• Local, regional and pulmonary failures in the randomised PET-boost trial for NSCLC patients

      Cooke, S.; De Ruysscher, D; Reymen, B.; Lambrecht, M.; Persson, G. F.; Faivre-Finn, Corinne; Dieleman, E.; Van Diessen, J.; Sikorska, K.; Lalezari, F.; et al. (2021)
      Introduction: In the phase II PET-Boost trial (NCT01024829), patients with stage II-III non-small cell lung cancer (NSCLC) were treated with hypofractionated dose escalation to either the primary tumour (PT) as a whole (armA) or the high FDG-uptake region inside the PT (>50%SUVmax) (armB). Results on Freedom From Local Failure at 1-year (primary endpoint), and overall survival (a secondary endpoint) were reported previously (Cooke et al,ESTRO,2020). Here we report on local and regional failure. Methods: Patients with stage II-III NSCLC were randomised to armA or armB, after a treatment plan was made for both arms that were normalized to the mean lung dose. Concurrent/ sequential/no chemotherapy was allowed. Followup chest CT-scans - scheduled at 3/6/12/18 months - were centrally reviewed by a thoracic radiologist. Definitions: local failure (LF): 20% growth of PT. Regional failure (RF): lymph node (LN) failure either in-field (IF) or out-of-field (OF) on CT-scan. Kaplan Meier analysis was performed to assess LF and RF rates at 2 years. Analysis of distant metastases is on-going. Results: Between April 2010 and Sep 2017, 107 patients were randomised. 82% had stage III disease and 80% had N 1 disease. Most patients received concurrent-chemoradiotherapy (72%). In arms A and B, median GTV-PT was 100 and 115cm3, median GTV-LN was 18 and 20cm3, median fraction dose was 3.25Gy to PTVwhole PT and 3.50Gy to PTV50%SUVmax, resulting in total planned physical dose 78.0 and 84.0 Gy, in 24 fractions (median OTT 34 days in both arms). Median follow-up for CT-scans in central review was 12.6months. In armsA and B respectively, loco-regional failure occurred in 12 and 15 patients, of which 2 and 4 had LF-without-RF, while 9 and 10 had RF-without- LF. One patient in armA had LF with synchronous RF, while in armB one patient had non-synchronous LF and RF. Analysis of all RF’s (10 and 11 total) showed 3 and 4 IF, 3 and 5 OF, 3 and 0 IF as well as OF (missing n¼3). In arms A and B respectively, the 2-year cumulative incidence of LF was 11% and 18%, and for RF 28% and 25% Conclusion: In this randomised, phase II trial dose escalation to the whole PT or 50%SUVmax in NSCLC patients led to excellent local control rates in both treatment arms. The 2-year local failure rate was below 20% and regional failures rate about 27%. In future trials, dose escalation on the PT, sparing central structures as much as possible, may be considered.
    • The PET-boost trial: isotoxic homogeneous or FDG-directed dose escalation in stage II-III NSCLC

      Cooke, S.; De Ruysscher, D; Reymen, B.; Lambrecht, M.; Persson, G. F.; Faivre-Finn, Corinne; Dieleman, E.; Lewensohn, R.; Van Diessen, J.; Sikorska, K.; et al. (2020)
      Purpose or Objective The randomized phase II PET-boost trial(NCT01024829) aimed to improve freedom from local failure(FFLF) by boosting either the whole primary tumor(PT) or the high FDG uptake region inside the PT(> 50%SUVmax) in non-small cell lung cancer (NSCLC) patients. Here we report on the primary endpoint FFLF at 1 year, and secondary endpoint overall survival(OS). Material and Methods Eligible patients had stage II-III NSCLC with a primary tumor ≥4 cm, SUVmax ≥5.0 and WHO PS ≤ 2. For each patient, before randomization, a treatment plan (24x2.75Gy) was made for both arms with a simultaneously integrated boost to the whole PT (armA) or to the PT 50%SUVmax area (armB). The boost dose (up to 5.4 Gy per fraction) was maximized by normal tissue constraints while the mean lung dose of the two plans was normalized. In case dose escalation of ≥3 Gy per fraction was not possible, patients were not randomized. Response was assessed with (PET/)CT at 3, 6, 12 and 18 months. All CT-scans were centrally reviewed by a dedicated radiologist. Local failure was defined as 20% growth from nadir (akin to RECIST). The trial was powered(one sided α=0.05;β=0.80) to detect an increase of FFLF at 1 year from 70% (historical rate) to 85%, requiring 82 randomized patients in each arm. Results Between Apr 2010 and Sep 2017, 150 patients were included in 7 institutions. The trial was closed after randomization of 107 patients (initial target 164): 54 to armA and 53 to armB. Patient characteristics are summarized in Table1. Median FU for FFLF was 12.6 months (IQR 5.2-24.6). Median escalated prescribed dose to the PTVwhole tumor (armA) was 3.25 Gy per fraction (IQR 3.13-3.40), and median total dose was 78.0 Gy (IQR 75.0-81.6). Median prescribed dose to the PTV50%SUVmax (armB) was 3.50 Gy per fraction (IQR 3.35-3.90), and median total dose was 84.0 Gy (IQR 80.4-93.6). 72% of patients received concurrent chemo-radiotherapy. Central review showed that the PT was non-measurable in 27% of CT-scans (96/352), mainly due to inflammation, fibrosis and/or atelectasis. If lesions remained stable over time, this was scored as no local failure. In the first year, 22 patients died without known local failure, 16 were lost to CT follow-up and 8 were not-evaluable. The 1-year FFLF rate in evaluable patients was 97% (95% CI 91-100) in armA, and 91% (95% CI 82-100) in armB. The 1- and 3-year OS rates were 77% and 37% in armA, and 62% and 33% in armB, respectively. Conclusion In this randomized phase II trial, dose escalation to the primary tumor as a whole or 50%SUVmax in NSCLC patients led to respectively 97% and 91% FFLF at 1 year in central CT review. Many scans were not evaluable (27%), likely due to the effect of high dose radiation. Predefined FFLF increase from 70% to 85% was achieved in both arms, however the trial did not reach predefined sample size. In locally advanced non-resectable NSCLC a homogeneous boost, sparing central structures as much as possible, should be considered in future research.
    • Sites of first progression in the randomized PET-boost trial for patients with locally advanced NSCLC

      Cooke, S.; De Ruysscher, D.; Reymen, B.; Lambrecht, M.; Persson, G. F.; Faivre-Finn, C.; Dieleman, E. M.; Van Diessen, J.; Sikorska, K.; Lalezari, F.; et al. (2021)
      Purpose/Objective(s) Curative intent conventional chemoradiotherapy for patients with locally advanced NSCLC is typically associated with high progression rates. In the PET-Boost trial, individualized dose escalation utilizing hypofractionation and functional imaging was tested as a strategy to improve local control. Here we report on sites of first recurrence. Materials/Methods We conducted a multi-institutional phase II study (NCT01024829). Patients with stage II-III NSCLC were randomized to receive either a boosted dose to the primary tumor (PT) as a whole (arm A) or to a region inside the PT with high FDG-uptake (> 50%SUVmax) (arm B). Boosted dose was delivered in 24 fractions of 3.0 Gy up to 5.4 Gy, limited by predefined OAR limits. Individualized isotoxic treatment plans were produced by equalizing the mean lung dose. Concurrent/sequential/no chemotherapy was allowed. This trial was conducted before immunotherapy became standard adjuvant treatment. Follow-up (PET/)CT-scans were scheduled at 3, 6, 12 and 18-months. The trial had a phase II, “pick the winner”, non-comparative design with freedom from local failure rate at 1-year as primary endpoint. Overall survival was estimated using the Kaplan-Meier method. Local and regional failures (LF, RF) were assessed by central review of chest-CT scans. Distant metastases (DM) were reported by local investigators. LF, RF and DM are reported as site of first recurrence. Cumulative incidence rates of first recurrence site were, in competing risk with death, estimated by Aalen-Johansen method. Results Between April 2010 and Sept 2017, 54 patients were randomized to arm A and 53 to arm B. Majority of patients had a good performance status (WHO 0-1, 93%), stage III disease (82%) and were treated with concurrent-chemotherapy (72%). In arms A and B respectively, median PT GTV was 99 cc (IQR 67-175) and 115 cc (IQR 64-179). Median fraction dose was 3.25 Gy to PTVwhole PT and 3.5 Gy to PTV50%SUVmax, resulting in median total planned physical dose 78 Gy and 84 Gy respectively. Central review identified 9 patients with missing scans, and 8 not-evaluable scans at 1 year (n = 4 due to surgery, n = 4 due to atelectasis, inflammation or fibrosis). Median FU for LF and RF was 12.6 months. At time of analysis, 36 and 39 patients had experienced a recurrence or died. In arms A and B respectively, the 1-year cumulative incidence rates (reported with 95% CI) for LF as site of first recurrence were 1.9% (0-6%) and 1.9% (0-6%), for RF 1.9% (0-6%) and 5.7% (0-12%), for DM 37.4% (24-50%) and 35.8% (23-49%), and for simultaneous multiple sites 3.7% (0-8%) and 1.9% (0-6%). Median FU for OS was 70.4 months. In arms A and B respectively, estimated 1-year survival was 77% and 62%. Conclusion While high local control rates were achieved in this phase II trial of hypofractionated dose escalation in patients with stage II-III NSCLC, distant metastases were frequently seen in this patient cohort with large primary tumors.