Introducing FDG PET/CT-guided chemoradiotherapy for stage III NSCLC in low- and middle-income countries: preliminary results from the IAEA PERTAIN trial

The PERTAIN study was approved by the medical ethics committee of Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital (ref. M14PRI). In addition, each centre received ethical clearance from their local medical research ethics committee. Written informed consent was obtained from all patients included in the prospective phase.

Nine medical centres in seven countries met the technical requirements to participate in the PERTAIN study, including six middle-income countries: Brazil, India, Jordan, Pakistan, Turkey and Vietnam. The seventh country, Estonia, is classified as a high-income country by the World Bank, but did not routinely use PET/CT for RTP. The first component of the study was data collection from a retrospective cohort, which included consecutive patients with stage III NSCLC who had been treated in the participating centres between January 2010 and July 2014 according to existing local protocols. Over a 1-year period, nine pairs of trainees each including a RO and a NMP with limited experience in PET/CT-based TVD in NSCLC from seven different countries took part in multiple training interventions. Teams were given hands-on training in delineating the primary tumour according to IAEA protocol guidelines. An online webinar training session was held on TVD in NSCLC, and lectures for ROs and NMPs on current best practice in NSCLC were given [19]. All PET/CT scanners received annual European Association of Nuclear Medicine (EANM) Research Ltd. (EARL) FDG PET/CT accreditation. After the training intervention and scanner calibration, patients with stage III NSCLC were included in the prospective cohort between August 2015 and October 2018. The study entry criteria are summarized in the Supplementary material S1 (Form 1). Patients who did not meet the study entry criteria were excluded from the study.

Patient data were collected using electronic case report forms (eCRFs). Five different eCRFs were designed to collect information on patient eligibility, before and after treatment, and follow-up. More details on eCRFs and their format can be found in the Supplementary material S1.

The primary endpoint was OS, defined as the time between the start of treatment and date of death or loss to follow-up. The secondary endpoint was progression-free survival (PFS). PFS was defined as the time from the start of treatment to local failure, time to regional failure, and/or time to distant failure. Local failure was defined as progression in the primary tumour, and regional failure as progression in involved lymph nodes as assessed on follow-up scans. Distant failure was defined according to the 8th edition of the TNM classification for NSCLC [27]. The intervals for the follow-up assessments and imaging were as per local follow-up guidelines.

Patients in the retrospective cohort were treated according to respective institutional practice with sequential concurrent CRT, neoadjuvant chemotherapy or RT alone, but with curative intent. In the prospective cohort, patients were treated with concurrent CRT to a total dose of at least 60 Gy in fractions of 2 Gy over 6 weeks. Centres were free to select chemotherapy regimens according to local practice.

Patients underwent whole-body FDG PET/CT using one of the following scanners: Discovery ST, Discovery 710, Discovery STE (GE Medical Systems, Chicago, IL, USA), Biograph 40 mCT, and Biograph 64 mCT (Siemens Medical Solutions, Erlangen, Germany). The reconstruction voxel size of the PET data varied from 2.0 × 2.0 × 3.3 mm to 5.5 × 5.5 × 3.3 mm. Patients fasted for at least 8 h to ensure low levels of serum glucose. The total injected dose ranged between 226 MBq and 441 MBq (data not available for all patients). Patients were scanned approximately 60 min after injection of ¹⁸F-FDG according to EANM guidelines [28]. The acquisition times of the PET/CT scanners were in the range 2–5 min per bed position.

To assess the overall impact of the multiple training interventions and the routine use of FDG PET/CT-based concurrent CRT, survival outcomes in the retrospective cohort were compared with those in the prospective cohort. Although the training programme focused mainly on standardized PET/CT-based TVD, in general, the whole RTP procedure was also standardized to ensure the use of current treatment standards. Differences in the RTP procedures between the retrospective and prospective cohorts are summarized in Table 1.

To ensure that participating centres in the prospective study complied with the IAEA study protocol, central QC review of TVD was performed for the first three patients included per centre, and thereafter as needed. In the QC process anonymized PET/CT data and RT structure sets were made available through a secure online storage service and were reviewed by at least two members of the study trial management group.

Any differences in continuous variables between the retrospective and prospective cohorts were assessed using the independent t test. Any differences in categorical variables were assessed using the chi-squared test. Strong prognostic factors were identified using univariate Cox regression analysis. Kaplan–Meier analysis was performed to assess OS and PFS in the retrospective and prospective groups. The log-rank statistic was used to assess the significance of any differences. Statistical analysis was performed using IBM SPSS statistics for Windows, version 22.0 (IBM Corp., Armonk, NY). Values of p less than 0.05 were considered significant.

The retrospective cohort included 230 patients with stage III NSCLC treated with sequential or concurrent CRT or RT alone. The prospective cohort included 69 patients with stage III NSCLC. In all centres, a high percentage of patients (up to 51%) were upstaged to stage IV after staging with PET/CT became the standard. Overall, five patients did not meet the study inclusion criteria, and were therefore excluded. Reasons for exclusion were inability to provide informed consent (one patient), unable to start treatment within 4 weeks of PET/CT (two patients), and an ECOG performance status (PS) of 2 (two patients). An overview of the patient and tumour characteristics is given in Table 2.

All participating centres completed the first step of the QC procedure, in which the first three patients were accepted in the PERTAIN study. In total, 35 patients were submitted for TVD QC. Nine patients (26%) were excluded after evaluation. The reasons for not accepting the TVD as acceptable were: incorrect staging (two patients), involved lymph nodes not included (two patients), tumours too large to treat radically (≥60 Gy) without exceeding dose constraints (three patients), and noncompliance with IAEA study guidelines (two patients). All other patients in the prospective cohort were accepted for inclusion and treatment with concurrent CRT.

In the retrospective cohort, 18 patients were treated with RT only (8%), 65 patients received sequential CRT (28%), and 147 patients (64%) received concurrent CRT. In contrast, all patients in the prospective cohort received concurrent CRT with curative intent. In both the retrospective and prospective cohorts various chemotherapy regimens were intravenously administered weekly: either carboplatin-based or cisplatin-based in combination with paclitaxel, etoposide, docetaxel, pemetrexed or gemcitabine. Of the 230 patients in the retrospective cohort, 32 (14%) were treated using an IMRT technique and 198 (86%) using three-dimensional conformal RT (3DCT). By comparison, of the 69 patients in the prospective cohort, 29 (42%) were treated with IMRT, 2 (3%) with volumetric modulated arc therapy (VMAT), and 38 (55%) with 3DCT. The prescribed dose fractionation scheme varied between 50 Gy in 30 fractions and 70 Gy in 35 fractions in the retrospective cohort, with a mean prescribed dose of 61.4 ± 2.8 Gy. In the prospective cohort the dose fractionation scheme varied between 60 Gy in 30 fractions and 66 Gy in 33 fractions, with a mean prescribed dose of 60.7 ± 1.7 Gy.

Prognostic factors were evaluated in the retrospective and prospective cohorts separately. In the retrospective cohort, age and ECOG PS were significant prognostic factors (p = 0.039 and 0.024, respectively), and T stage demonstrated borderline significance (p = 0.053). In the prospective cohort, univariate Cox regression analysis showed no significant prognostic factors. No significant differences between the retrospective and the prospective cohorts in any of these prognostic variables were found, and therefore these variables were considered balanced. However, TNM staging was significantly higher in the prospective cohort than in the retrospective cohort (p = 0.021), and histological subtype was significantly different between the cohorts (p = 0.013) The difference in histological subtype was due to the absence of large-cell and lack of not otherwise specified types in the prospective cohort (see Table 2).

In the retrospective cohort, Kaplan–Meier analysis showed no significant differences in OS or PFS between patients who were and were not PET/CT-staged (p = 0.867 and 0.304, respectively; Fig. 1). Only 18.1% of the retrospective data were censored; in contrast, 52.2% of the prospective data were censored. Median survival was 14 months (95% CI 12–15 months) in the retrospective cohort and 23 months (95% CI 15–30 months) in the prospective cohort (p = 0.012, log-rank test). Two-year OS was 27% in the retrospective cohort and and 47% in the prospective cohort. The corresponding Kaplan–Meier analysis is shown in Fig. 2.

Kaplan–Meier analysis of PFS in the retrospective and the prospective cohorts is shown in Fig. 3. Median time to progression was 11 months (95% CI 9–12 months) in the retrospective cohort and 17 months (95% CI 10–23 months) in the prospective cohort (p = 0.012, log-rank test). Two-year PFS was 22% in the retrospective cohort and 45% in the prospective cohort.

The initial analysis of the PERTAIN study showed that a combined package of FDG PET/CT-planned RT, the routine use of concurrent CRT with training support, and a robust QC process led to improved OS and PFS in patients with stage III NSCLC patients in low- and middle-income countries.