Abstract
Aim
The aim of the study was to assess the feasibility of an individualized 18F fluorodeoxyglucose positron emission tomography (FDG-PET)-guided dose escalation boost in non-small cell lung cancer (NSCLC) patients and to assess its impact on local tumor control and toxicity.
Patients and methods
A total of 13 patients with stage II–III NSCLC were enrolled to receive a dose of 62.5 Gy in 25 fractions to the CT-based planning target volume (PTV; primary turmor and affected lymph nodes). The fraction dose was increased within the individual PET-based PTV (PTVPET) using intensity modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) until the predefined organ-at-risk (OAR) threshold was reached. Tumor response was assessed during follow-up by means of repeat FDG-PET/computed tomography. Acute and late toxicity were recorded and classified according to the CTCAE criteria (Version 4.0). Local progression-free survival was determined using the Kaplan-Meier method.
Results
The average dose to PTVPET reached 89.17 Gy for peripheral and 75 Gy for central tumors. After a median follow-up period of 29 months, seven patients were still alive, while six had died (four due to distant progression, two due to grade 5 toxicity). Local progression was seen in two patients in association with further recurrences. One and 2-year local progression free survival rates were 76.9% and 52.8%, respectively. Three cases of acute grade 3 esophagitis were seen. Two patients with central tumors developed late toxicity and died due to severe hemoptysis.
Conclusion
These results suggest that a non-uniform and individualized dose escalation based on FDG-PET in IMRT delivery is feasible. The doses reached were higher in patients with peripheral compared to central tumors. This strategy enables good local control to be achieved at acceptable toxicity rates. However, dose escalation in centrally located tumors with direct invasion of mediastinal organs must be performed with great caution in order to avoid severe late toxicity.
Zusammenfassung
Zielsetzung
Ziel der Studie war es, die Anwendbarkeit einer individualisierten Fluordesoxyglukose-Positronenemissionstomographie(FDG-PET)-geführten partiellen Dosissteigerung beim nichtkleinzelligen Lungenkarzinom (NSCLC) zu prüfen und deren Einfluss auf die lokale Tumorkontrolle und Toxizität zu beurteilen.
Patienten und Methoden
Dreizehn Patienten mit NSCLC in Stadium II–III wurden in die Studie einbezogen und erhielten im Rahmen einer Radiochemotherapie eine Dosis von 62,5 Gy in 25 Fraktionen auf das CT-basierte Planungszielvolumen (PTV; primärer Tumor und betroffene Lymphknoten). Dabei wurde die Fraktionsdosis innerhalb des individuellen PET-basierten PTV (PTVPET) unter Anwendung einer intensitätsmodulierten Radiotherapie (IMRT) mit simultan-integriertem Boost (SIB) bis zum Erreichen der vordefinierten Organ-at-risk(OAR)-Grenze erhöht. In der Nachbeobachtungszeit wurde die Tumorantwort mit wiederholter FDG-PET/Computertomographie überprüft. Die frühe und späte Toxizität wurden erfasst und anhand der Common-Terminology-Criteria-for-Adverse-Events(CTCAE)-Kriterien (Version 4.0) klassifiziert. Das lokale progressionsfreie Überleben wurde anhand der Kaplan-Meier-Methode bestimmt.
Ergebnisse
Die Durchschnittsdosis auf das PTVPET erreichte 89,17 Gy für periphere und 75 Gy für zentrale Tumoren. Nach einer medianen Nachbeobachtungszeit von 29 Monaten waren 7 Patienten weiterhin am Leben, 6 waren verstorben (4 davon an Fernrezidiven, 2 an einer Toxizität fünften Grades). Bei 2 Patienten trat eine lokale Progression in Verbindung mit weiteren Rezidiven auf. Die lokalen progressionsfreien 1‑ und 2‑Jahres-Überlebensraten lagen bei 76,9 % bzw. 52,8 %. Es wurden 3 Fälle akuter Ösophagitiden dritten Grades beobachtet. Zwei Patienten mit zentralen Tumoren entwickelten eine späte Toxizität und verstarben infolge einer schwerwiegenden Hämoptyse.
Schlussfolgerung
Gemäß diesen Ergebnissen ist für Patienten mit NSCLC eine im Rahmen der IMRT angewendete, auf der FDG-PET basierende individualisierte Dosiseskalation möglich. Die erreichte Strahlendosis ist bei peripheren Tumoren höher als bei zentralen. Mit dieser Strategie wird eine hohe lokale Kontrolle bei akzeptabler Toxizitätsrate erreicht. Dennoch sollte die Dosissteigerung für zentrale Tumoren mit direktem Eindringen in Mediastinalorgane mit äußerster Vorsicht erfolgen, um eine schwere späte Toxizität zu vermeiden.
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Funding
This research program was supported by a grant from the Belgian national fund for scientific research (FRS-FNRS Télévie, grant number, 7.4537.09). X. Geets is a Postdoctoral Researcher with the FRS-FNRS, partly funded by the Clinical and Experimental Research Institute (IREC). John A. Lee is a Research Associate with the FRS-FNRS (FC 63880).
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M. Wanet, A. Delor, F.-X. Hanin, B. Ghaye, A. Van Maanen, V. Remouchamps, C. Clermont, S. Goossens, J.A. Lee, G. Janssens, A. Bol and X. Geets declare that they have no competing interests.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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Authors Contributions
M. Wanet participated in the design and coordination of the trial, recruited patients, carried out all imaging sessions and all volume delineations. MW also performed the follow-up during and after the treatment of all patients, tumor assessment on both imaging modalities and drafted the manuscript. A. Delor planned the treatment of 11 patients. F.-X. Hanin supervised the tumor response assessment on FDG-PET imaging (PERCIST and EORTC). B. Ghaye supervised and performed the tumor response assessment on CT imaging (RECIST). A. Van Maanen performed the statistical analysis. V. Remouchamps recruited the patients at the second center (two patients) and performed the follow-up during and after treatment of these patients. C. Clermont planned the treatment of two patients. S. Goossens helped during the imaging session. J.A. Lee participated by providing the method and segmentation algorithm for PET imaging delineation and helped to draft the manuscript. G. Janssens participated by providing the method and non-rigid registration algorithm for ITV generation on CT and PET imaging. A. Bol helped during and after imaging sessions, as well as in tumor response assessment according to PERCIST (SULpeak measures). X. Geets designed the trial and recruited patients, supervised all steps of the trial as well as manuscript drafting. All authors read and approved the final manuscript.
Trial Registration
EU Clinical Trials Register, EudraCT number 2011-003124-12.
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Wanet, M., Delor, A., Hanin, FX. et al. An individualized radiation dose escalation trial in non-small cell lung cancer based on FDG-PET imaging. Strahlenther Onkol 193, 812–822 (2017). https://doi.org/10.1007/s00066-017-1168-z
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DOI: https://doi.org/10.1007/s00066-017-1168-z