Geert Bosmans

Stability of 18F-deoxyglucose uptake locations within tumor during radiotherapy for NSCLC: a prospective study.

PURPOSE Because individual tumors are heterogeneous, including for (18)F-deoxyglucose (FDG) uptake and, most likely, for radioresistance, selective boosting of high FDG uptake zones within the tumor has been suggested. To do this, it is critical to know whether the location of these high FDG uptake patterns within the tumor remain stable during radiotherapy (RT). METHODS AND MATERIALS Twenty-three patients with Stage I-III non-small-cell lung cancer underwent repeated FDG positron emission tomography computed tomography scans before radical RT (Day 0) and at Days 7 and 14 of RT. On all scans, the high and low FDG uptake regions were autodelineated using several standardized uptake value thresholds, varying from 34% to 80% of the maximal standardized uptake value. The volumes and overlap fractions of these delineations were calculated to demonstrate the stability of the high FDG uptake regions during RT. RESULTS The mean overlap fraction of the 34% uptake zones at Day 0 with Days 7 and 14 was 82.8% +/- 8.1% and 84.3% +/- 7.6%, respectively. The mean overlap fraction of the high uptake zones (60%) was 72.3% +/- 15.0% and 71.3% +/- 19.7% at Day 0 with Days 7 and 14, respectively. The volumes of the thresholds varied markedly (e.g., at Day 0, the volume of the 60% zone was 16.8 +/- 20.3 cm(3)). In contrast, although the location of the high FDG uptake patterns within the tumor during RT remained stable, the delineated volumes varied markedly. CONCLUSION The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: A planning study

BACKGROUND AND PURPOSE To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). MATERIAL AND METHODS Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. RESULTS FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. CONCLUSIONS Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

Radiation Dose Prescription for Non–Small-Cell Lung Cancer According to Normal Tissue Dose Constraints: An In Silico Clinical Trial

PURPOSE Local tumor recurrence remains a major problem in patients with inoperable non-small-cell lung cancer undergoing radiotherapy. We investigated the theoretical gain in the estimated tumor control probability (TCP) using an individualized maximal tolerable dose (MTD) prescription, for both conventional and accelerated fractionation schemes. METHODS AND MATERIALS For 64 non-small-cell lung cancer patients, five treatment plans were compared, dependent on the normal tissue dose constraints for the lung and spinal cord. The first two used a classic fractionation (2 Gy/d, 5 d/wk) to a total dose of 60 Gy (QD(classic)) or determined by the individualized MTD (QD(MTD)). The third scheme assumed a hypofractionated schedule of 2.75-Gy fractions (QD(hypofr)). The fourth and fifth assumed hyperfractionation and acceleration (1.8 Gy twice daily, either BID(classic) or BID(MTD)). The TCPs for the groups of patients were estimated. RESULTS The mean biologic equivalent dose in 2-Gy fractions for tumor, corrected for accelerated repopulation was significantly greater for the BID(MTD) scheme (62.1 Gy) than for any other scheme (QD(classic), 47.5 Gy; QD(MTD), 52.0 Gy; QD(hypofr), 56.9 Gy; and BID(classic), 56.9 Gy; p < 0.001). Although both dose-escalation (QD(MTD)) and hypofractionation (QD(hypofr)) resulted in an increase in the mean estimated TCP of 5.6% (p < 0.001) and 14.6% (p < 0.001), respectively, compared with QD(classic), the combination of escalation and acceleration (BID(MTD)) improved the mean estimated TCP by 26.4% (p < 0.001). CONCLUSION The results of this planning study showed a large gain in the estimated TCP using an MTD scheme with 1.8-Gy fractions BID compared with other fractionation schedules. Clinical studies implementing this concept are ongoing.

Phased attenuation correction in respiration correlated computed tomography/positron emitted tomography

The motion of lung tumors with respiration causes difficulties in the imaging with computed tomography (CT) and positronemitted tomography (PET). Since an accurate knowledge of the position of the tumor and the surrounding tissues is needed for radiation treatment planning, it is important to improve CT/PET image acquisition. The purpose of this study was to evaluate the potential to improve image acquisition using phased attenuation correction in respiration correlated CT/PET, where data of both modalities were binned retrospectively. Respiration correlated scans were made on a Siemens Biograph Sensation 16 CT/PET scanner which was modified to make a low pitch CT scan and list mode PET scan possible. A lollipop phantom was used in the experiments. The sphere with a diameter of 3.1 cm was filled with approximately 20 MBq 18F-FDG. Three longitudinal movement amplitudes were tested: 2.5, 3.9, and 4.8 cm. After collection of the raw CT data, list mode PET data, and the respiratory signal CT/PET images were binned to ten phases with the help of in-house-built software. Each PET phase was corrected for attenuation with CT data of the corresponding phase. For comparison, the attenuation correction was also performed with nonrespiration correlated (non-RC) CT data. The volume and the amplitude of the movement were calculated for every phaseof both the CT and PET data (with phased attenuation correction). Maximum and average activity concentrations were compared between the phased and nonphased attenuation corrected PET. With a standard non-RC CT/PET scan, the volume was underestimated by as much as 46% in CT and the PET volume was overestimated to 370%. The volumes found with RC-CT/PET scanning had average deviations of 1.9% (+/- 4.8%) and 1.5% (+/- 3.4%) from the actual volume, for the CT and PET volumes, respectively. Evaluation of the maximum activity concentration showed a clear displacement in the images with non-RC attenuation correction, and activity values were on average14% (+/- 12%) lower than with phased attenuation correction. The standard deviation of the maximum activity values found in the different phases was a factor of 10 smaller when phased attenuation correction was applied. In this phantom study, we have shown that a combination of respiration correlated CT/PET scanning with application of phased attenuation correction can improve the imaging of moving objects and can lead to improved volume estimation and a more precise localization and quantification of the activity.

INDIVIDUALIZED RADICAL RADIOTHERAPY OF NON-SMALL-CELL LUNG CANCER BASED ON NORMAL TISSUE DOSE CONSTRAINTS: A FEASIBILITY STUDY

PURPOSE Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. METHODS AND MATERIALS Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An (18)F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. RESULTS Mean delivered dose was 63.0 +/- 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. CONCLUSIONS Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.

Correlation of intra-tumour heterogeneity on 18F-FDG PET with pathologic features in non-small cell lung cancer: A feasibility study

We evaluated the feasibility to correlate intra-tumour heterogeneity as visualized on 18F-FDG PET with histology for NSCLC. For this purpose we used an ex-vivo model. The procedure was feasible in all operated patients. We have shown that this method is suitable for correlating intra-tumour heterogeneity in tracer uptake with histology.

The integration of PET-CT scans from different hospitals into radiotherapy treatment planning

PURPOSE To integrate PET-CT scans from different hospitals into radiotherapy treatment planning. METHODS AND MATERIALS A cylindrical phantom with spheres of different diameters was scanned on three different Siemens Biograph PET-CT scanners in three hospitals. The spheres and cylinder were filled with 18F-FDG such that different sphere-to-background (S/B) ratios were obtained. Scans were analyzed using dedicated software for automated delineation based on standardized uptake value (SUV) and using different reconstruction parameters. RESULTS SUV thresholding curves for different S/B ratios were obtained for the different scanners. Differences in SUV auto-contouring thresholds were found to be significant for PET-CT simulators from different radiotherapy and nuclear medicine departments. A change in PET reconstruction parameters showed a significant effect on the results. CONCLUSION Synchronization of PET-CT imaging protocols between cooperating hospitals is important for reliable determination of SUV auto-contouring thresholds. Whenever this goal has been achieved automated SUV delineation based on a S/B ratio using PET-CT images from different institutions can reliably be performed using individually determined threshold curves.

Respiratory-gated CT as a tool for the simulation of breathing artifacts in PET and PET/CT.

Respiratory motion in PET and PET/CT blurs the images and can cause attenuation-related errors in quantitative parameters such as standard uptake values. In rare instances, this problem even causes localization errors and the disappearance of tumors that should be detectable. Attenuation errors are severe near the diaphragm and can be enhanced when the attenuation correction is based on a CT series acquired during a breath-hold. To quantify the errors and identify the parameters associated with them, the authors performed a simulated PET scan based on respiratory-gated CT studies of five lung cancer patients. Diaphragmatic motion ranged from 8 to 25 mm in the five patients. The CT series were converted to 511-keV attenuation maps which were forward-projected and exponentiated to form sinograms of PET attenuation factors at each phase of respiration. The CT images were also segmented to form a PET object, moving with the same motion as the CT series. In the moving PET object, spherical 20 mm mobile tumors were created in the vicinity of the dome of the liver and immobile 20 mm tumors in the midchest region. The moving PET objects were forward-projected and attenuated, then reconstructed in several ways: phase-matched PET and CT, gated PET with ungated CT, ungated PET with gated CT, and conventional PET. Spatial resolution and statistical noise were not modeled. In each case, tumor uptake recovery factor was defined by comparing the maximum reconstructed pixel value with the known correct value. Mobile 10 and 30 mm tumors were also simulated in the case of a patient with 11 mm of breathing motion. Phase-matched gated PET and CT gave essentially perfect PET reconstructions in the simulation. Gated PET with ungated CT gave tumors of the correct shape, but recovery was too large by an amount that depended on the extent of the motion, as much as 90% for mobile tumors and 60% for immobile tumors. Gated CT with ungated PET resulted in blurred tumors and caused recovery errors between -50% and +75%. Recovery in clinical scans would be 0%-20% lower than stated because spatial resolution was not included in the simulation. Mobile tumors near the dome of the liver were subject to the largest errors in either case. Conventional PET for 20 mm tumors was quantitative in cases of motion less than 15 mm because of canceling errors in blurring and attenuation, but the recovery factors were too low by as much as 30% in cases of motion greater than 15 mm. The 10 mm tumors were blurred by motion to a greater extent, causing a greater SUV underestimation than in the case of 20 mm tumors, and the 30 mm tumors were blurred less. Quantitative PET imaging near the diaphragm requires proper matching of attenuation information to the emission information. The problem of missed tumors near the diaphragm can be reduced by acquiring attenuation-correction information near end expiration. A simple PET/CT protocol requiring no gating equipment also addresses this problem.

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.

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.