO performance status 1. In this analysis the KPS was used to evaluate the clinical condition with a postoperative KPS 70 in 175 patients (92.6%). During the combined radio/chemotherapy of the EORTC analysis, there was an interruption or delay of radiotherapy in 92 patients (32%) and a discontinuation of radiotherapy in 14 patients (5%) and in TMZ therapy in 37 patients (13%). We observed an interruption or delay of radiotherapy in 10 patients (5%) and a discontinuation of radiotherapy in 9 patients (5%) and in TMZ therapy in 27 patients (14%). The main observed reasons were toxicity (26% EORTC study
versus 6.9%), clinical deterioration (3%), and tumor progression (4% EORTC study versus 0.5%). Therapy interruption during intermittent TMZ chemotherapy was observed in 118 patients (78%) in the EORTC study and in 61 patients (39%) in our patient cohort. The main complications were toxicity and disease progression (EORTC study 8% and 39%; our analysis, 5% and 26%, respectively). Further analysis and comparison of the hematotoxic events are summarized in ►Table 3. During the EORTC study, 105 patients (47%) finished the complete therapy scheme consisting of the combined radiochemotherapy and the intermittent six TMZ cycles in contrast to 95 patients (61%) in our analysis. Data are summarized in ►Table 4.
Table 4 Comparison between our data analyses and the EORTC data Our patient cohort n ¼ 189 (%)
EORTC study n ¼ 287 (%)
10 (5)
92 (32)
Radiotherapy Interruption/delay Due to toxicity
12 (4)
Discontinuation
9 (5)
14 (5)
Concomitant TMZ Never started
6 (2)
Interruption
27 (14)
37 (13)
Due to toxicity
13 (6.9)
14 (5)
Due to disease progression
1 (0.5)
11 (4)
Completion without further events
161 (85)
Intermittent TMZ Therapy started
156 (83)
223 (78)
Median cycles
6
3
Interruption
61 (39)
118 (53)
Due to toxicity
8 (5)
17 (8)
Due to disease progression
41 (26)
86 (39)
95 (61)
105 (47)
105 (67)
149 (67)
Completing six cycles Dose escalated to 200 mg/m
2
Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; TMZ, temozolomide. Journal of Neurological Surgery—Part A
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Abbreviation: EORTC, European Organization for Research and Treatment of Cancer.
Feasibility of the EORTC/NCIC Trial Protocol
Rapp et al.
Discussion The EORTC/NCIC study defined a new treatment standard with superior results regarding progression-free survival and OS.1 Since 2005 the neuro-oncologic community has been confronted with the challenge to transfer the new treatment protocol into daily practice. Before 2005, patients with GBMs were not routinely treated with alkylating chemotherapy. Therefore the introduction of concomitant and intermittent chemotherapy required additional efforts in patient management. The implementation of new and rather complex treatment protocols into the daily routine cannot be taken for granted. On these grounds, an evaluation of treatment compliance and safety from the perspective of the practical implementation outside the framework of a prospective, monitored, and therefore well-controlled phase 3 study is of interest. It is suspected that compliance to fulfill the treatment protocol and the safety of the treatment in daily practice might differ from the treatment quality within trial conditions. Against this background our central question for this retrospective analysis was whether a neurosurgical outpatient unit is able to administer complex chemotherapeutic treatment schemes with comparable efficacy and safety as defined by a prospective randomized study. The analysis of 189 patients treated by our group revealed that treatment efficacy and safety are comparable reflecting the general practicability of this treatment protocol in a neurosurgical neuro-oncologic setting. Some minor differences are subsequently discussed. For assessment of the neurologic clinical status, the EORTC study used the WHO performance status, whereas in this analysis the KPS was applied. Both scales describe the clinical status of oncologic patients for further treatment evaluation and are comparable with each other,2 whereas a KPS 70 correlates with a WHO performance status 1. Regarding established prognostic factors,3,4 our patient cohort tended to be older compared with the EORTC patient cohort (median: 61 versus 56 years) and received more TMZ cycles (median: three versus six) with comparable hematotoxic events (►Table 3). We interpret this higher compliance rate due to close and regular patient support during adjuvant therapy. Survival dates in our patient cohort tend to be better compared with the OS and TTP as published by Stupp et al1 (OS: 19 versus 14.6 months; TTP: 9 versus 6.9 months). One possible explanation could be the higher rate of stereotactically biopsied patients in the EORTC patient cohort (48 patients [17%] versus 13 patients [7%] in our patient cohort) reflecting the impact of surgery on survival.5 Another reason might be a different evaluation of the MR imaging concerning tumor progression versus pseudo progression. During the EORTC/NCIC study, MR imaging evaluation was performed according to the MacDonald criteria and defined according to the modified WHO criteria as an increase in tumor size by 25%, the appearance of new lesions, or an increased need for corticosteroids. Due to the recently increased awareness of pseudo progression, we defined progression according
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to the Response Assessment in Neuro-Oncology criteria.1,6–8 Another difference might be the higher rate of treatment interruptions due to tumor progression in the EORTC/NCIC study compared with our results. This was observed both for the concomitant as well as intermittent arm (concomitant 0.5% versus 4%; intermittent 26% versus 39%). Interestingly, only one patient who had to stop concomitant TMZ chemotherapy because of hematotoxic side effects could complete the intermittent therapy without further events. This may argue against a potential hematotoxic effect of radiotherapy during the concomitant therapy scheme. But it definitely underlines the importance of individual treatment discussions. Patients with grade III or IV hematotoxic events during the concomitant therapy need to be considered for a different adjuvant treatment scheme without risking further adverse events during the intermittent chemotherapy treatment.
Conclusion Apart from minor differences, our data are comparable with the EORTC data, confirming that this protocol is suitable for daily use with acceptable side effects. This analysis underlines that good patient guidance with regular monitoring is essential for the feasibility of further adjuvant treatment independent of the observing specialization.
References 1 Stupp R, Mason WP, van den Bent MJ, et al; European Organisation
2
3
4
5 6
7
8
for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–996 Picot J, Cooper K, Bryant J, Clegg AJ. The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation. Health Technol Assess 2011;15(41):1–204 Kumar N, Kumar P, Angurana SL, et al. Evaluation of outcome and prognostic factors in patients of glioblastoma multiforme: A single institution experience. J Neurosci Rural Pract 2013;4(Suppl 1): S46–S55 Michaelsen SR, Christensen IJ, Grunnet K, et al. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution. BMC Cancer 2013;13:402 Stummer W, Kamp MA. The importance of surgical resection in malignant glioma. Curr Opin Neurol 2009;22(6):645–649 Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8(7):1277–1280 van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol 2011;12(6):583–593 Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010;28(11): 1963–1972
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Feasibility of the EORTC/NCIC Trial Protocol in a Neurosurgical Outpatient Unit: The Case for Neurosurgical Neuro-Oncology Marion Rapp1 Hosai Sadat1 Michael Sabel1
Philipp Joerg Slotty1
1 Department of Neurosurgery, Heinrich Heine Medical Centre,
Düsseldorf, Germany 2 Neurochirurgische Klinik, Universitätsklinik Düsseldorf, Düsseldorf, Germany 3 Department of Radiation Oncology, Heinrich Heine Medical Centre, Düsseldorf, Germany
Hans Jakob Steiger2
Wilfried Budach3
Address for correspondence Marion Rapp, MD, Department of Neurosurgery, Heinrich Heine Medical Centre, Moorenstr. 5, Düsseldorf 40225, Germany (e-mail: [email protected]).
J Neurol Surg A 2015;76:298–302.
Abstract
Keywords
► glioblastoma ► temozolomide ► concomitant radio chemotherapy
received March 7, 2014 accepted after revision September 15, 2014 published online April 27, 2015
Objective With the publication of the European Organization for Research and Treatment of Cancer/National Cancer Information Center (EORTC/NCIC) trial, concomitant radiochemotherapy followed by intermittent chemotherapy became the new treatment standard for patients with primary glioblastoma. Eight years after widespread introduction of this protocol, it is of interest to investigate whether this new standard has been established in daily neuro-oncologic practice. We were particularly interested in its practicality within a neurosurgical neuro-oncologic setting. Patients and Methods We analyzed primary glioblastoma patients diagnosed between 2005 and 2013 treated at our center according to the EORTC/NCIC trial. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were retrospectively analyzed and compared with the available data from the EORTC/NCIC trial. Results In this single-center retrospective study, we identified 189 patients (116 men, 73 women; median age: 62 years) who were treated according to the EORTC/NCIC trial protocol. A total of 176 patients received cytoreductive surgery; 13 patients had stereotactic biopsy only (EORTC/NCIC trial: 239 patients and 48 patients, respectively). Radiotherapy had to be interrupted in 9 patients (5%) (EORTC/NCIC trial: 15 patients [5%]) and concomitant chemotherapy in 26 patients (14%) (EORTC/NCIC trial: 37 patients [13%]). In 156 patients (83%), adjuvant TMZ chemotherapy was initiated (6 median temozolomide [TMZ] cycles; range: 1–30). In the EORTC/NCIC trial, 223 patients (47%) received the intermittent chemotherapy protocol (median: 3 cycles; range: 1–7). Overall, 97 patients (62%) completed 6 TMZ cycles (EORTC/NCIC-trial: 105 patients [47%]); dose escalation to 200 mg/qm at the second cycle was performed in 91 patients (58%) (versus 149 patients [67%]). Intermittent TMZ therapy was discontinued in 59 patients (38%) (versus 118 patients [53%]). Median overall survival in our patient
© 2015 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0034-1396437. ISSN 2193-6315.
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Rapp et al.
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Introduction In one of the most important studies on adjuvant treatment for glioblastoma (GBM), the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) prospective clinical trial 26981–22981/CE.3 (EORTC protocol) demonstrated that the combination of conformal radiotherapy with daily (concomitant) temozolomide (TMZ) followed by six cycles of (intermittent) TMZ increased median survival (14.6 versus 12.1 months) and the 2-year survival rate (26.5% versus 10.4%) compared with radiation therapy alone.1 Since the trial defined the new standard for adjuvant treatment, the vast majority of patients with newly diagnosed GBM are now subject to concomitant radiochemotherapy. As yet, little is known about the feasibility of this treatment protocol outside the setting of a prospective randomized study, that is, in a patient population not subject to rigid inclusion criteria and controls of treatment performance and complications. Furthermore, transfer of the new treatment protocol into common neuro-oncologic practice might be hampered by insufficient logistics and the competence of the individual treatment centers, resulting in a lack of compliance with the treatment protocol and insufficient management of complications. Moreover, we were interested in the practicability of the protocol within the setting of a neurosurgical neuro-oncologic unit.
Patients and Methods In this retrospective single-center study, a database search identified patients treated for primary GBM at our center. Adjuvant treatment was performed according to the EORTC/NCIC protocol. Concomitant radiochemotherapy was performed at our center or elsewhere (three-dimensional [3D] conformal or intensity-modulated radiation therapy [IMRT] technique; the clinical target volume encompassed the contrast enhancement in T1-weighted magnetic resonance imaging [MR]) with a 1.5 cm anatomically adapted safety margin; 2 Gy per fraction, for a total dose of 60 Gy; concomitant TMZ chemotherapy at a dose of 75 mg/m2). Upon completion of the concomitant part, after a 4-week interval, our neurosurgical neuro-oncologic outpatient unit initiated the intermittent part of therapy. Patients received six cycles of intermittent TMZ therapy according to the 5-day schedule every 28 days (first cycle 150 mg/m2 following by 200 mg/m2). Hematologic controls were routinely performed at the expected nadir (21 days after the first dose). Patients
presented for a prescription of the subsequent cycle in our neurosurgical neuro-oncologic outpatient clinic, consisting of two consultant neurosurgeons specialized in neuro-oncology and one study nurse. Here patient evaluation (neurologic status by National Institutes of Health Stroke Scale score, Karnofsky performance status [KPS]) was performed every month with a cranial MRI every 3 months. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were prospectively entered in a dedicated database and retrospectively analyzed. Data were compared with data derived from the original publication by Stupp et al.1
Patients Inclusion criteria for this retrospective single-center study were as follows: 1. Histopathology confirmed newly diagnosed GBM (World Health Organization [WHO] class IV) 2. Postoperative combined radiotherapy with concomitant TMZ according to the EORTC protocol 3. Following intermittent TMZ therapy The university ethics committee approved the study (no. 4202). ►Table 1 summarizes the patient characteristics.
Evaluation of Treatment Side Effects Toxic effects were graded according to the National Cancer Institute Common Toxicity Criteria, with a score 3 indicating severe adverse effects (thrombocytopenia < 50,000/µL; neutropenia < 1.0 109/dm3). According to the criteria suggested by the EORTC/NCIC protocol, therapy was postponed until recovery if the patient presented with a thrombocytopenia < 100,000/µL or leukocytopenia < 3,000/µL. A dose reduction in the subsequent cycle was induced by thrombocytopenia < 25,000/µL or a leukocytopenia < 1,000/µL. Continuous myelosuppression > 4 weeks resulted in a discontinuation of treatment.
Results Patients Between January 2005 and January 2013, our department treated 430 patients with newly diagnosed GBM. Due to incomplete data or inclusion into different therapy protocols, Journal of Neurological Surgery—Part A
Vol. 76
No. A4/2015
Downloaded by: Karolinska Institutet. Copyrighted material.
cohort was 19 months (versus 14.6 months); median time to progression was 9 months (versus 6.9 months). Conclusion Comparison between the feasibility of the treatment protocol established by the EORTC/NCIC trial (performed within the setting of a prospective randomized trial) and the daily routine in a dedicated neurosurgical neuro-oncologic department demonstrates that the protocol is suitable for daily practice within a neurosurgical unit.
Feasibility of the EORTC/NCIC Trial Protocol
Rapp et al.
Table 1 Patient characteristics Patients, n (%)
Characteristics Age, y Median
61
Range
24–85
< 50 y
31 (16)
> 50 y
158 (84)
Sex Male
116 (62)
Female
73 (38)
KPS pretreatment < 70
8 (4)
> 70
170 (90)
KPS posttreatment < 70
6 (3)
> 70
175 (93)
Extent of surgery Biopsy
13 (7)
Complete resection
116 (62)
Partial resection
60 (31)
Time to progression Median, mo
9
Overall survival Median, mo
19
Abbreviation: KPS, Karnofsky performance status.
241 patients were not eligible for this analysis. Therefore, 189 newly diagnosed GBM patients (116 men, 73 women; median age: 61 years) were available for analysis. Cytoreductive surgery was performed in 176 patients (116 gross total [66%], 60 incomplete resection [34%]). In 13 patients a diagnostic stereotactic biopsy was performed. Median overall survival (OS) was 19 months; median time to progression (TTP) was 9 months. At the time of final data analyses, 131 patients were dead due to tumor progression. In 143 patients a progression was diagnosed; 33 patients were lost to follow-up.
Radiotherapy Plus Concomitant Temozolomide Therapy The median time from diagnosis to radiation therapy was 4 weeks (range: 1–12 weeks). A total of 161 patients (85%) completed the combined therapy as planned without further side effects. A discontinuation of radiotherapy occurred in 10 patients (5%); one of these patients (0.5%) was able to resume therapy without further events. Radiotherapy was stopped in nine patients (5%) due to clinical deterioration (2%), tumor progression (0.5%), or patient’s decision (2%). Interruption of concomitant TMZ therapy was observed in 27 patients (14%); 6 patients (3%) could continue therapy after recovery. In 21 patients (11%), TMZ therapy had to be stopped because of (1) hematotoxic side effects in 13 patients Journal of Neurological Surgery—Part A
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(6.9%), thrombocytopenia in 11 patients (6%), leukocytopenia in 5 patients (3%), and anemia in 1 patient (0.5%); (2) infections in two patients (1.1%); (3) clinical deterioration in six patients (3.2%); and (4) hepatotoxicity in 3 patients (1.5%). Ten of these patients did not receive any further adjuvant therapy; one patient whose chemotherapy had to be stopped because of hematotoxic events was able to continue intermittent chemotherapy without further complications. Side effects and toxicity during the combined radio/chemotherapy are summarized in ►Table 2.
Intermittent Temozolomide Therapy In 156 patients (83%), intermittent TMZ chemotherapy was initiated (median: 6 cycles, range: 1–40). Overall, 95 patients (61%) completed six TMZ cycles without further adverse events; dose escalation to 200 mg/qm was performed in 105 patients (67%). Intermittent TMZ therapy was interrupted in 61 patients (39%) due to (1) tumor progression in 41 patients (26%), (2) hematotoxic side effects in 8 patients (5%), and (3) clinical deterioration in 8 patients (5%). After therapy interruption in 25 patients (16%), TMZ therapy could be continued after recovery; in 11 patients (7%) the adjuvant therapy scheme was changed; in 25 patients (16%) no further therapy was initiated. Side effects and toxicity during intermittent chemotherapy are summarized in ►Table 2; hematotoxic grade III and IV events are shown in ►Table 3.
Comparison with the EORTC/NCIC Data In the EORTC/NCIC study, 287 patients (median age: 56 years; 185 men and 102 women) were randomized for the concomitant therapy arm. In our analyses we reviewed 189 patients (median age: 62 years; 116 men and 73 women). Most of the EORTC/NCIC study patients (83%) were subject to open resection. A complete resection was performed in 113 patients (39%), partial resection in 126 patients (44%), whereas in 48 patients (17%) a stereotactic biopsy was performed. In our patient cohort, in 13 patients (7%) a stereotactic biopsy was performed, a complete resection in 116 (61.4%), and a partial resection in 60 (31.7%). For further clinical characterization of
Table 2 Reasons for therapy interruption during combined radio/chemotherapy and intermittent TMZ therapy in our patient cohort Concomitant TMZ therapy, patients, n (%)
Intermittent TMZ therapy, patients, n (%)
Tumor progression
2 (1.1)
41 (26.3)
Hematotoxic events
13 (6.9)
8 (5.1)
Infection
2 (1.1)
Clinical deterioration
11 (5.8)
8 (5.1)
Others
9 (4.7)
4 (2.6)
Abbreviation: TMZ, temozolomide.
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Table 3 Grade III and IV hematotoxic events in our patient cohort compared with the EORTC study Hematotoxic events, n (%)
Our patient cohort (n ¼ 189)
EORTC study (n ¼ 284)
Leukopenia
14 (7.4)
20 (7)
Thrombocytopenia
24 (12.7)
33 (12)
Neutropenia
4 (2.1)
21 (7)
Lymphocytopenia
13 (6.9)
Anemia
4 (2.1)
4 (1)
WHO performance status, the EORTC quality-of-life questionnaire and the Mini Mental State Examination score were evaluated during the EORTC study, reflecting 249 patients with a WHO performance status 1. In this analysis the KPS was used to evaluate the clinical condition with a postoperative KPS 70 in 175 patients (92.6%). During the combined radio/chemotherapy of the EORTC analysis, there was an interruption or delay of radiotherapy in 92 patients (32%) and a discontinuation of radiotherapy in 14 patients (5%) and in TMZ therapy in 37 patients (13%). We observed an interruption or delay of radiotherapy in 10 patients (5%) and a discontinuation of radiotherapy in 9 patients (5%) and in TMZ therapy in 27 patients (14%). The main observed reasons were toxicity (26% EORTC study
versus 6.9%), clinical deterioration (3%), and tumor progression (4% EORTC study versus 0.5%). Therapy interruption during intermittent TMZ chemotherapy was observed in 118 patients (78%) in the EORTC study and in 61 patients (39%) in our patient cohort. The main complications were toxicity and disease progression (EORTC study 8% and 39%; our analysis, 5% and 26%, respectively). Further analysis and comparison of the hematotoxic events are summarized in ►Table 3. During the EORTC study, 105 patients (47%) finished the complete therapy scheme consisting of the combined radiochemotherapy and the intermittent six TMZ cycles in contrast to 95 patients (61%) in our analysis. Data are summarized in ►Table 4.
Table 4 Comparison between our data analyses and the EORTC data Our patient cohort n ¼ 189 (%)
EORTC study n ¼ 287 (%)
10 (5)
92 (32)
Radiotherapy Interruption/delay Due to toxicity
12 (4)
Discontinuation
9 (5)
14 (5)
Concomitant TMZ Never started
6 (2)
Interruption
27 (14)
37 (13)
Due to toxicity
13 (6.9)
14 (5)
Due to disease progression
1 (0.5)
11 (4)
Completion without further events
161 (85)
Intermittent TMZ Therapy started
156 (83)
223 (78)
Median cycles
6
3
Interruption
61 (39)
118 (53)
Due to toxicity
8 (5)
17 (8)
Due to disease progression
41 (26)
86 (39)
95 (61)
105 (47)
105 (67)
149 (67)
Completing six cycles Dose escalated to 200 mg/m
2
Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; TMZ, temozolomide. Journal of Neurological Surgery—Part A
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Abbreviation: EORTC, European Organization for Research and Treatment of Cancer.
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Discussion The EORTC/NCIC study defined a new treatment standard with superior results regarding progression-free survival and OS.1 Since 2005 the neuro-oncologic community has been confronted with the challenge to transfer the new treatment protocol into daily practice. Before 2005, patients with GBMs were not routinely treated with alkylating chemotherapy. Therefore the introduction of concomitant and intermittent chemotherapy required additional efforts in patient management. The implementation of new and rather complex treatment protocols into the daily routine cannot be taken for granted. On these grounds, an evaluation of treatment compliance and safety from the perspective of the practical implementation outside the framework of a prospective, monitored, and therefore well-controlled phase 3 study is of interest. It is suspected that compliance to fulfill the treatment protocol and the safety of the treatment in daily practice might differ from the treatment quality within trial conditions. Against this background our central question for this retrospective analysis was whether a neurosurgical outpatient unit is able to administer complex chemotherapeutic treatment schemes with comparable efficacy and safety as defined by a prospective randomized study. The analysis of 189 patients treated by our group revealed that treatment efficacy and safety are comparable reflecting the general practicability of this treatment protocol in a neurosurgical neuro-oncologic setting. Some minor differences are subsequently discussed. For assessment of the neurologic clinical status, the EORTC study used the WHO performance status, whereas in this analysis the KPS was applied. Both scales describe the clinical status of oncologic patients for further treatment evaluation and are comparable with each other,2 whereas a KPS 70 correlates with a WHO performance status 1. Regarding established prognostic factors,3,4 our patient cohort tended to be older compared with the EORTC patient cohort (median: 61 versus 56 years) and received more TMZ cycles (median: three versus six) with comparable hematotoxic events (►Table 3). We interpret this higher compliance rate due to close and regular patient support during adjuvant therapy. Survival dates in our patient cohort tend to be better compared with the OS and TTP as published by Stupp et al1 (OS: 19 versus 14.6 months; TTP: 9 versus 6.9 months). One possible explanation could be the higher rate of stereotactically biopsied patients in the EORTC patient cohort (48 patients [17%] versus 13 patients [7%] in our patient cohort) reflecting the impact of surgery on survival.5 Another reason might be a different evaluation of the MR imaging concerning tumor progression versus pseudo progression. During the EORTC/NCIC study, MR imaging evaluation was performed according to the MacDonald criteria and defined according to the modified WHO criteria as an increase in tumor size by 25%, the appearance of new lesions, or an increased need for corticosteroids. Due to the recently increased awareness of pseudo progression, we defined progression according
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to the Response Assessment in Neuro-Oncology criteria.1,6–8 Another difference might be the higher rate of treatment interruptions due to tumor progression in the EORTC/NCIC study compared with our results. This was observed both for the concomitant as well as intermittent arm (concomitant 0.5% versus 4%; intermittent 26% versus 39%). Interestingly, only one patient who had to stop concomitant TMZ chemotherapy because of hematotoxic side effects could complete the intermittent therapy without further events. This may argue against a potential hematotoxic effect of radiotherapy during the concomitant therapy scheme. But it definitely underlines the importance of individual treatment discussions. Patients with grade III or IV hematotoxic events during the concomitant therapy need to be considered for a different adjuvant treatment scheme without risking further adverse events during the intermittent chemotherapy treatment.
Conclusion Apart from minor differences, our data are comparable with the EORTC data, confirming that this protocol is suitable for daily use with acceptable side effects. This analysis underlines that good patient guidance with regular monitoring is essential for the feasibility of further adjuvant treatment independent of the observing specialization.
References 1 Stupp R, Mason WP, van den Bent MJ, et al; European Organisation
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3
4
5 6
7
8
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