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Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial
Radiotherapy and Oncology xxx (2017) xxx–xxx
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Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial Søren Møller a,⇑, Per Munck af Rosenschöld a, Junia Costa a,b, Ian Law b, Hans Skovgaard Poulsen c,d, Svend Aage Engelholm a, Silke Engelholm a,e a Department of Oncology, Section for Radiotherapy, Rigshospitalet; b Department of Clinical Physiology, Nuclear Medicine & PET, Section 3982, Rigshospitalet; c Department of Radiation Biology, Section 6321, Rigshospitalet; d Department of Oncology, Section 5073, Rigshospitalet; and e Department of Oncology, Skåne University Hospital, Lund, Sweden
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Article history: Received 3 February 2017 Received in revised form 21 September 2017 Accepted 29 September 2017 Available online xxxx Keywords: Re-irradiation High-grade glioma phase I trial
a b s t r a c t Introduction: The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided reirradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. Material and methods: Patients with localized, recurrent HGG (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and 18F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose prescription of four consecutive groups was (1) 35 Gy/10fr., (2) 42 Gy/10fr., (3) 29.5 Gy/5fr. and (4) 35 Gy/10fr. to larger tumor volumes (100– 300 cm3), respectively. Results: Thirty-one patients were treated of which 81% had glioblastoma. The median progression-free survival was 2.8 months (95%CI: 2.1–3.5) and the median overall survival was 7.0 months (95%CI: 3.5– 10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis and irreversible white matter changes. Conclusion: Re-irradiation showed limited efficacy and 43% of patients achieving disease control suffered late toxicity that was manageable but not negligible. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
High-grade glioma are malignant primary brain tumors that arise from the glial cells of the brain. They grow infiltratively into healthy brain tissue and tend to relapse despite aggressive primary treatment consisting of surgery, radiotherapy and chemotherapy [1,2]. The prognosis at relapse is poor and no standard treatment currently exists [3]. In many centers re-irradiation is carried out, but some controversy exists about the safety and efficacy of this treatment. Whereas primary radiotherapy is considered safe and efficacious, repeating radiotherapy at recurrence may induce the risk of serious neurological toxicity such as symptomatic brain necrosis. Outcomes in retrospective series of re-irradiation of relapsed glioma have been favorable with nearly no serious adverse events (<1%) and long survival times [4,5]. Conversely, a prospective study by Shepherd et al. found considerable toxicity (36% rate of necrosis) [6].
⇑ Corresponding author at: Engbakkevej 12, 2920 Charlottenlund, Denmark. E-mail address: [email protected] (S. Møller).
The risk of brain necrosis has retrospectively been demonstrated to depend on radiotherapy dose, fraction size and target volume [7] but the impact of these factors has not been evaluated prospectively. Different radiotherapy dose- and schedules for re-irradiation have been proposed such as 3.5 Gy 10 [4] and 2 Gy 18 [8], but there is currently no international consensus on the most efficacious regimen. The purpose of this study was to evaluate the safety of reirradiation and to assess the impact of radiotherapy dose, fractionation and target volume on toxicity in a prospective phase I clinical trial in which we escalate radiation dose and volume in four sequential treatment regimes.
Material and methods The study was carried out in accordance with the Helsinki II Declaration and approved by the Ethics Board of the Capital Region of Denmark (protocol: H-2-2011-092). It is registered in
https://doi.org/10.1016/j.radonc.2017.09.039 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
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Toxicity of re-irradiation of glioma
ized to background brain tissue (Tmax/B) was calculated from the maximal tumor activity (SUVmax) and background activity [10].
the ClinicalTrials.gov database (NCT02025231). Written informed consent was required for entry into the study. The primary clinical endpoint of the study was early and late treatment toxicity as defined by CTCAE ver. 3.0 [9]. Secondary endpoints included the objective response rate. The trial also examined the value of 18F-FET PET in treatment planning and followup but those results have been published earlier in this journal [10].
Target delineation and imaging The target for radiotherapy was defined using both MRI and 18FFET PET. The GTV MRI was the contrast-enhancing tumor as contoured by a radiologist using a T1-post Gd-contrast MRI sequence. The GTV PET was derived as described in the previous section. The clinical target volume (CTV) equaled the union of the GTV-MRI + the GTV-PET and the planning target volume (PTV) equaled the CTV plus a 2 mm margin. Both imaging modalities were used for each evaluation at follow-up, but the time of tumor progression was determined using the MRI-based RANO criteria [11]
Treatment study groups Each of the four sequential treatment groups was to include at least six patients (Table 1). An observation time (latency) of three months for all six patients was required before the next dose level could be started, but new patients could be treated in the current dose level in this time period.
Radiotherapy Stereotactic radiotherapy was delivered using Volumetric Modulated Arc Therapy (VMAT) (Novalis Tx accelerator, RapidArc, Varian Medical Systems) with 5 fractions per week. Daily stereoscopic kilovoltage X-ray imaging was performed to ensure accurate patient positioning using 6-degrees of freedom (6D Robotics CouchÒ and), using a 1 mm tolerance. A thermoplastic mask was used for fixation. The permitted dose variation was 97–105% of the prescribed dose. Organs at risk were the brainstem, optic nerves/chiasm, hippocampi, eyes and healthy brain tissue. Maximum allowed total doses for all RT were 59.4 Gy for the brainstem, 65.3 Gy for small volumes (<10 ml) of brainstem and 60 Gy for the chiasm (EQD2, alpha/beta = 3), while the doses to other structures were minimized. These total doses were derived from QUANTEC reports [13,14] and, in addition, a conservative estimate of recovery of 10% in the spinal cord following primary RT was applied [15].
Follow-up Follow-up was scheduled at: 4-, 10-, 16-, 22-, 28-, 34-, 46- and 58- weeks after treatment. Evaluation comprised MRI, 18F-FET PET/ CT, clinical evaluation, QOL questionnaires and neurocognitive testing. Patients went off-study after 58 weeks of follow-up or at progression, death or withdrawal of consent. Patients Inclusion criteria: Recurrent high-grade glioma (WHO grade III or IV) as defined by the RANO criteria [11]; ECOG (Eastern Cooperative Oncology Group) performance status 0–2; localized disease; previous radiotherapy completed >6 months prior; no standard treatments available; expected life span >3 months; age > 18 years. A histological diagnosis of HGG (2007 WHO classification [12]) was required but not necessarily at recurrence. Exclusion criteria: Diffuse/large recurrences (planning target volume (PTV) > 100 cm3 for treatment groups 1, 2, and 3. For group 4, the maximal PTV allowed was 300 cm3); early recurrence following primary radiotherapy (3 months); fistula or other local pathologic conditions; contraindications to MRI- or 18F-FET PET CT. MRI and
Results Thirty-one patients were recruited and treated between December 2011 and December 2014. Patients’ baseline characteristics including treatment group allocation are listed in Table 2 and have been shown previously [10]. The study was terminated early in April 2015 due to slow accrual and only 5 patients were treated in dose levels 3 and 4, respectively. All patients have died – one of myocardial infarction after disease progression and the remainder from progressive glioma. Of the 31 patients, 30 were evaluable by RANO criteria. There were no objective responses. In 48% of cases the best response was stable disease. The median progression-free survival from the time of inclusion in the study was 2.8 months (95% CI: 2.1–3.5) and the median overall survival was 7.0 months (95% CI: 3.5–10.5). Seven patients (23%) were progression-free 10 weeks after treatment and they were considered assessable for late toxicity. Of these seven patients, 5 were treated in group 1 (3.5 Gy 10) and two were treated in group 2 (4.2 Gy 10). No patients treated in groups 3 (n = 5) or 4 (n = 5) were progression-free at 10 weeks.
18
F-FET PET image acquisition
Image acquisition for the study has been described previously [10]. Briefly, MRI was carried out on a Siemens Magnetom Espree 1.5 T scanner. Standard clinical sequences (T1 pre-and post Gadolinium (Gd)-contrast (GadovistÒ, 0.1 ml/kg) and T2/T2 fluid attenuation inversion recovery (FLAIR)) were acquired. 18 F-FET PET and planning CT was performed in a single session with an integrated 64 CT slice hybrid PET/CT system (Siemens Biograph mCT scanner). A single static frame of the brain was acquired 20–40 min after i.v. injection of 200 MBq 18F-FET. A threshold of 1.6 of mean SUV (standardized uptake value) in the background ROI was used for 3D auto-contouring of the biological tumor volume (BTV) used as GTV-PET. The maximal tumor uptake normal-
Table 1 Overview of treatment groups. Dose
PTV 3
Group 1 Group 2
3.5 Gy 10 3.5 Gy 10 + 7 Gy boost
<100 cm <100 cm3
Group 3 Group 4
5.9 Gy 5 3.5 Gy 10
<100 cm3 100–300 cm3
EQD2 tumor
EQD2 brain
39.4 39.4 49.7 39.1 39.4
45.5 45.5 60.5 (PET pos. volumes) 52.5 45.5
Radiotherapy regimes used in the Re-irradiation study. EQD2-doses were calculated using the linear-quadratic model and assuming a/btumor = 10 and a/bbrain = 3. All radiotherapy was given with 5 fractions/week. Abbreviations: PTV (planning target volume), EQD2 (2-Gy dose equivalent).
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
S. Møller et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 2 Baseline patient characteristics. Patients
n = 31
Age, years, median (range) Performance status 0 1 2 Diagnosis Glioblastoma Glioma WHO gr. III Recurrence number 1 2 3 Previous treatment Radiotherapy 60 Gy 44–45 Gy 34 Gy Temozolomide Bevacizumab Surgery prior to reirradiation Months since diagnosis, median (range) Treatment allocation in study Group 1 (3.5 Gy 10) Group 2 (3.5 Gy 10 + 7 Gy boost) Group 3 (5.9 Gy 5) Group 4 (3.5 Gy 10 to large tumors) Target volumes for radiotherapy, median (cm3) Planning target volume
54 (30–74) 10 (32%) 15 (48%) 6 (19%) 25 (81%) 6 (19%) 2 (6%) 16 (52%) 13 (42%)
26 (84%) 4 (13%) 1 (3%) 31 (100%) 20 (65%) 4 (13%) 23 (6–129) 12 (39%) 9 (29%) 5 (16%) 5 (16%) 67.0 (16.4–325.0)
Patterns of recurrence were analyzed and showed local failure only in 61%, local and distant failure in 13%, distant failure only in 10%. In 16% there was no radiological progression either due to cancelation of imaging due to severe clinical progression or no significant progression according to RANO criteria.
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Minor early toxicity (CTCAE grades 1–2 observed <10 weeks post-treatment) included seizure (3%), headache (25%), fatigue (19%), nausea (10%), skin reaction (10%) and increased steroid use (19%). Two patients (6%) were hospitalized following seizures that were potentially due to post-radiation edema. Serious late events (CTCAE grades 3–4 observed >10 weeks post-treatment) were observed in three cases (43% of the seven assessable patients). Two patient cases are described in Figs. 1 and 2. In addition to these two cases, one patient from group 2 developed grade 3 elevated intracranial pressure and edema on MRI four months post treatment and was hospitalized. The condition was treatable with steroids and regressed six months post treatment. Discussion In this prospective phase I study we aimed to assess the safety of re-irradiation to relapsed high-grade glioma. Our secondary aim was to determine an optimal dose regimen based on toxicity and efficacy. A minority of patients were progression-free 10 weeks after treatment and for these patients we observed an actuarial rate of serious late adverse radiotherapy induced events of 43%. We consider this an acceptable, but not negligible, rate of toxicity. The results indicate that re-irradiation may be more toxic than reported in the often cited retrospective reports by Fogh et al. [4], Combs et al. [5] and others [8,16], where almost no adverse events were observed. Conversely, our results are well in line with the rate of late adverse events of 36% reported by Shepherd et al. in a similar prospective study of single modality fractionated stereotactic re-irradiation of recurrent HGG [6] published almost 20 years ago. The large variation in reported toxicity (also reviewed by Amichetti et al. [17]) may be due to insufficient detection of adverse events in retrospective studies as well as different inter-
Fig. 1. Post-treatment sequential MRI- and 18F-FET PET scans of a patient with anaplastic astrocytoma (WHO grade III) who received 3.5 Gy 10. On the right, a plot of the biological tumor volume (BTV) and the maximal tumor uptake (Tmax/B) measured by 18F-FET PET at 11 time points. Four months post treatment, MRI and 18FET-PET scans concordantly indicated tumor growth on consecutive examinations. On PET, Tmax/B rose significantly from 2.3 to 3.1 and the BTV increased from 9 to 55 cm3. On MRI, both contrast-enhancing and non-contrast enhancing areas increased. Clinically, the patient showed no deterioration. Re-resection was performed approximately 24 weeks after re-irradiation (arrow). Histopathological examination revealed almost exclusively radionecrosis. Imaging (MRI and 18F-FET PET) three months after surgery showed increasing lesion size again with a BTV of 89 cm3, but this regressed spontaneously to baseline levels at 6- and 10-months after surgery. The patient continued to receive low dose corticosteroid treatment (10 mg/day of prednisolone). Due to the serious nature of the instituted treatment (neurosurgery) this event was categorized as grade 3–4 (CTCAE).
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
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Toxicity of re-irradiation of glioma
4 months post-treatment
10 months post-treatment
12 months post-treatment
Fig. 2. Post-treatment sequential T2 weighted FLAIR MRI- and 18F-FET PET scans of a glioblastoma patient who received 3.5 Gy 10 + 7 Gy boost to 18F-FET PET positive areas. Nine months after re-irradiation, this patient experienced balance problems, weakened bilateral fine motor coordination and reduced general psychomotor speed. 18FFET-PET scans showed no uptake but T2 weighted FLAIR MRI showed bilateral white matter changes extending backward, interpreted as edema. Steroid treatment was effective but could not be tapered due to recurrence of symptoms. The patient was treated with bevacizumab 10 mg/kg for one month but developed pulmonary embolisms whereupon treatment was stopped. No biopsy or surgery was performed.
pretations of follow-up imaging. In addition, real differences in rates of necrosis could be expected due to differences in patients and radiotherapy prescription (e.g. -dosis, -fractionation, volume) [7]. Lastly, the available prospective studies (including this one) are very small and subject to statistical variation. The patient in case number 1 displayed asymptomatic, focal gray matter necrosis that regressed during follow-up. MRI is known to discriminate poorly between necrosis and recurrent tumor [18] but 18F-FET PET also yielded a false positive result in this case. This may occur in a fraction of patients, particularly when a high local radiation dose is delivered and may be ascribed to inflammatory changes/reactive astrocytosis [19]. The patient in case nr. 2 exhibited different clinical and radiological findings more consistent with diffuse white matter changes extending backwards from the irradiated area. In this case, the 18FFET PET examination showed low uptake in the white matter. The pathophysiology of radiation induced brain necrosis is not completely understood but different theories exist. These include the ‘vascular theory’ (e.g. damage to the ever proliferating endothelium causes thrombosis, hemorrhage, and, ultimately, hypoxia and necrosis in the tissue supplied by the vessel) and the ’oligodendrocyte theory’ (e.g. high radiosensitivity of oligodendrocytes as compared to neurons causes gradual symptomatic demyelination) [20,21]. Due to the poor outcomes observed and due to poor recruitment to study groups 3 and 4, only a small number of patients
(n = 7) were assessable for late toxicity. In addition, there were no observable differences in responses or progression-free survival between groups and therefore no clear recommendations can be made. However, since both patients in treatment group 2 (3.5 Gy 10 + 7 Gy boost to PET + areas) who were free from disease progression beyond 3 months suffered from radionecrosis (cases 1 and 2), we cannot recommend this regime despite obvious statistical insufficiencies. In treatment group 4, patients with large tumors (PTV 100–300 cm3) were treated with 3.5 Gy 10. However, the pretreatment tumor volume (measured by 18F-FET PET or MRI) was shown to be a negative prognostic factor in multivariate analysis [10] and we therefore question the value of re-irradiation to large tumors. Dose level 1 (3.5 Gy 10) had been described previously and we did not expect significant toxicity but included it as a ‘safe’ dose. Dose level 2 (3.5 Gy + 7 Gy boost to PET + areas) was novel and represents a 20% increase in dose that was deemed necessary to obtain a meaningful separation of dose levels in each treatment plan, as well as a clinically meaningful escalation. Dose level 3 (5.9 Gy 5) was novel and aimed to test a possible effect of fraction size by delivering an equal EQD2-dose as level 1 (39.4 Gy) in 5 fractions instead of 10 fractions. Dose level 4 (3.5 Gy 10) was included to test the feasibility and toxicity of treating larger tumors (PTV 100–300 cm3). The choice of hypofractionated schedules as opposed to well described 2-Gy regimes for reirradiation [22] was motivated by a wish to limit overall treatment time rather
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
S. Møller et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
than by radiobiological considerations of alpha/beta ratios for glioblastoma. For calculation of EQD2, an alpha/beta ratio for tumor of 10 was assumed. This is within the range of 5.0–10.8 proposed in a recent meta analysis based on clinical studies, [23] but due to a scarcity of clinical data, any estimate of alpha/beta ratio is inherently uncertain and may be subject to controversy. The margins for radiotherapy (2 mm added to CTV for PTV) were to account only for setup uncertainty. A low tumor-tobackground threshold of 1.6 for tumor delineation with 18F-FET PET was chosen instead of adding a larger isotropic margin to a smaller volume defined by a higher threshold (e.g. 2.0). We expected this strategy to yield a CTV that to a higher degree reflected the true extent of tumor infiltration [24], although this remains to be validated in recurrent and previously treated HGG. Recurrence patterns are sometimes reported as ‘in-field’ or ‘marginal’. But because no objective responses were observed, these terms are not applicable and no further recommendations on margins can be made. In at least 74% of patients (please refer to Results), tumor progressed locally, which implies that radiotherapy doses were insufficient to achieve disease control. The median progression-free survival and the median overall survival times (median 2.8 mos and 7.0 mos, respectively) were very poor and do not indicate significant efficacy of re-irradiation for this patient group, although there was no control group in this study. These results compare poorly to those by Fogh et al. where a median survival of 11 mos. was achieved [4]. Combining reirradiation (2 Gy 18) with bevacizumab, Schnell et al. have recently demonstrated a long median survival of 13 mos. from treatment [25]. The poor survival times may be due to heavy pre-treatment (65% previously received bevacizumab and 42% had 3rd or later recurrence), a high percentage of glioblastoma (81%), and may also reflect an unbiased, prospective population. Finally, only 13% of patients underwent salvage tumor resection before re-irradiation (which has been established a positive prognostic factor [26]) as opposed to 57% reported by Fogh et al. [4]. To conclude, we found a considerable rate of serious adverse events (3 out of 7, 43%) in the minority of patients who were progression-free 10 weeks after treatment (7 out of 31, 23%). Although these adverse events included brain necrosis, the symptoms were mostly manageable. The efficacy of re-irradiation in this group of heavily pretreated patients was limited and we suggest that future research in this field should focus on re-irradiation as an adjunct to other treatment modalities such as immunotherapy or anti-angiogenic drugs. Acknowledgements This work was funded by the Capital Region of Denmark and by The Lundbeck Foundation Centre for Interventional Research in Radiation Oncology (CIRRO). We are grateful to our colleagues at Aalborg University Hospital for patient referrals. Conflict of interest statement None.
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Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial Søren Møller a,⇑, Per Munck af Rosenschöld a, Junia Costa a,b, Ian Law b, Hans Skovgaard Poulsen c,d, Svend Aage Engelholm a, Silke Engelholm a,e a Department of Oncology, Section for Radiotherapy, Rigshospitalet; b Department of Clinical Physiology, Nuclear Medicine & PET, Section 3982, Rigshospitalet; c Department of Radiation Biology, Section 6321, Rigshospitalet; d Department of Oncology, Section 5073, Rigshospitalet; and e Department of Oncology, Skåne University Hospital, Lund, Sweden
a r t i c l e
i n f o
Article history: Received 3 February 2017 Received in revised form 21 September 2017 Accepted 29 September 2017 Available online xxxx Keywords: Re-irradiation High-grade glioma phase I trial
a b s t r a c t Introduction: The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided reirradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. Material and methods: Patients with localized, recurrent HGG (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and 18F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose prescription of four consecutive groups was (1) 35 Gy/10fr., (2) 42 Gy/10fr., (3) 29.5 Gy/5fr. and (4) 35 Gy/10fr. to larger tumor volumes (100– 300 cm3), respectively. Results: Thirty-one patients were treated of which 81% had glioblastoma. The median progression-free survival was 2.8 months (95%CI: 2.1–3.5) and the median overall survival was 7.0 months (95%CI: 3.5– 10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis and irreversible white matter changes. Conclusion: Re-irradiation showed limited efficacy and 43% of patients achieving disease control suffered late toxicity that was manageable but not negligible. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
High-grade glioma are malignant primary brain tumors that arise from the glial cells of the brain. They grow infiltratively into healthy brain tissue and tend to relapse despite aggressive primary treatment consisting of surgery, radiotherapy and chemotherapy [1,2]. The prognosis at relapse is poor and no standard treatment currently exists [3]. In many centers re-irradiation is carried out, but some controversy exists about the safety and efficacy of this treatment. Whereas primary radiotherapy is considered safe and efficacious, repeating radiotherapy at recurrence may induce the risk of serious neurological toxicity such as symptomatic brain necrosis. Outcomes in retrospective series of re-irradiation of relapsed glioma have been favorable with nearly no serious adverse events (<1%) and long survival times [4,5]. Conversely, a prospective study by Shepherd et al. found considerable toxicity (36% rate of necrosis) [6].
⇑ Corresponding author at: Engbakkevej 12, 2920 Charlottenlund, Denmark. E-mail address: [email protected] (S. Møller).
The risk of brain necrosis has retrospectively been demonstrated to depend on radiotherapy dose, fraction size and target volume [7] but the impact of these factors has not been evaluated prospectively. Different radiotherapy dose- and schedules for re-irradiation have been proposed such as 3.5 Gy 10 [4] and 2 Gy 18 [8], but there is currently no international consensus on the most efficacious regimen. The purpose of this study was to evaluate the safety of reirradiation and to assess the impact of radiotherapy dose, fractionation and target volume on toxicity in a prospective phase I clinical trial in which we escalate radiation dose and volume in four sequential treatment regimes.
Material and methods The study was carried out in accordance with the Helsinki II Declaration and approved by the Ethics Board of the Capital Region of Denmark (protocol: H-2-2011-092). It is registered in
https://doi.org/10.1016/j.radonc.2017.09.039 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
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Toxicity of re-irradiation of glioma
ized to background brain tissue (Tmax/B) was calculated from the maximal tumor activity (SUVmax) and background activity [10].
the ClinicalTrials.gov database (NCT02025231). Written informed consent was required for entry into the study. The primary clinical endpoint of the study was early and late treatment toxicity as defined by CTCAE ver. 3.0 [9]. Secondary endpoints included the objective response rate. The trial also examined the value of 18F-FET PET in treatment planning and followup but those results have been published earlier in this journal [10].
Target delineation and imaging The target for radiotherapy was defined using both MRI and 18FFET PET. The GTV MRI was the contrast-enhancing tumor as contoured by a radiologist using a T1-post Gd-contrast MRI sequence. The GTV PET was derived as described in the previous section. The clinical target volume (CTV) equaled the union of the GTV-MRI + the GTV-PET and the planning target volume (PTV) equaled the CTV plus a 2 mm margin. Both imaging modalities were used for each evaluation at follow-up, but the time of tumor progression was determined using the MRI-based RANO criteria [11]
Treatment study groups Each of the four sequential treatment groups was to include at least six patients (Table 1). An observation time (latency) of three months for all six patients was required before the next dose level could be started, but new patients could be treated in the current dose level in this time period.
Radiotherapy Stereotactic radiotherapy was delivered using Volumetric Modulated Arc Therapy (VMAT) (Novalis Tx accelerator, RapidArc, Varian Medical Systems) with 5 fractions per week. Daily stereoscopic kilovoltage X-ray imaging was performed to ensure accurate patient positioning using 6-degrees of freedom (6D Robotics CouchÒ and), using a 1 mm tolerance. A thermoplastic mask was used for fixation. The permitted dose variation was 97–105% of the prescribed dose. Organs at risk were the brainstem, optic nerves/chiasm, hippocampi, eyes and healthy brain tissue. Maximum allowed total doses for all RT were 59.4 Gy for the brainstem, 65.3 Gy for small volumes (<10 ml) of brainstem and 60 Gy for the chiasm (EQD2, alpha/beta = 3), while the doses to other structures were minimized. These total doses were derived from QUANTEC reports [13,14] and, in addition, a conservative estimate of recovery of 10% in the spinal cord following primary RT was applied [15].
Follow-up Follow-up was scheduled at: 4-, 10-, 16-, 22-, 28-, 34-, 46- and 58- weeks after treatment. Evaluation comprised MRI, 18F-FET PET/ CT, clinical evaluation, QOL questionnaires and neurocognitive testing. Patients went off-study after 58 weeks of follow-up or at progression, death or withdrawal of consent. Patients Inclusion criteria: Recurrent high-grade glioma (WHO grade III or IV) as defined by the RANO criteria [11]; ECOG (Eastern Cooperative Oncology Group) performance status 0–2; localized disease; previous radiotherapy completed >6 months prior; no standard treatments available; expected life span >3 months; age > 18 years. A histological diagnosis of HGG (2007 WHO classification [12]) was required but not necessarily at recurrence. Exclusion criteria: Diffuse/large recurrences (planning target volume (PTV) > 100 cm3 for treatment groups 1, 2, and 3. For group 4, the maximal PTV allowed was 300 cm3); early recurrence following primary radiotherapy (3 months); fistula or other local pathologic conditions; contraindications to MRI- or 18F-FET PET CT. MRI and
Results Thirty-one patients were recruited and treated between December 2011 and December 2014. Patients’ baseline characteristics including treatment group allocation are listed in Table 2 and have been shown previously [10]. The study was terminated early in April 2015 due to slow accrual and only 5 patients were treated in dose levels 3 and 4, respectively. All patients have died – one of myocardial infarction after disease progression and the remainder from progressive glioma. Of the 31 patients, 30 were evaluable by RANO criteria. There were no objective responses. In 48% of cases the best response was stable disease. The median progression-free survival from the time of inclusion in the study was 2.8 months (95% CI: 2.1–3.5) and the median overall survival was 7.0 months (95% CI: 3.5–10.5). Seven patients (23%) were progression-free 10 weeks after treatment and they were considered assessable for late toxicity. Of these seven patients, 5 were treated in group 1 (3.5 Gy 10) and two were treated in group 2 (4.2 Gy 10). No patients treated in groups 3 (n = 5) or 4 (n = 5) were progression-free at 10 weeks.
18
F-FET PET image acquisition
Image acquisition for the study has been described previously [10]. Briefly, MRI was carried out on a Siemens Magnetom Espree 1.5 T scanner. Standard clinical sequences (T1 pre-and post Gadolinium (Gd)-contrast (GadovistÒ, 0.1 ml/kg) and T2/T2 fluid attenuation inversion recovery (FLAIR)) were acquired. 18 F-FET PET and planning CT was performed in a single session with an integrated 64 CT slice hybrid PET/CT system (Siemens Biograph mCT scanner). A single static frame of the brain was acquired 20–40 min after i.v. injection of 200 MBq 18F-FET. A threshold of 1.6 of mean SUV (standardized uptake value) in the background ROI was used for 3D auto-contouring of the biological tumor volume (BTV) used as GTV-PET. The maximal tumor uptake normal-
Table 1 Overview of treatment groups. Dose
PTV 3
Group 1 Group 2
3.5 Gy 10 3.5 Gy 10 + 7 Gy boost
<100 cm <100 cm3
Group 3 Group 4
5.9 Gy 5 3.5 Gy 10
<100 cm3 100–300 cm3
EQD2 tumor
EQD2 brain
39.4 39.4 49.7 39.1 39.4
45.5 45.5 60.5 (PET pos. volumes) 52.5 45.5
Radiotherapy regimes used in the Re-irradiation study. EQD2-doses were calculated using the linear-quadratic model and assuming a/btumor = 10 and a/bbrain = 3. All radiotherapy was given with 5 fractions/week. Abbreviations: PTV (planning target volume), EQD2 (2-Gy dose equivalent).
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
S. Møller et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 2 Baseline patient characteristics. Patients
n = 31
Age, years, median (range) Performance status 0 1 2 Diagnosis Glioblastoma Glioma WHO gr. III Recurrence number 1 2 3 Previous treatment Radiotherapy 60 Gy 44–45 Gy 34 Gy Temozolomide Bevacizumab Surgery prior to reirradiation Months since diagnosis, median (range) Treatment allocation in study Group 1 (3.5 Gy 10) Group 2 (3.5 Gy 10 + 7 Gy boost) Group 3 (5.9 Gy 5) Group 4 (3.5 Gy 10 to large tumors) Target volumes for radiotherapy, median (cm3) Planning target volume
54 (30–74) 10 (32%) 15 (48%) 6 (19%) 25 (81%) 6 (19%) 2 (6%) 16 (52%) 13 (42%)
26 (84%) 4 (13%) 1 (3%) 31 (100%) 20 (65%) 4 (13%) 23 (6–129) 12 (39%) 9 (29%) 5 (16%) 5 (16%) 67.0 (16.4–325.0)
Patterns of recurrence were analyzed and showed local failure only in 61%, local and distant failure in 13%, distant failure only in 10%. In 16% there was no radiological progression either due to cancelation of imaging due to severe clinical progression or no significant progression according to RANO criteria.
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Minor early toxicity (CTCAE grades 1–2 observed <10 weeks post-treatment) included seizure (3%), headache (25%), fatigue (19%), nausea (10%), skin reaction (10%) and increased steroid use (19%). Two patients (6%) were hospitalized following seizures that were potentially due to post-radiation edema. Serious late events (CTCAE grades 3–4 observed >10 weeks post-treatment) were observed in three cases (43% of the seven assessable patients). Two patient cases are described in Figs. 1 and 2. In addition to these two cases, one patient from group 2 developed grade 3 elevated intracranial pressure and edema on MRI four months post treatment and was hospitalized. The condition was treatable with steroids and regressed six months post treatment. Discussion In this prospective phase I study we aimed to assess the safety of re-irradiation to relapsed high-grade glioma. Our secondary aim was to determine an optimal dose regimen based on toxicity and efficacy. A minority of patients were progression-free 10 weeks after treatment and for these patients we observed an actuarial rate of serious late adverse radiotherapy induced events of 43%. We consider this an acceptable, but not negligible, rate of toxicity. The results indicate that re-irradiation may be more toxic than reported in the often cited retrospective reports by Fogh et al. [4], Combs et al. [5] and others [8,16], where almost no adverse events were observed. Conversely, our results are well in line with the rate of late adverse events of 36% reported by Shepherd et al. in a similar prospective study of single modality fractionated stereotactic re-irradiation of recurrent HGG [6] published almost 20 years ago. The large variation in reported toxicity (also reviewed by Amichetti et al. [17]) may be due to insufficient detection of adverse events in retrospective studies as well as different inter-
Fig. 1. Post-treatment sequential MRI- and 18F-FET PET scans of a patient with anaplastic astrocytoma (WHO grade III) who received 3.5 Gy 10. On the right, a plot of the biological tumor volume (BTV) and the maximal tumor uptake (Tmax/B) measured by 18F-FET PET at 11 time points. Four months post treatment, MRI and 18FET-PET scans concordantly indicated tumor growth on consecutive examinations. On PET, Tmax/B rose significantly from 2.3 to 3.1 and the BTV increased from 9 to 55 cm3. On MRI, both contrast-enhancing and non-contrast enhancing areas increased. Clinically, the patient showed no deterioration. Re-resection was performed approximately 24 weeks after re-irradiation (arrow). Histopathological examination revealed almost exclusively radionecrosis. Imaging (MRI and 18F-FET PET) three months after surgery showed increasing lesion size again with a BTV of 89 cm3, but this regressed spontaneously to baseline levels at 6- and 10-months after surgery. The patient continued to receive low dose corticosteroid treatment (10 mg/day of prednisolone). Due to the serious nature of the instituted treatment (neurosurgery) this event was categorized as grade 3–4 (CTCAE).
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
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Toxicity of re-irradiation of glioma
4 months post-treatment
10 months post-treatment
12 months post-treatment
Fig. 2. Post-treatment sequential T2 weighted FLAIR MRI- and 18F-FET PET scans of a glioblastoma patient who received 3.5 Gy 10 + 7 Gy boost to 18F-FET PET positive areas. Nine months after re-irradiation, this patient experienced balance problems, weakened bilateral fine motor coordination and reduced general psychomotor speed. 18FFET-PET scans showed no uptake but T2 weighted FLAIR MRI showed bilateral white matter changes extending backward, interpreted as edema. Steroid treatment was effective but could not be tapered due to recurrence of symptoms. The patient was treated with bevacizumab 10 mg/kg for one month but developed pulmonary embolisms whereupon treatment was stopped. No biopsy or surgery was performed.
pretations of follow-up imaging. In addition, real differences in rates of necrosis could be expected due to differences in patients and radiotherapy prescription (e.g. -dosis, -fractionation, volume) [7]. Lastly, the available prospective studies (including this one) are very small and subject to statistical variation. The patient in case number 1 displayed asymptomatic, focal gray matter necrosis that regressed during follow-up. MRI is known to discriminate poorly between necrosis and recurrent tumor [18] but 18F-FET PET also yielded a false positive result in this case. This may occur in a fraction of patients, particularly when a high local radiation dose is delivered and may be ascribed to inflammatory changes/reactive astrocytosis [19]. The patient in case nr. 2 exhibited different clinical and radiological findings more consistent with diffuse white matter changes extending backwards from the irradiated area. In this case, the 18FFET PET examination showed low uptake in the white matter. The pathophysiology of radiation induced brain necrosis is not completely understood but different theories exist. These include the ‘vascular theory’ (e.g. damage to the ever proliferating endothelium causes thrombosis, hemorrhage, and, ultimately, hypoxia and necrosis in the tissue supplied by the vessel) and the ’oligodendrocyte theory’ (e.g. high radiosensitivity of oligodendrocytes as compared to neurons causes gradual symptomatic demyelination) [20,21]. Due to the poor outcomes observed and due to poor recruitment to study groups 3 and 4, only a small number of patients
(n = 7) were assessable for late toxicity. In addition, there were no observable differences in responses or progression-free survival between groups and therefore no clear recommendations can be made. However, since both patients in treatment group 2 (3.5 Gy 10 + 7 Gy boost to PET + areas) who were free from disease progression beyond 3 months suffered from radionecrosis (cases 1 and 2), we cannot recommend this regime despite obvious statistical insufficiencies. In treatment group 4, patients with large tumors (PTV 100–300 cm3) were treated with 3.5 Gy 10. However, the pretreatment tumor volume (measured by 18F-FET PET or MRI) was shown to be a negative prognostic factor in multivariate analysis [10] and we therefore question the value of re-irradiation to large tumors. Dose level 1 (3.5 Gy 10) had been described previously and we did not expect significant toxicity but included it as a ‘safe’ dose. Dose level 2 (3.5 Gy + 7 Gy boost to PET + areas) was novel and represents a 20% increase in dose that was deemed necessary to obtain a meaningful separation of dose levels in each treatment plan, as well as a clinically meaningful escalation. Dose level 3 (5.9 Gy 5) was novel and aimed to test a possible effect of fraction size by delivering an equal EQD2-dose as level 1 (39.4 Gy) in 5 fractions instead of 10 fractions. Dose level 4 (3.5 Gy 10) was included to test the feasibility and toxicity of treating larger tumors (PTV 100–300 cm3). The choice of hypofractionated schedules as opposed to well described 2-Gy regimes for reirradiation [22] was motivated by a wish to limit overall treatment time rather
Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039
S. Møller et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
than by radiobiological considerations of alpha/beta ratios for glioblastoma. For calculation of EQD2, an alpha/beta ratio for tumor of 10 was assumed. This is within the range of 5.0–10.8 proposed in a recent meta analysis based on clinical studies, [23] but due to a scarcity of clinical data, any estimate of alpha/beta ratio is inherently uncertain and may be subject to controversy. The margins for radiotherapy (2 mm added to CTV for PTV) were to account only for setup uncertainty. A low tumor-tobackground threshold of 1.6 for tumor delineation with 18F-FET PET was chosen instead of adding a larger isotropic margin to a smaller volume defined by a higher threshold (e.g. 2.0). We expected this strategy to yield a CTV that to a higher degree reflected the true extent of tumor infiltration [24], although this remains to be validated in recurrent and previously treated HGG. Recurrence patterns are sometimes reported as ‘in-field’ or ‘marginal’. But because no objective responses were observed, these terms are not applicable and no further recommendations on margins can be made. In at least 74% of patients (please refer to Results), tumor progressed locally, which implies that radiotherapy doses were insufficient to achieve disease control. The median progression-free survival and the median overall survival times (median 2.8 mos and 7.0 mos, respectively) were very poor and do not indicate significant efficacy of re-irradiation for this patient group, although there was no control group in this study. These results compare poorly to those by Fogh et al. where a median survival of 11 mos. was achieved [4]. Combining reirradiation (2 Gy 18) with bevacizumab, Schnell et al. have recently demonstrated a long median survival of 13 mos. from treatment [25]. The poor survival times may be due to heavy pre-treatment (65% previously received bevacizumab and 42% had 3rd or later recurrence), a high percentage of glioblastoma (81%), and may also reflect an unbiased, prospective population. Finally, only 13% of patients underwent salvage tumor resection before re-irradiation (which has been established a positive prognostic factor [26]) as opposed to 57% reported by Fogh et al. [4]. To conclude, we found a considerable rate of serious adverse events (3 out of 7, 43%) in the minority of patients who were progression-free 10 weeks after treatment (7 out of 31, 23%). Although these adverse events included brain necrosis, the symptoms were mostly manageable. The efficacy of re-irradiation in this group of heavily pretreated patients was limited and we suggest that future research in this field should focus on re-irradiation as an adjunct to other treatment modalities such as immunotherapy or anti-angiogenic drugs. Acknowledgements This work was funded by the Capital Region of Denmark and by The Lundbeck Foundation Centre for Interventional Research in Radiation Oncology (CIRRO). We are grateful to our colleagues at Aalborg University Hospital for patient referrals. Conflict of interest statement None.
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Please cite this article in press as: Møller S et al. Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.09.039