Impact of radiotherapy protocol adherence in NSCLC patients treated with concurrent chemoradiation: RTQA results of the PET-Plan trial.

INTRODUCTION: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial. METHODS: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by 1F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed. RESULTS: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities. CONCLUSIONS: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Improved inter-observer agreement of an expert review panel in an oncology treatment trial--Insights from a structured interventional process.

PURPOSE: Oncologic imaging is a key for successful cancer treatment. While the quality assurance (QA) of image acquisition protocols has already been focussed, QA of reading and reporting offers still room for improvement. The latter was addressed in the context of a prospective multicentre trial on fluoro-deoxyglucose (FDG)-positron-emission tomography (PET)/CT-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: An expert panel was prospectively installed performing blinded reviews of mediastinal NSCLC involvement in FDG-PET/CT. Due to a high initial reporting inter-observer disagreement, the independent data monitoring committee (IDMC) triggered an interventional harmonisation process, which overall involved 11 experts uttering 6855 blinded diagnostic statements. After assessing the baseline inter-observer agreement (IOA) of a blinded re-review (phase 1), a discussion process led to improved reading criteria (phase 2). Those underwent a validation study (phase 3) and were then implemented into the study routine. After 2 months (phase 4) and 1 year (phase 5), the IOA was reassessed. RESULTS: The initial overall IOA was moderate (kappa 0.52 CT; 0.53 PET). After improvement of reading criteria, the kappa values improved substantially (kappa 0.61 CT; 0.66 PET), which was retained until the late reassessment (kappa 0.71 CT; 0.67 PET). Subjective uncertainty was highly predictive for low IOA. CONCLUSION: The IOA of an expert panel was significantly improved by a structured interventional harmonisation process which could be a model for future clinical trials. Furthermore, the low IOA in reporting nodal involvement in NSCLC may bear consequences for individual patient care.

Radioguided surgery in urological malignancies.

The current literature was reviewed for articles focusing on radioguided surgery in urological malignancies.In penile cancer sentinel lymph node dissection is part of international guidelines. By detailed histopathological analysis (serial sections, immunohistochemical staining) more micrometastases are detectable improving the histopathological staging.In prostate cancer this technique also improves staging since a high percentage of patients have lymph node metastases located outside the region of standard lymphadenectomy. Compared to extended lymph node dissection radioguided surgery has a lower morbidity, especially a lower rate of lymphoceles.In bladder cancer the sentinel lymph node (SLN) technique has some limitations. Combined with extended lymph node dissection more positive lymph nodes are removed which possibly improves survival.In renal cell and testicular cancer there are only preliminary results. Further investigations will show whether this technique will play an important role in the diagnostics and therapy of these tumors.In all urological malignancies the SLN concept is only a staging procedure. When the sentinel node(s) is (are) negative, the other lymph nodes are negative, too. Since there are no randomized prospective trials comparing the results of sentinel lymphadenectomy with other techniques of lymph node dissection, it is not clear whether sentinel lymph node dissection also has a prognostic impact.

Reliability of preoperative diagnostics and location of lymph node metastases in presumed unilateral prostate cancer.

OBJECTIVE: To investigate the reliability of preoperative diagnostics in predicting the true histopathological stage and grade of prostate cancer, and to examine whether lymph node (LN) metastases in unilateral prostate cancer are located unilaterally and therefore whether it is justified to dissect only the ipsilateral LNs in presumed unilateral disease. PATIENTS AND METHODS: LN metastases in clinically localized prostate cancer are often located near the internal iliac vessels. They will be detected by extended or sentinel pelvic LN dissection (PLND). Both techniques might be time-consuming and require extensive surgical experience. In all, 564 men with impalpable or unilateral palpable prostate cancer and positive biopsy cores only in one prostate lobe had a radical prostatectomy (RP) combined with radio-guided PLND and in some cases an extended PLND. RESULTS: A median of six sentinel LNs (mean, seven) and six non-sentinel LNs (mean, seven) were dissected per patient; 52 of 564 men (9.2%) had positive LNs. Most men with unilateral disease had LN metastases on the same side of the pelvis. Comparing the clinical stage and grade with the tumour stage and grade of the RP specimen, there was a high percentage of upstaging and upgrading even in men with only one positive biopsy core. CONCLUSION: Unilateral prostate cancer preferentially metastasizes to the ipsilateral pelvic LNs. Because there are a few cases of bilateral LN metastases even in unilateral disease, and as it is not possible to reliably predict unilateral disease on the basis of biopsy features, PLND only on the tumour-bearing side has a high risk of understaging, and would possibly leave LN metastases behind.

Limitations of radioguided surgery in high-risk prostate cancer.

OBJECTIVES: To determine how many men with high-risk prostate cancer (prostate-specific antigen [PSA]>20 ng/ml or biopsy Gleason score 8-10) have positive lymph nodes (sentinel lymph nodes [SLNs] and nonsentinel lymph nodes [NSLNs]) and whether these positive nodes are localised in the region of SLN dissection or in other regions, too. METHODS: In 228 men with high-risk prostate cancer radical retropubic prostatectomy combined with radioguided pelvic lymph node dissection and extended lymphadenectomy were performed. Serial sections of the SLNs were analysed immunohistochemically. RESULTS: A median of 7 SLNs (mean, 7) and 11 NSLNs (mean, 11) were dissected per patient. Ninety-six of 228 men (42.1%) had lymph node metastases. Most men had positive lymph nodes along the internal iliac artery alone or in combination with other regions. Twenty-two men had only micrometastatic disease. In 94 of 96 men the SLNs were positive. Twenty-six of 96 men had also positive NSLNs. When SLNs and NSLNs were positive, in more than half the patients the NSLNs were localised outside the region of sentinel lymphadenectomy. CONCLUSIONS: The dissection of SLNs in prostate cancer has a high sensitivity in detecting positive nodes. When SLNs are negative, the other pelvic lymph nodes are also negative in a high percentage of men (sensitivity 97.1%). When the SLNs are positive, patients with high-risk disease also have a high incidence of positive NSLNs. Therefore, when it is aspired to remove all pelvic lymph node metastases sentinel and extended lymphadenectomy should be performed.