Jasper Nijkamp

Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy

PURPOSE We evaluated the relationship between the mean lung dose (MLD) and the incidence of radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT), and compared this with conventional fractionated radiation therapy (CFRT). MATERIALS AND METHODS For both SBRT (n=128) and CFRT (n=142) patients, RP grade > or = 2 was scored. Toxicity models predicting the probability of RP as a function of the MLD were fitted using maximum log likelihood analysis. The MLD was NTD (Normalized Total Dose) corrected using an alpha/beta ratio of 3 Gy. RESULTS SBRT patients were treated with 6-12 Gy per fraction with a median MLD of 6.4 Gy (range: 1.5-26.5 Gy). CFRT patients were treated with 2 Gy or 2.25 Gy per fraction, the median MLD was 13.2 Gy (range: 3.0-23.0 Gy). The crude incidence rates of RP were 10.9% and 17.6% for the SBRT and CFRT patients, respectively. A significant dose-response relationship for RP was found after SBRT, which was not significantly different from the dose-response relationship for CFRT (p=0.18). CONCLUSION We derived a significant dose-response relationship between the risk of RP and the MLD for SBRT from the clinical data. This relation was not significantly different from the dose-response relation for CFRT, although statistical analysis was hampered by the low number of patients in the high dose range.

Breast Patient Setup Error Assessment: Comparison of Electronic Portal Image Devices and Cone-Beam Computed Tomography Matching Results

PURPOSE To quantify the differences in setup errors measured with the cone-beam computed tomography (CBCT) and electronic portal image devices (EPID) in breast cancer patients. METHODS AND MATERIALS Repeat CBCT scan were acquired for routine offline setup verification in 20 breast cancer patients. During the CBCT imaging fractions, EPID images of the treatment beams were recorded. Registrations of the bony anatomy for CBCT to planning CT and EPID to digitally reconstructed-radiographs (DRRs) were compared. In addition, similar measurements of an anthropomorphic thorax phantom were acquired. Bland-Altman and linear regression analysis were performed for clinical and phantom registrations. Systematic and random setup errors were quantified for CBCT and EPID-driven correction protocols in the EPID coordinate system (U, V), with V parallel to the cranial-caudal axis and U perpendicular to V and the central beam axis. RESULTS Bland-Altman analysis of clinical EPID and CBCT registrations yielded 4 to 6-mm limits of agreement, indicating that both methods were not compatible. The EPID-based setup errors were smaller than the CBCT-based setup errors. Phantom measurements showed that CBCT accurately measures setup error whereas EPID underestimates setup errors in the cranial-caudal direction. In the clinical measurements, the residual bony anatomy setup errors after offline CBCT-based corrections were Σ(U) = 1.4 mm, Σ(V) = 1.7 mm, and σ(U) = 2.6 mm, σ(V) = 3.1 mm. Residual setup errors of EPID driven corrections corrected for underestimation were estimated at Σ(U) = 2.2mm, Σ(V) = 3.3 mm, and σ(U) = 2.9 mm, σ(V) = 2.9 mm. CONCLUSION EPID registration underestimated the actual bony anatomy setup error in breast cancer patients by 20% to 50%. Using CBCT decreased setup uncertainties significantly.

Prospective randomized double-blind pilot study of site-specific consensus atlas implementation for rectal cancer target volume delineation in the cooperative group setting

PURPOSE Variations in target volume delineation represent a significant hurdle in clinical trials involving conformal radiotherapy. We sought to determine the effect of a consensus guideline-based visual atlas on contouring the target volumes. METHODS AND MATERIALS A representative case was contoured (Scan 1) by 14 physician observers and a reference expert with and without target volume delineation instructions derived from a proposed rectal cancer clinical trial involving conformal radiotherapy. The gross tumor volume (GTV), and two clinical target volumes (CTVA, including the internal iliac, presacral, and perirectal nodes, and CTVB, which included the external iliac nodes) were contoured. The observers were randomly assigned to receipt (Group A) or nonreceipt (Group B) of a consensus guideline and atlas for anorectal cancers and then instructed to recontour the same case/images (Scan 2). Observer variation was analyzed volumetrically using the conformation number (CN, where CN = 1 equals total agreement). RESULTS Of 14 evaluable contour sets (1 expert and 7 Group A and 6 Group B observers), greater agreement was found for the GTV (mean CN, 0.75) than for the CTVs (mean CN, 0.46-0.65). Atlas exposure for Group A led to significantly increased interobserver agreement for CTVA (mean initial CN, 0.68, after atlas use, 0.76; p = .03) and increased agreement with the expert reference (initial mean CN, 0.58; after atlas use, 0.69; p = .02). For the GTV and CTVB, neither the interobserver nor the expert agreement was altered after atlas exposure. CONCLUSION Consensus guideline atlas implementation resulted in a detectable difference in interobserver agreement and a greater approximation of expert volumes for the CTVA but not for the GTV or CTVB in the specified case. Visual atlas inclusion should be considered as a feature in future clinical trials incorporating conformal RT.

Three-Dimensional Analysis of Recurrence Patterns in Rectal Cancer: The Cranial Border in Hypofractionated Preoperative Radiotherapy Can Be Lowered

PURPOSE The aim of this study was to determine whether and where the radiotherapy (RT) clinical target volume (CTV) could be reduced in short-course preoperative treatment of rectal cancer patients. METHODS AND MATERIALS Patients treated in the Dutch total mesorectal excision trial, with a local recurrence were analyzed. For 94 (25 who underwent radiation therapy 69 who did not) of 114 patients with a local recurrence, the location of the recurrence was placed in a three-dimensionalthree (3D) model. The data in the 3D model were correlated to the clinical trial data to distinguish a group of patients eligible for CTV reduction. Effects of CTV reduction on dose to the small bowel was tested retrospectively in a dataset of 8 patients with three-field conformal plans and intensity-modulated RT (IMRT). RESULTS The use of preoperative RT mainly reduces anastomotic, lateral, and perineal recurrences. In patients without primary nodal involvement, no recurrences were found cranially of the S2-S3 interspace, irrespective of the delivery of RT. In patients without primary nodal involvement and a negative circumferential resection margin (CRM), only one recurrence was found cranial to the S2-S3 interspace. With a cranially reduced CTV to the S2-S3 interspace, over 60% reduction in absolute small bowel exposure at dose levels from 15 to 35 Gy could be achieved with three-field conventional RT, increasing to 80% when IMRT is also added. CONCLUSIONS The cranial border of the CTV can safely be lowered for patients without expected nodal or CRM involvement, yielding a significant reduction of dose to the small bowel. Therefore, a significant reduction of acute and late toxicity can be expected.

Target volume delineation variation in radiotherapy for early stage rectal cancer in the Netherlands

PURPOSE The aim of this study was to measure and improve the quality of target volume delineation by means of national consensus on target volume definition in early-stage rectal cancer. METHODS AND MATERIALS The CTVs for eight patients were delineated by 11 radiation oncologists in 10 institutes according to local guidelines (phase 1). After observer variation analysis a workshop was organized to establish delineation guidelines and a digital atlas, with which the same observers re-delineated the dataset (phase 2). Variation in volume, most caudal and cranial slice and local surface distance variation were analyzed. RESULTS The average delineated CTV volume decreased from 620 to 460 cc (p<0.001) in phase 2. Variation in the caudal CTV border was reduced significantly from 1.8 to 1.2 cm SD (p=0.01), while it remained 0.7 cm SD for the cranial border. The local surface distance variation (cm SD) reduced from 1.02 to 0.74 for anterior, 0.63 to 0.54 for lateral, 0.33 to 0.25 for posterior and 1.22 to 0.46 for the sphincter region, respectively. CONCLUSIONS The large variation in target volume delineation could significantly be reduced by use of consensus guidelines and a digital delineation atlas. Despite the significant reduction there is still a need for further improvement.

Acute esophagus toxicity in lung cancer patients after intensity modulated radiation therapy and concurrent chemotherapy.

PURPOSE The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m(2)). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D(mean) and D(max) of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade ≥ 2 and grade ≥ 3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade ≥ 2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment. RESULTS In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade ≥ 3 AET (P=.012). The derived V50 model was shown to predict grade ≥ 2 AET significantly better than the clinical V35 model (P<.001). CONCLUSIONS For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade ≥ 3 AET. There was no difference in the incidence of grade ≥ 2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.

Radiation Pneumonitis After Hypofractionated Radiotherapy: Evaluation of the LQ(L) Model and Different Dose Parameters

PURPOSE To evaluate the linear quadratic (LQ) model for hypofractionated radiotherapy within the context of predicting radiation pneumonitis (RP) and to investigate the effect if a linear (L) model in the high region (LQL model) is used. METHODS AND MATERIALS The radiation doses used for 128 patients treated with hypofractionated radiotherapy were converted to the equivalent doses given in fractions of 2 Gy for a range of alpha/beta ratios (1 Gy to infinity) according to the LQ(L) model. For the LQL model, different cut-off values between the LQ model and the linear component were used. The Lyman model parameters were fitted to the events of RP grade 2 or higher to derive the normal tissue complication probability (NTCP). The lung dose was calculated as the mean lung dose and the percentage of lung volume (V) receiving doses higher than a threshold dose of xGy (V(x)). RESULTS The best NTCP fit was found if the mean lung dose, or V(x), was calculated with an alpha/beta ratio of 3 Gy. The NTCP fit of other alpha/beta ratios and the LQL model were worse but within the 95% confidence interval of the NTCP fit of the LQ model with an alpha/beta ratio of 3 Gy. The V(50) NTCP fit was better than the NTCP fit of lower threshold doses. CONCLUSIONS For high fraction doses, the LQ model with an alpha/beta ratio of 3 Gy was the best method for converting the physical lung dose to predict RP.

Target volume shape variation during hypo-fractionated preoperative irradiation of rectal cancer patients

PURPOSE To quantify the day-to-day target volume shape variation in rectal-cancer patients treated with preoperative 5x5Gy radiotherapy. MATERIALS AND METHODS For 27 patients a prone position plan-CT (pCT) and five daily pre-treatment cone-beam-CT (CBCT) scans were acquired. A sub-region of the CTV (MesoRect, anus up to the cranial end of the mesorectal-fascia) was delineated on all scans. The MesoRect deformation was quantified by the distance between pCT- and CBCT-delineations and was stored in surface-maps. Finally, the influence of bladder and rectum filling on MesoRect deformation was evaluated. Data were analyzed for male and female patients separately. RESULTS A large range of systematic and random deformations, 1-7mm (1SD), on different areas of the MesoRect were found. The maximum deformations were located at the upper-anterior-side of the MesoRect. For females the errors were up to 3mm larger than for males. Small correlations, r(2)0.4, were found with changes in bladder volume. Larger correlations, r(2)0.7, were found for rectal volume in a distinctive area in the upper-half of the MesoRect. CONCLUSIONS Substantial and heterogeneous deformations of the MesoRect were found. Therefore different PTV margins in positions along the cranio-caudal axis, in the anterior-posterior direction. Margins should also be larger for female patients compared to male patients.

Strategies for Online Organ Motion Correction for Intensity-Modulated Radiotherapy of Prostate Cancer: Prostate, Rectum, and Bladder Dose Effects

PURPOSE To quantify and evaluate the accumulated prostate, rectum, and bladder dose for several strategies including rotational organ motion correction for intensity-modulated radiotherapy (IMRT) of prostate cancer using realistic organ motion data. METHODS AND MATERIALS Repeat computed tomography (CT) scans of 19 prostate patients were used. Per patient, two IMRT plans with different uniform margins were created. To quantify prostate and seminal vesicle motion, repeat CT clinical target volumes (CTVs) were matched onto the planning CTV using deformable registration. Four different strategies, from online setup to full motion correction, were simulated. Rotations were corrected for using gantry and collimator angle adjustments. Prostate, rectum, and bladder doses were accumulated for each patient, plan, and strategy. Minimum CTV dose (D(min)), rectum equivalent uniform dose (EUD, n = 0.13), and bladder surface receiving >or=78 Gy (S78), were calculated. RESULTS With online CTV translation correction, a 7-mm margin was sufficient (i.e., D(min) >or= 95% of the prescribed dose for all patients). A 4-mm margin required additional rotational correction. Margin reduction lowered the rectum EUD(n = 0.13) by approximately 2.6 Gy, and the bladder S78 by approximately 1.9%. CONCLUSIONS With online correction of both translations and rotations, a 4-mm margin was sufficient for 15 of 19 patients, whereas the remaining four patients had an underdosed CTV volume <1%. Margin reduction combined with online corrections resulted in a similar or lower dose to the rectum and bladder. The more advanced the correction strategy, the better the planned and accumulated dose agreed.

Breast-Conserving Therapy: Radiotherapy Margins for Breast Tumor Bed Boost

PURPOSE To quantify the interfraction position variability of the excision cavity (EC) and to compare the rib and breast surface as surrogates for the cavity. Additionally, we sought to determine the required margin for on-line, off-line and no correction protocols in external beam radiotherapy. METHODS AND MATERIALS A total of 20 patients were studied who had been treated in the supine position for 28 daily fractions. Cone-beam computed tomography scans were regularly acquired according to a shrinking action level setup correction protocol based on bony anatomy registration of the ribs and sternum. The position of the excision area was retrospectively analyzed by gray value cone-beam computed tomography-to-computed tomography registration. Subsequently, three setup correction strategies (on-line, off-line, and no corrections) were applied, according to the rib and breast surface registrations, to estimate the residual setup errors (systematic [Sigma] and random [sigma]) of the excision area. The required margins were calculated using a margin recipe. RESULTS The image quality of the cone-beam computed tomography scans was sufficient for localization of the EC. The margins required for the investigated setup correction protocols and the setup errors for the left-right, craniocaudal and anteroposterior directions were 8.3 mm (Sigma = 3.0, sigma = 2.6), 10.6 mm (Sigma = 3.8, sigma = 3.2), and 7.7 mm (Sigma = 2.7, sigma = 2.9) for the no correction strategy; 5.6 mm (Sigma = 2.0, Sigma = 1.8), 6.5 mm (Sigma = 2.3, sigma = 2.3), and 4.5 mm (Sigma = 1.5, sigma = 1.9) for the on-line rib strategy; and 5.1 mm (Sigma = 1.8, sigma = 1.7), 4.8 mm (Sigma = 1.7, sigma = 1.6), and 3.3 mm (Sigma = 1.1, sigma = 1.6) for the on-line surface strategy, respectively. CONCLUSION Considerable geometric uncertainties in the position of the EC relative to the bony anatomy and breast surface have been observed. By using registration of the breast surface, instead of the rib, the uncertainties in the position of the EC area were reduced.