Access the full text.
Sign up today, get DeepDyve free for 14 days.
Background: Stage III non-small cell lung cancer (NSCLC) represents a highly heterogeneous disease and treatment burden. Advances in imaging modality show promising results for radiotherapy planning. In this multicentric study, we evaluated the impact of PET/CT-based radiotherapy planning on the prognosis of patients with stage III NSCLC. Method and patients: A retrospective observational cohort study (ARO 2017-01/NCT03055715) was conducted by the young DEGRO trial group of the German Society for Radiation Oncology (DEGRO) with the primary objective to assess the effect of tumour volume change during chemoradiotherapy and the secondary objective to assess the effect of treatment planning on survival. Three hundred forty-seven patients with stage III NSCLC treated at 21 univer - sity centers between January 2010 and December 2013 were enrolled in this trial. Patients received primary curative chemoradiotherapy with an intended dose of 50 Gy (hypofractionated) or > 60 Gy (normofractionated). To assess the effect of radiotherapy planning modality on overall survival, we used multivariate frailty models. Models were adjusted for gross tumor volume at the initiation of therapy, age, sex, simultaneous chemotherapy, lung comorbidi- ties, RT dose and tumor grade. By considering the random effect, we can account for heterogeneity in survival and considered covariates within the model in relation to the study side. Results: Patients were predominantly male (n = 269, 78.4%) with mainly adenocarcinoma (56.4%) and an average of 67.2 years. Adaptation of radiotherapy with consecutive reduction of irradiation volume showed no significant disadvantage for patient survival (HR = 1.21, 95% CI 0.89–1.64). The use of PET/CT co-registration in radiation planning tended to result in better oncologic outcomes, although no significant association could be shown (HR = 0.8, 95% CI 0.56–1.16). Centers with a consistent planning strategy performed better than those without a preferred planning method (0.62, 95% CI 0.41–0.94). Conclusion: A consistent planning strategy has positive effects on overall survival. The use of PET/CT-based adaptive radiotherapy planning shows a similar survival prospect with the prospective of lower treatment volumes. In future research, toxicities need to be analysed in order to assess such reasoning. Keywords: Lung cancer, Non small cell lung cancer, PET/CT, Adaptive radiotherapy *Correspondence: firstname.lastname@example.org Department of Radiation Oncology, University Medical Center Jena, Jena, Germany Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mäurer et al. Radiation Oncology (2022) 17:29 Page 2 of 6 Spain (n = 1), Switzerland (n = 1), Belgium (n = 1) and Introduction Austria (n = 1) participated in the trial. Data of n = 347 Lung cancer is the leading cause of cancer-related deaths patients who received curative-intent radiation therapy worldwide [1, 2]. The prognosis for patients with locally with curative intent (± chemotherapy) between January advanced stage III non-small cell lung cancer (NSCLC) 1st 2010 and December 31st 2013 were analyzed. remains poor despite the use of modern immunothera- Inclusion criteria were (1) inoperable UICC stage III pies [3–5]. A or B NSCLC (adenocarcinoma or squamous cell car- One strategy to improve the prognosis is an optimi- cinoma) confirmed by biopsy, (2) CT-based radiation zation of tolerability of treatment by more precise irra- treatment planning (PET- or PET/CT-based if available), diation methods [6, 7]. Technological improvements in (3) completed curatively intended radiotherapy ± chem- recent years have enabled dose escalation with better otherapy (planned total dose ≥ 60 Gy conventionally tumor coverage and optimized sparing of normal tissues, fractionated or ≥ 50 Gy hypo-fractionated) and (4) resulting in a survival advantage with lower toxicity [8– age ≥ 18 years. Patients with a secondary malignancy 10]. These techniques include intensity-modulated radio - within 5 years prior to the diagnosis of the NSCLC and therapy, adaptive image-guided radiotherapy and the use patients who received stereotactic body radiotherapy of F-FDG PET/CT in radiation planning [11, 12]. In were excluded from the study. particular, information on metabolism provided by F- Demographical, treatment, and clinical data was FDG PET/CT can improve target volume definition and extracted from the patients’ clinical records at the par- dose planning before and during radiotherapy (RT), ena- ticipating sites and was collected using electronic case bling better selection of patients and individualization of report forms (eCRF) which were stored in the RadPlan- therapeutic strategies [13, 14]. A systematic review and Bio data base of the German Cancer Consortium (DKTK) meta-analysis could demonstrate a relevant change in and the German Cancer Research Center (DKFZ) . target volume definition in about 40% of NSCLC with the Written informed consent of all patients was available use of a planning PET/CT . Accordingly, the multi- prior to data acquisition and analysis. centric PET-plan study showed a possible isotoxic dose- escalation for the use PET-guided RT . The use of Statistics further PET-tracers like FMISO may additionally tailor To assess the effect of PET planning on overall sur - individual (and possibly smaller) metabolic tumor vol- vival we used multivariate frailty models. Models were umes . However, the reduction of target volume for adjusted for gross tumor volume (GTV) at the initiation dose escalation has to be carefully balanced with ade- of therapy, age, sex, simultaneous chemotherapy, lung quate coverage of the tumor. In the RTOG 0617 trial, comorbidities, RT dose and tumour grade. By consider- high-dose chemo-RT with 74 Gy did result in adverse ing the random effect, we can account for heterogeneity overall survival (OS) when compared with standard dose in survival and considered covariates within the model in RT 60 Gy, the later RT strategy revealing better dose cov- relation to study side. erage of the target [17, 18]. In another Cox regression models, we used ‘study Despite the new data on the treatment of NSCLC, it is center’ as predictor by forming four groups according to unclear how the radiation planning strategy and the use which method (no PET planning, PET co-registration, of PET/CT for radiation planning affect local control and PET without co-registration) was the predominant choice survival. In addition, it is not known when and how often of the respective center (≥ 50% of all cases planned by a PET/CT should be performed in the setting of chemora- one method). Center with no preferred method (no sin- diotherapy and whether it should be performed as staging gle planning method exceeding 50%) were merged to the PET/CT or in the RT planning position. In the present fourth group. analysis, we evaluated the relevance of F-FDG-PET- In the models, we computed hazard ratios (HRs) with based radiotherapy planning on the prognosis of patients respective 95% confidence intervals (95%-CIs). with stage III NSCLC in multicenter study including 347 All analyses were performed with SAS, version 9.4. patients. Results Methods and patients The study included equal numbers of stage IIIA and IIIB Study population, treatment and participating institutions patients (Table 1). This retrospective observational cohort study (ARO RT was combined with concurrent chemotherapy 2017-01/NCT03055715) was conducted by the young (CHT) in 250 patients (72.2%), 96 patients (27.8%) DEGRO trial group (yDEGRO) of the German Society received sequential chemoradiotherapy. 75 patients (30%) for Radiation Oncology (DEGRO). Twenty-one univer- were treated with combined cisplatin-vinorelbine CHT, sity centers for Radiation Oncology in Germany (n = 17), M äurer et al. Radiation Oncology (2022) 17:29 Page 3 of 6 Table 1 Sociodemographic patient and disease characteristics 0.89–1.64, after covariate adjustment, Fig. 1, Table 1) (Table 2). Patient number (%) In the analysis of PET, cases with PET co-registration Sex showed a similar survival rate as compared to cases Male 269 (78.4%) without consideration of PET imaging (HR = 0.8, 95% Female 74 (21.6%) CI 0.56–1.16 after covariate adjustment, Fig. 2, Table 1). Age Mean (SD): 67.2 (10.7) Analyzing centers according to the preferred plan- Pack years Mean (SD): 38.2 (25.1) ning strategy, we found that centers with no preferred UICC stage (7th edition) method performed worse than those with a pre- IIIA 174 (50.1%) dominant planning method (0.62, 95% CI 0.41–0.94, IIIB 173 (49.9%) after covariate adjustment, Fig. 3, Table 1). However, Histology this finding is based on only one center in the mixed Adenocarcinoma 134 (39.2%) method group. Squamous cell carcinoma 193 (56.4%) Grading 1 7 (2.0%) 2 104 (30.0%) 3 120 (34.6%) 4 5 (1.4%) na 111 (32.0%) T stage T1 32 (9.2%) T2 63 (18.2%) T3 106 (30.5%) T4 144 (41.5%) TX 2 (0.6%) N stage N0 32 (9.2%) N1 42 (12.1%) N2 172 (49.7%) N3 97 (28%) Fig. 1 Kaplan–Meier plot of patients with (blue) and without (green) NX 3 (0.9%) adaptive planning Sequential chemotherapy Yes 96 (28.0%) Table 2 Hazard ratios from frailty survival models using center No 247 (72.0%) as a random variable Dose Mean (SD): a b 63.5 (5.4) Crude Adj. Adeno carcinoma, squamous-cell carcinoma 2 well, moderate, poor, Eec ff t of re-planning undifferentiated (1–4) No Re.-pl Ref Ref Not available Re.-pl 1.15 (0.84–1.57) 1.21 (0.89–1.64) Eec ff t of PET 48 (19.2%) carboplatin-vinorelbine, 52 (20.8%) carbopl- No PET Ref Ref atin-docetaxel, and 75 (30%) other chemotherapy doublet PET 0.85 (0.58–1.24) 0.91 (0.62–1.34) combinations. PET coreg 0.76 (0.53–1.09) 0.8 (0.56–1.16) In 314 (90.8%) patients’ conventional fractionation Eec ff t of PET usage in study centers was used, compared to 7 (2%) patients were treated with PET coreg. versus No 0.83 (0.55–1.24) 0.72 (0.48–1.08) hyperfractionated regimens, and 5 patients (1.5%) under- PET coreg. versus PET 0.96 (0.63–1.46) 0.8 (0.54–1.19) going a simultaneous-integrated boost (SIB) concept. 20 PET coreg. versus div 0.59 (0.37–0.94) 0.62 (0.41–0.94) patients (5.7%) received other RT concepts. Adjusted for GTV1, age, sex, sim. Chemotherapy, lung comorbidities, RT dose, In analysis of adaptive planning, no significant effect grade on survival was found for replanned cases when com- “center” as random variable, Re.-pl. re-planning, coreg. coregistration, div. diverse planning strategies pared to cases with no re-planning (HR = 1.21, 95% CI Adj. for GTV1, age, sex, sim. Chemotherapy, lung comorbidities, RT dose, grade Mäurer et al. Radiation Oncology (2022) 17:29 Page 4 of 6 The multicentric randomized PET-plan study demon - strates the ability of an isotoxic RT dose escalation (mean dose 65.3 Gy vs. 67.3 Gy for the standard vs. the experi- mental arm) with the use of 18F-FDG PET/CT for plan- ning . Despite smaller target volumes in the PET-arm, locoregional failure was not inferior (30% vs. 17% in the intention-to-treat population after 1 year for the stand- ard vs. experimental arm) . Consistent with our data, no significant impact on OS could be shown. However, a safe RT-volume reduction with improved sparing of healthy lung is likely to results in lower toxicity [21–23]. As shown previously by our group, we found a mean reduction in GTV volume at the time of re-planning of 48.2 mL or 31.1% . Based on our findings, the consistency of centers Fig. 2 Kaplan–Meier plot of PET application in performing each standard, regardless of modality, appears to have a prognostic impact. Patients from cent- ers with no stringently applied RT planning procedure experienced a worse outcome compared to centers with consistent RT planning protocols (CT versus PET/CT). In this respect, it seems advisable not to switch too fre- quently between different adaptive procedures, but to apply a homogenous in-house protocol. Although not statistically significant patients with a co- registered PET actually numerically outperformed those with staging PET/CT. This is of importance as planning PET/CT are not mandatory in most studies: in RTOG 0617 around 90% of patients had a PET-staging in each arm, whereas its use for RT-planning was only encour- aged . u Th s, the use of PET/CT in radiation planning (co-reg - istered or in RT treatment position) should be considered in accordance with modern guidelines (ESTRO-ACROP Fig. 3 Kaplan–Meier plot of centers according to applied planning NSCLC). From a public health perspective the applica- strategy tion of PET-based RT planning was shown to be cost- effective when compared to CT-based planning . Other concepts such as simultaneous integrated boost Discussion need to take account for altering treatment volumes . The present analysis demonstrates prognostic supe - As variability in the application of planning techniques riority of a consistent imaging strategy for advanced might be associated with an adverse survival prospect NSCLC. Our results confirm non-inferiority of target PET-based planning might additionally contribute to a volume reduction in terms of outcome and therefore reduced heterogeneity in the definition of target struc - encourage PET/CT based RT planning for NSCLC. tures . Our results go along with the findings of Nestle et al. At the time of enrollment to our study, sequential dur- which could show that PET/CT-based reduction of valumab maintenance implemented by the PACIFIC trial radiotherapy target volume may improve local con- was not the standard of care for patients with inopera- trol without increasing toxicity in patients with locally ble stage III NSCLC, but needs to be taken into account advanced NSCLC . The correct identification of today . Importantly, PET/CT staging and treat- PET-avid tumor tissue is pivotal as it acts as a starting ment planning was not mandatory in the PACIFIC trial point for local recurrence: a patterns-of-failure study but should be considered standard of care based on our on NSCLC patients demonstrates local recurrences to findings consistent with recent literature [11, 28]. Since occur predominantly within the previous active volume increased lung toxicity has been previously reported in . patients treated for stage III NSCLC with durvalumab, M äurer et al. Radiation Oncology (2022) 17:29 Page 5 of 6 scientists ( WI 830/12-1). Lukas Käsmann was supported by the Munich Excel- reduction of irradiated lung is of increasing importance lence Training Initiative for Physician Scientists (Metiphys) and the Bavarian . Cancer Research Center (BZKF). From the results of our retrospective study, further Availability of data and materials direction of future research on RT treatment of patients The datasets generated during and/or analysed during the current study are with locally advanced NSCLC should focus on the pos- not publicly available but may become available upon request with permis- sibilities of PET/CT-based RT planning regarding further sion from corresponding author and host institution following sufficient maturation of data. improvement of local control monitored by PET/CT- based recurrence pattern analyses. Declarations Limitations Ethics approval and consent to participate The local ethics (Reference number: 2017-15) and data protection committees In our study the majority of institutions preferred one of the participating institutions approved the study protocol. The study was approach above others with only one centre using mul- carried-out in accordance to the declaration of Helsinki of 1975 (as revised in tiple planning strategies. In order to gain a broader per- 2008). In accordance with local law, all patients consented to scientific data processing before the initiation of treatment. Additional patient consent was spective, the inclusion of more centers with different not required as this study was retrospective according to the recommenda- planning methods should be envisaged. Furthermore, tions of the Institutional Review Board. as real-life data were used, there was no standard- Consent for publication ized method for target volume delineation. u Th s, PET Not applicable. information might have been used differently for target volume delineation among study centres. Finally, PET Competing interests The authors declare that they have no competing interests. imaging might lead to differences in clinical stages, espe - cially in the amount of lymph node involvement. This Author details might lead to an up- or down-staging of respective cases. Department of Radiation Oncology, University Medical Center Jena, Jena, Germany. Department of Radiation Oncology, University Hospital, LMU However, in our study this might affect our results only in Munich, Munich, Germany. Department of Radiation Oncology, University so far as the covariate adjusted models or inclusion crite- 4 Medical Center Muenster, Muenster, Germany. Department of Particle ria are concerned. Therapy, West German Proton Therapy Centre Essen ( WPE), West German Cancer Center ( WTZ), University Hospital Essen, Essen, Germany. Depar tment of Radiation Oncology, Faculty of Medicine, Martin Luther University Halle- Conclusion Wittenberg, Halle (Saale), Germany. A consistent radiotherapy planning strategy should be Received: 22 October 2021 Accepted: 25 January 2022 followed for patients undergoing definitive chemoradio - therapy for stage III NSCLC. The use of PET/CT-based adaptive radiotherapy planning shows comparable onco- logic outcomes and should be considered to avoid radio- References genic toxicities. 1. Chen H, et al. Treatment-related toxicity in patients with early-stage non- small cell lung cancer and coexisting interstitial lung disease: a systematic review. Int J Radiat Oncol Biol Phys. 2017;98(3):622–31. Abbreviations 2. Molina JR, et al. Non-small cell lung cancer: epidemiology, risk factors, 18 18 F-FDG PET: F-fludeoxyglucose positron emission tomography; CT: Com- treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584–94. puted tomography; DEGRO: German Society for Radiation Oncology; DKFZ: 3. Huber RM, et al. Interdisciplinary multimodality management of stage III German Cancer Research Center; DKTK: German Cancer Consortium; NSCLC: nonsmall cell lung cancer. Eur Respir Rev. 2019;28(152):190024. Non-small cell lung cancer; RT: Radiotherapy; UICC: Union for International 4. Ettinger DS, et al. NCCN guidelines insights: non-small cell lung cancer, Cancer Control. Version 5.2018. J Natl Compr Cancer Netw. 2018;16(7):807–21. 5. Bradley JD, et al. Long-term results of RTOG 0617: a randomized phase 3 Acknowledgements comparison of standard dose versus high dose conformal chemoradia- The yDEGRO Trial Group thanks the German Society for Radiation Oncology tion therapy +/- cetuximab for stage III NSCLC. Int J Radiat Oncol Biol (DEGRO) and radiologic oncology working group (ARO) of the German Cancer Phys. 2017;99(2):S105. Society (DKG) for their support. In addition, we would like to thank German 6. Jaksic N, et al. Optimized radiotherapy to improve clinical out- Cancer Consortium (DKTK) and the German Cancer Research Center (DKFZ) comes for locally advanced lung cancer. Radiat Oncol (Lond Engl). for providing data base space for the storage of the patient data and Tomas 2018;13(1):147–147. Scripcak as the central data base manager. 7. Ostheimer C et al. Prognostic impact of gross tumor volume during radi- cal radiochemotherapy of locally advanced non-small cell lung cancer- Authors’ contributions results from the NCT03055715 multicenter cohort study of the Young MM, DM, LK and MO were involved in the conceptualization of the project, DEGRO Trial Group. Strahlenther Onkol. 2021. data collection and text drafting. DF and DJ critically reviewed and edited the 8. Zheng Y, et al. FDG-PET/CT imaging for tumor staging and definition of text. DM visualized the data and performed the statistical analysis. All authors tumor volumes in radiation treatment planning in non-small cell lung read and approved the final manuscript. cancer. Oncol Lett. 2014;7(4):1015–20. 9. Konert T, et al. PET/CT imaging for target volume delineation in curative Funding intent radiotherapy of non-small cell lung cancer: IAEA consensus report Open Access funding enabled and organized by Projekt DEAL. Matthias Mäu- 2014. Radiother Oncol. 2015;116(1):27–34. rer was supported by the DFG through the OrganAge programme for clinician Mäurer et al. Radiation Oncology (2022) 17:29 Page 6 of 6 10. Hoeller U, et al. Late sequelae of radiotherapy. Dtsch Arztebl Int. 2021;118(12):205–12. 11. Nestle U, et al. Imaging-based target volume reduction in chemora- diotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial. Lancet Oncol. 2020;21(4):581–92. 12. Simsek FS, et al. Is it possible to achieve more accurate mediastinal nodal radiotherapy planning for NSCLC with PET/CT? J Pak Med Assoc. 2020;70(1):29–34. 13. Schild SE, et al. Toxicity related to radiotherapy dose and targeting strat- egy: a pooled analysis of cooperative group trials of combined modality therapy for locally advanced non-small cell lung cancer. J Thorac Oncol. 2019;14(2):298–303. 14. Steenbakkers RJHM, et al. Reduction of observer variation using matched CT-PET for lung cancer delineation: a three-dimensional analysis. Int J Radiat Oncol Biol Phys. 2006;64(2):435–48. 15. Hallqvist A, et al. Positron emission tomography and computed tomo- graphic imaging (PET/CT ) for dose planning purposes of thoracic radia- tion with curative intent in lung cancer patients: a systematic review and meta-analysis. Radiother Oncol. 2017;123(1):71–7. 16. Thureau S, et al. FDG and FMISO PET-guided dose escalation with inten- sity-modulated radiotherapy in lung cancer. Radiat Oncol. 2018;13(1):208. 17. Bradley JD, et al. Long-term results of NRG oncology RTOG 0617: stand- ard- versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer. J Clin Oncol. 2020;38(7):706–14. 18. Bradley JD, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187–99. 19. Skripcak T, et al. Creating a data exchange strategy for radiotherapy research: towards federated databases and anonymised public datasets. Radiother Oncol. 2014;113(3):303–9. 20. Kandi M, et al. Local failure after radical radiotherapy of non-small cell lung cancer in relation to the planning FDG-PET/CT. Acta Oncol. 2018;57(6):813–9. 21. Berkovic P, et al. Adaptive radiotherapy for locally advanced non-small cell lung cancer, can we predict when and for whom? Acta Oncol. 2015;54(9):1438–44. 22. Wang W, et al. Eec ff t of normal lung definition on lung dosimetry and lung toxicity prediction in radiation therapy treatment planning. Int J Radiat Oncol Biol Phys. 2013;86(5):956–63. 23. Hoegen P, et al. Cone-beam-CT guided adaptive radiotherapy for locally advanced non-small cell lung cancer enables quality assurance and superior sparing of healthy lung. Front Oncol. 2020;10:564857. 24. Ostheimer C, et al. Prognostic impact of gross tumor volume during radi- cal radiochemotherapy of locally advanced non-small cell lung cancer— results from the NCT03055715 multicenter cohort study of the Young DEGRO Trial Group. Strahlenther Onkol. 2021;197(5):385–95. 25. Bongers ML, et al. Pet-based radiotherapy treatment planning is highly cost-effective compared to CT-based planning: a model-based evalua- tion. Value Health. 2013;16(7):A414. 26. Jeter MD, et al. Simultaneous integrated boost for radiation dose escala- tion to the gross tumor volume with intensity modulated (photon) radiation therapy or intensity modulated proton therapy and concurrent chemotherapy for stage II to III non-small cell lung cancer: a phase 1 Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : study. Int J Radiat Oncol Biol Phys. 2018;100(3):730–7. 27. De Ruysscher D, et al. PET scans in radiotherapy planning of lung cancer. fast, convenient online submission Lung Cancer. 2012;75(2):141–5. thorough peer review by experienced researchers in your ﬁeld 28. Antonia SJ, et al. Durvalumab after chemoradiotherapy in stage III non- small-cell lung cancer. N Engl J Med. 2017;377(20):1919–29. rapid publication on acceptance 29. Tonk EHJ, et al. Acute-onset pneumonitis while administering the first support for research data, including large and complex data types dose of durvalumab. Case Rep Oncol. 2019;12(2):621–4. • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- At BMC, research is always in progress. lished maps and institutional affiliations. Learn more biomedcentral.com/submissions
Radiation Oncology – Springer Journals
Published: Feb 9, 2022
Keywords: Lung cancer; Non small cell lung cancer; PET/CT; Adaptive radiotherapy
Access the full text.
Sign up today, get DeepDyve free for 14 days.