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Policies for reirradiation of recurrent high-grade gliomas: a survey among Italian radiation oncologists

Abstract

Purpose

To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach.

Methods

In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach.

Results

A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy.

Conclusions

Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.

Post author correction

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000615

Authors

Carlo Furlan, Stefano Arcangeli, Michele Avanzo, Maria A. Mirri, Fernando Munoz, Stefania Giudici, Antonio Perrone, Dante Amelio, Luigi Tomio, Loredana Draghini, Aniko M. Deli, Giovanni Pavanato, Francesca M. Giugliano, Antonio Pontoriero, Patrizia Ciammella, Pierina Navarria, Alberto Iannalfi, Michela Buglione, Cesare Guida, Silvia Cammelli, Vincenzo Iorio, Massimo Cardinali, Domenico Genovesi, Lucia Barsacchi, Mario Balducci, Rita Bagnoli, Franco Berti, Giampaolo Montesi, Francesco Pasqualetti, Paolo Bonome, Riccardo Santoni, Daniela Doino, Patrizia Schirru, Valentina Pinzi, Valentina Borzillo, Fabio Ferrarese, Marica Ferro, Luigi De Cicco, Marco Krengli, Silvia Scoccianti, Vittorio Donato

Article History

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.

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Introduction

High-grade gliomas (HGG) are aggressive and rapidly progressive brain tumors. They include glioblastoma multiforme and WHO grade III glioma. Radiation therapy (RT) represents a part of the combined modality approach for initial treatment of HGG, and is associated with improved local control and survival (1). Maximal surgical resection followed by adjuvant chemoradiotherapy (typically 60 Gy plus concurrent and adjuvant temozolomide) is considered the standard of care for HGG (2). Despite the use of such combined modality approach, the majority of patients relapse after initial therapy.

The management of patients with recurrent HGG is not defined. Surgical reoperation, reirradiation (reRT), and systemic therapy may be beneficial for selected patients, but each of these options is palliative, and exposes the patients to the risk of neurotoxicity in absence of any evidence from a randomized controlled trial demonstrating a survival benefit compared to supportive care alone (3-4-5-6).

Systemic therapy with bevacizumab, nitrosureas, and rechallenge with temozolomide represent the first choice for the majority of patients with diffuse or multiple HGG recurrence, while reoperation is an option for selected patients (7).

Focal reRT can be offered as a treatment option in selected cases, but there are several uncertainties with respect to its use in this clinical setting. First, since most patients had undergone adjuvant radiation at the time of initial treatment, the reRT dose is limited by the risk of life-threatening complications, including symptomatic necrosis (8). Second, clinical criteria for patient selection are not defined. Third, its role with respect to reoperation and systemic treatment remains uncertain due to a lack of prospective data. Novel reRT strategies have been developed to reduce the reRT dose to the normal brain, and several options for stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) are available. The Italian Association of Radiation Oncology (AIRO) reRT workgroup and the AIRO Central Nervous System Study workgroup decided to investigate the policies of Italian radiation oncologists (ROs) regarding the use of reRT in recurrent HGG.

Methods

In November 2015, a survey comprising 15 items was sent to all RO members of the AIRO. In case of multiple answers from 1 center, we asked for 1 answer from the head RO or from the RO working with neurology patients. The questionnaire focused on clinical factors for patient selection, dose prescription, chemotherapy association, and radiation techniques for reRT in patients with recurrent HGG.

The survey was sent on November 11, 2015, to all RT centers using the latest version of the AIRO e-mail list.

Questions 1-3 regarded the overall number of patients with HGG treated per year with reRT, if implemented, and the number of patients who underwent reRT during the last 5 years (Tab. I). Questions 4-7 focused on the clinical characteristics of patients with recurrent HGG who were candidates for reRT, and the factors considered for treatment decisions (Tab. II). Questions 8-14 focused on radiation delivery modalities and the use of concurrent systemic agents (Tab. III). The final question interrogated the RO’s attitude on being involved in research programs on reRT of HGG.

Institutional experience with respect to the use of reirradiation (reRT) for recurrent high-grade gliomas (HGG)

Question No. (%) or range (median)
Is reRT for recurrent HGG implemented in your Institution?
 Yes 31 (84)
 No 6 (16)
 Skipped question 0
If yes, how many HGG patients per year are managed with reRT?
 <5 22 (59)
 5-10 7 (19)
 >10 3 (8)
 Skipped question 5 (14)
How many patients underwent reRT during the last 5 years?
 Total patients; number in all responding centers 697; 0-236 (10)
 Skipped question 3 (8)

Results

A total of 37 of 210 questionnaires were returned (18% of all centers). Respondents represented a variety of working settings: nonacademic hospitals (n = 16 [43%]), academic hospitals (n = 14 [38%]), private institutions (n = 5 [13%]), and hadron therapy centers (n = 2 [6%]). From a geographic perspective, 17 out of 37 responding centers were located in the north (46%), 12 in the center (32%), and 8 in the south of Italy (22%). During the last 5 years (2010-2015), 697 patients were treated with reRT in the responding centers, and the majority of centers (59%) treated fewer than 5 cases per year (Tab. I). Performance status at the time of recurrence along with a target dimension and an extended time interval elapsed from primary RT were the prevalent predictive factors considered for re-RT. Indeed, a consistent agreement (62%) was met to consider fit the patients with an interval of at least 6 months from primary radiation to reRT, and in whom the target lesion measured less than <5 cm (67%) (Tab. II). With respect to the role of reRT versus other interventions, the majority of patients (60%) had already received a salvage therapy before reRT, either chemotherapy (40% of cases) or reoperation (20%).

Patient selection and criteria to consider for reirradiation (reRT) in patients with recurrent high-grade gliomas (HGG)

Question No. (%) or range (median)
Are there selection criteria for reRT?
 Yes 32 (86)
 No 3 (8)
 Skipped question 2 (6)
If yes, what?
 Age 15 (40)
 Performance status 31 (84)
  Methylguanine DNA methyltransferase 0
 Dimension of the target 30 (81)
 Time from primary therapy to recurrence 26 (70)
 Type of surgery at the time of diagnosis 1 (3)
 Location of the target 20 (54)
 Other criteria: Radiation dose at the time of primary therapy 1 (3)
How much time from primary therapy to reRT is necessary?
 At least 3 months 1 (3)
 At least 6 months 23 (62)
 At least 12 months 4 (11)
 It does not matter 4 (11)
 Skipped question 5 (13)
What dimensional cutoff do you apply for reRT?
 <5 cm 25 (67)
 5-10 cm 5 (13)
 Other measures: Planning target volume <100 mL 1 (3)
 Skipped question 7 (19)
Were patients offered other therapies before reRT for their HGG recurrence?
 Yes 22 (60)
 No 9 (24)
 Skipped question 6 (16)
If yes, specify
 Chemotherapy (no. of patients) 0-30 (4)
 Surgery (no. of patients) 0-47 (1)
 Other: Radiosurgery 1 case
 Skipped question 12 (32)

The survey investigated many aspects regarding reRT delivery (Tab. III). Eighteen centers used FSRT for reRT. The FSRT was linac-based or helical tomotherapy in 15 centers, and Cyberknife in 4 centers. Only 5 centers claimed to routinely perform SRS for HGG relapse; it was delivered by linac-based (4 centers), Cyberknife (3 centers), and/or gamma knife (2 centers) techniques. Two centers performed proton beam therapy. Dose prescriptions by single center according to radiation modality are reported in Figure 1; FSRT 25 Gy/5 fractions was the prevalent reRT schedule (32% of responding centers). With respect to dose constraints, ROs were asked to report their references for assessment of radiation tolerance of surrounding normal tissues; 15 out of 31 respondents refer to normal tissue complication probability models (Quantitative Analysis of Normal Tissue Effects in the Clinic) (8), and 5 respondents refer to the AIRO recommendations for the irradiation of the brain (radioterapiaitalia.it) and to other additional references (9-10-11-12-13). Seven centers did not declare any reference for definition of their dose constraints. All respondents declared their interest in the AIRO collaboration on brain reRT for recurrent HGG, including participation in a prospective multicenter study.

Reirradiation (reRT) modalities in patients with recurrent high-grade gliomas (HGG)

Question No. (%) or range (median)
Which radiation technique for reRT?
 3D conformal RT 8 (22)
 Stereotactic radiosurgery 5 (14)
 Fractionated stereotactic radiotherapy 18 (46)
 Intensity-modulated radiotherapy 14 (38)
 Protons 2 (6)
 Other 0
 Skipped question 4 (11)
Acquisition of data from the prior treatment plans
 By paper reports 10 (27)
 By DICOM files 30 (81)
 Skipped question 4 (11)
What kind of imaging do you use for reRT simulation?
 Morphologic magnetic resonance imaging 29 (78)
 Functional magnetic resonance imaging 10 (27)
 Positron emission tomography 7 (19)
 Skipped question 3 (8)
Do you apply expansion margins around the gross tumor volume to define the clinical target volume?
 Yes 19 (51)
 No 12 (33)
 Skipped question 6 (16)
 If yes, specify 0-10 mm (5 mm)
Do you use chemotherapy during reRT?
 Yes 11 (30)
 No 20 (54)
 Skipped question 6 (16)
 If yes, specify Temozolomide in 10/11 cases

Prevalence of reirradiation dosages. Data are referred to the 30 Italian centers that responded to this item. Multiple choices were allowed.

Discussion

Many Italian centers practice reRT for recurrent HGG, but with the exception of some large-volume centers for neuro-oncology, the clinical practice is fragmented in many low-volume centers, since 59% of respondents treated fewer than 5 patients per year. Moreover, reRT is not a common practice, given that only 18% of all radiotherapy centers responded to the survey and centers that do not practice reRT would not respond. On the other hand, a growing interest was documented, as 31/37 (84%) claim that reRT for recurrent HGG is being implemented. Radiation oncologists agree that patient performance status is the most important factor for benefit from reRT. This indication is consistent with literature data, where patients who maintain a good performance status at the time of recurrence showed a high likelihood of response to further therapy (3-4-5-6). Moreover, the approach of Italian ROs was generally consistent with the National Comprehensive Cancer Network as well as the European Association for Neuro-Oncology consensus-based guidelines with respect to taking into account patients’ pattern of failure and prior therapies for treatment decisions (7, 14). Along with these guidelines, good performance status patients with <5 cm localized recurrence, who had disease recurrence after a >6-month interval, were the best candidates for reRT. However, compared to other medical interventions, the role of reRT often was auxiliary, since 60% of reirradiated patients had already received a rescue therapy, either chemotherapy (40%) or reoperation (20%).

The most common reRT techniques in recurrent HGG were FSRT, linac-based (71%), or helical tomotherapy (41%). There was a large consensus to define the gross tumor volume on T1-weighted morphologic magnetic resonance imaging, while the clinical target volume margins varied between 3 and 5 mm.

The role of reRT in recurrent HGG remains uncertain, and evidence is based on retrospective series and small prospective studies. Observational experiences with fractionated reRT (15, 16) report a median survival of 8-12 months for selected HGG patients who underwent reRT with FSRT technique, with a median dose to the isocenter of 36 Gy (range 15-62 Gy).

In our survey, there was scarce agreement with respect to the radiation schedules, due to different radiation delivery facilities by single institutions. By formulation of the photon normalized total dose at 2 Gy per fraction (NTD2) with an alpha/beta of 3 Gy (17), and using a 1.1 relative biological effectiveness coefficient for proton beam therapy (18), we calculated the mean photon reRT dose, which was 41.6 Gy NTD2 with a standard deviation of 26.3 Gy (SRS was excluded from the NTD2 analysis). Photon NTD2 analysis was obtained to compare reRT schedules among responding centers. The mean reRT dose of 41.6 Gy NTD2 largely parallels the aforementioned literature experiences, although no clear differences among different radiation delivery modalities have been documented.

The use of systemic therapy combined with reRT is another important issue for the implementation of reRT in this clinical setting, and the Radiation Therapy Oncology Group (RTOG) is now investigating reRT combined with concurrent bevacizumab (RTOG 1205, NCT01730950). With respect to concurrent systemic regimens, the majority of Italian ROs did not perform rechallenge with temozolomide during reRT, and methylation of methylguanine DNA methyltransferase promotor was not considered a predictive factor for reRT. Moreover, concurrent bevacizumab is adopted only by 2 centers. This is consistent with a lack of solid data regarding the use of combined modality approaches for recurrent HGG outside clinical trials.

In conclusion, this survey provides a general consensus among Italian RO centers with respect to several topics regarding brain reRT. Focal reRT is a reliable option for good performance status patients after a prolonged period of stability. In particular, FSRT with 25 Gy/5 fractions schedule (photon NTD2 = 40 Gy), planned on T1-weighted morphologic magnetic resonance imaging, with or without concurrent temozolomide chemotherapy, represents the preferred reRT modality. These data provide a basis for encouraging a national collaborative study to develop, implement, and monitor corrective efforts to encourage the use of reRT in the management of recurrent HGG. Meanwhile, they represent a set of data to consult for treatment decisions for ROs in this challenging setting.

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.
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Authors

Affiliations

  • Radiation Oncology, Centro di Riferimento Oncologico, Aviano (Pordenone) - Italy
  • Radiation Oncology, Azienda Ospedaliera San Camillo-Forlanini, Rome - Italy
  • Radiation Therapy, Presidio Ospedaliero San Filippo-Neri, Rome - Italy
  • Radiation Therapy, Ospedale di Aosta, Aosta - Italy
  • Radiation Therapy, Ospedale di Sanremo, Sanremo (Imperia) - Italy
  • Radiation Therapy, Ospedale Casa Sollievo della Sofferenza, Foggia - Italy
  • Proton Therapy, Azienda Provinciale per i Servizi Sanitari, Trento - Italy
  • Radiation Oncology, Ospedale Santa Chiara, Trento - Italy
  • Radiation Oncology, Azienda Ospedaliera Santa Maria, Terni - Italy
  • Radiation Oncology, Ospedale San Raffaele, IRCCS, Milan - Italy
  • Radiation Therapy, Ospedale Santa Maria della Misericordia, Rovigo - Italy
  • Radiation Therapy, Emicenter-Casavatore, Napoli - Italy
  • Radiation Therapy, Università degli Studi di Messina, Messina - Italy
  • Radiation Therapy, Arcispedale degli Studi Santa Maria, Nuova-IRCCS Reggio Emilia - Italy
  • Radiation Therapy, Istituto Humanitas Cancer Center and Research Hospital, Milan - Italy
  • Radiotherapy and Radiosurgery, Istituto CNAO (Centro Nazionale Adroterapia Oncologica), Pavia - Italy
  • Radiation Therapy, Spedali Civili-Università di Brescia, Brescia - Italy
  • Radiation Therapy, Azienda Ospedaliera San Giuseppe Moscati, Avellino - Italy
  • Radiation Therapy, Policlinico S-Orsola-Malpighi, Bologna - Italy
  • Radiation Therapy, Studio di Radiologia Prof. V. Muto, Napoli - Italy
  • Radiation Therapy, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Ancona - Italy
  • Radiation Therapy, Azienda Ospedaliero-Universitaria Policlinico SS. Annunziata, Chieti - Italy
  • Radiation Therapy, Ospedale Sant’Anna, Como - Italy
  • Radiation Therapy, Policlinico Agostino Gemelli, Rome - Italy
  • Radiation Therapy, Presidio Ospedaliero Campo di Marte, Lucca - Italy
  • Radiation Therapy, Istituto Oncologico Veneto, Padova - Italy
  • Radiation Therapy, Azienda Ospedaliera-Università degli Studi di Perugia, Perugia - Italy
  • Radiation Oncology, Azienda Ospedaliera Universitaria Pisana, Pisa - Italy
  • Radiation Therapy, Azienda Ospedaliera Sant’Andrea, Rome - Italy
  • Radiation Oncology, Policlinico Tor Vergata, Rome - Italy
  • Radiation Therapy, Ospedale di Circolo-Fondazione Macchi, Varese - Italy
  • Radiation Therapy, Ospedale dell’Angelo di Mestre, Venezia - Italy
  • Radiation Therapy, Istituto Neurologico IRCCS Fondazione Carlo Besta, Milan - Italy
  • Radiation Therapy, Istituto Nazionale per lo Studio e la Cura dei Tumori - Fondazione “G. Pascale”, Napoli - Italy
  • Radiation Therapy, Ospedale Ca’ Foncello di Treviso, Treviso - Italy
  • Radiation Therapy, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Campobasso - Italy
  • Radiation Therapy, Ospedale di Circolo di Busto Arsizio, Busto Arsizio (Varese) - Italy
  • Radiation Therapy, Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara - Italy
  • Radiation Oncology, Azienda Ospedaliero-Universitaria Careggi, Firenze - Italy

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