Bart Reymen

Radical Treatment of Non-Small-Cell Lung Cancer Patients with Synchronous Oligometastases Long-Term Results of a Prospective Phase II Trial (Nct01282450)

Background: Stage IV non–small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available. Methods: A prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450. Results: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44–81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6–19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6–14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and 18F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated. Conclusion: In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed.

‘Rapid Learning health care in oncology’ – An approach towards decision support systems enabling customised radiotherapy’ ☆ ☆☆

PURPOSE An overview of the Rapid Learning methodology, its results, and the potential impact on radiotherapy. MATERIAL AND RESULTS Rapid Learning methodology is divided into four phases. In the data phase, diverse data are collected about past patients, treatments used, and outcomes. Innovative information technologies that support semantic interoperability enable distributed learning and data sharing without additional burden on health care professionals and without the need for data to leave the hospital. In the knowledge phase, prediction models are developed for new data and treatment outcomes by applying machine learning methods to data. In the application phase, this knowledge is applied in clinical practice via novel decision support systems or via extensions of existing models such as Tumour Control Probability models. In the evaluation phase, the predictability of treatment outcomes allows the new knowledge to be evaluated by comparing predicted and actual outcomes. CONCLUSION Personalised or tailored cancer therapy ensures not only that patients receive an optimal treatment, but also that the right resources are being used for the right patients. Rapid Learning approaches combined with evidence based medicine are expected to improve the predictability of outcome and radiotherapy is the ideal field to study the value of Rapid Learning. The next step will be to include patient preferences in the decision making.

Is high-dose stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) overkill? A systematic review

BACKGROUND AND PURPOSE For stereotactic body radiotherapy (SBRT), typically a scheme of 60 Gy in 3-8 fractions is applied, producing local tumour control rates around 90%. The dose specification is in one point only and ignores possible underdosages at the edge of the planning target volume (PTV). We investigated the doses at the edge of the PTV and correlated this with local tumour control with the aim to shed light on the radiation dose needed to eradicate stage I NSCLC. MATERIALS AND METHODS Published data on the freedom from local progression (FFLP) data from SBRT and accelerated high-dose conventional radiotherapy series for stage I NSCLC with a follow up of at least 30 months were included. The EQD(2,T) was calculated from the dose at the periphery of the PTV. RESULTS Fifteen studies for SBRT (1076 patients) showed a median FFLP of 88.0±10.4% with a median EQD(2,T) of 76.9±17.4 Gy. The median FFLP was 87.6±6.0% for the accelerated schedules with an EQD(2,T) of 86.9±39.1 Gy, respectively. No significant relation was found between FFLP and the EQD(2,T) (p=0.23). CONCLUSIONS Several fractionated and accelerated schedules with equal biological doses achieve the same tumour control rates as SBRT. Lower, but more uniform doses to the whole PTV may be sufficient to achieve similar control rates, with the possibility to deliver SBRT in adapted schedules, beneficial to centrally located tumours in the vicinity of critical structures like the oesophagus and great vessels.

Hypoxia imaging with [18F]HX4 PET in NSCLC patients: Defining optimal imaging parameters

BACKGROUND AND PURPOSE [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to-blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions. RESULTS Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 ± 0.3) to 4 h p.i. (2.0 ± 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 ± 0.10) with a DICE similarity coefficient of 0.69 ± 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min. CONCLUSIONS The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF.

In Vivo Quantification of Hypoxic and Metabolic Status of NSCLC Tumors Using [18F]HX4 and [18F]FDG-PET/CT Imaging

Purpose: Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non–small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[18F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging. Experimental Design: FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high-fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to-blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. Results: At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm3 of the HX4-HV was outside the FDG–HV; for 37%, this volume was 1.9 to 12 cm3. Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV. Conclusion: Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment. Clin Cancer Res; 20(24); 6389–97. ©2014 AACR.

Mature results of a phase II trial on individualised accelerated radiotherapy based on normal tissue constraints in concurrent chemo-radiation for stage III non-small cell lung cancer.

BACKGROUND Sequential chemotherapy and individualised accelerated radiotherapy (INDAR) has been shown to be effective in non-small cell lung cancer (NSCLC), allowing delivering of high biological doses. We therefore performed a phase II trial (clinicaltrials.gov; NCT00572325) investigating the same strategy in concurrent chemo-radiation in stage III NSCLC. METHODS 137 stage III patients fit for concurrent chemo-radiation (PS 0-2; FEV(1) and DLCO ≥ 30%) were included from April 2006 till December 2009. An individualised prescribed dose based on normal tissue dose constraints was applied: mean lung dose (MLD) 19 Gy, spinal cord 54 Gy, brachial plexus 66 Gy, central structures 74 Gy. A total dose between 51 and 69 Gy was delivered in 1.5 Gy BID up to 45 Gy, followed by 2 Gy QD. Radiotherapy was started at the 2nd or 3rd course of chemotherapy. Primary end-point was overall survival (OS) and secondary end-point toxicity common terminology criteria for adverse events v3.0 (CTCAEv3.0). FINDINGS The median tumour volume was 76.4 ± 94.1 cc; 49.6% of patients had N2 and 32.1% N3 disease. The median dose was 65.0 ± 6.0 Gy delivered in 35 ± 5.7 days. Six patients (4.4%) did not complete radiotherapy. With a median follow-up of 30.9 months, the median OS was 25.0 months (2-year OS 52.4%). Severe acute toxicity (≥ G3, 35.8%) consisted mainly of G3 dysphagia during radiotherapy (25.5%). Severe late toxicity (≥ G3) was observed in 10 patients (7.3%). INTERPRETATION INDAR in concurrent chemo-radiation based on normal tissue constraints is feasible, even in patients with large tumour volumes and multi-level N2-3 disease, with acceptable severe late toxicity and promising 2-year survival.

Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine.

ABSTRACT Background. Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided. Aim. The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm. Discussion. Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

PET-based dose painting in non-small cell lung cancer: Comparing uniform dose escalation with boosting hypoxic and metabolically active sub-volumes

BACKGROUND AND PURPOSE We compared two imaging biomarkers for dose-escalation in patients with advanced non-small cell lung cancer (NSCLC). Treatment plans boosting metabolically active sub-volumes defined by FDG-PET or hypoxic sub-volumes defined by HX4-PET were compared with boosting the entire tumour. MATERIALS AND METHODS Ten NSCLC patients underwent FDG- and HX4-PET/CT scans prior to radiotherapy. Three isotoxic dose-escalation plans were compared per patient: plan A, boosting the primary tumour (PTVprim); plan B, boosting sub-volume with FDG >50% SUVmax (PTVFDG); plan C, boosting hypoxic volume with HX4 tumour-to-background >1.4 (PTVHX4). RESULTS Average boost volumes were 507 ± 466 cm(3) for PTVprim, 173 ± 127 cm(3) for PTVFDG and 114 ± 73 cm(3) for PTVHX4. The smaller PTVHX4 overlapped on average 87 ± 16% with PTVFDG. Prescribed dose was escalated to 87 ± 10 Gy for PTVprim, 107 ± 20 Gy for PTVFDG, and 117 ± 15 Gy for PTVHX4, with comparable doses to the relevant organs-at-risk (OAR). Treatment plans are available online (https://www.cancerdata.org/10.1016/j.radonc.2015.07.013). CONCLUSIONS Dose escalation based on metabolic sub-volumes, hypoxic sub-volumes and the entire tumour is feasible. Highest dose was achieved for hypoxia plans, without increasing dose to OAR. For most patients, boosting the metabolic sub-volume also resulted in boosting the hypoxic volume, although to a lower dose, but not vice versa.

Decision support systems for personalized and participative radiation oncology.

Abstract A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models ‘learn’ using advanced and innovative information technologies (ideally in a distributed fashion — please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi‐faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re‐evaluated (through quality assurance procedures) in different patient datasets in order to refine and re‐optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine. Graphical abstract Figure. No caption available.

Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: A prospective population-based study

BACKGROUND Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown. METHODS Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. RESULTS Patients (1002) with stage III NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p<0.001). The proportion of surgical patients remained below 5%. Sequential chemotherapy and conventional RT resulted in a median and a 5-year survival of 17.5 months and 8.4%, respectively, whereas with sequential chemotherapy and INDAR this was 23.6 months and 31%, respectively (p<0.001). Concurrent chemotherapy and INDAR was associated with a median and 2-year survival that was not reached and 66.7%, respectively (p=0.004). CONCLUSIONS The proportion of patients treated with a curative intention with chemo-RT has increased markedly over time of observation. INDAR is associated with longer survival when compared to standard dose RT alone given with or without chemotherapy.