Coen W. Hurkmans

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

BACKGROUND The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. METHODS Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). FINDINGS 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0-47·3) for the SABR group and 35·4 months (18·9-40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85-100) in the SABR group compared with 79% (64-97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017-1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74-100) in the SABR group and 80% (65-97) in the surgery group (HR 0·69 [95% CI 0·21-2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3-4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). INTERPRETATION SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. FUNDING Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.

Set-up verification using portal imaging; review of current clinical practice

In this review of current clinical practice of set-up error verification by means of portal imaging, we firstly define the various types of set-up errors using a consistent nomenclature. The different causes of set-up errors are then summarized. Next, the results of a large number of studies regarding patient set-up verification are presented for treatments of patients with head and neck, prostate, pelvis, lung and breast cancer, as well as for mantle field/total body treatments. This review focuses on the more recent studies in order to assess the criteria for good clinical practice in patient positioning. The reported set-up accuracy varies widely, depending on the treatment site, method of immobilization and institution. The standard deviation (1 SD, mm) of the systematic and random errors for currently applied treatment techniques, separately measured along the three principle axes, ranges from 1.6-4.6 and 1.1-2.5 (head and neck), 1.0-3.8 and 1.2-3.5 (prostate), 1.1-4.7 and 1.1-4.9 (pelvis), 1.8-5.1 and 2.2-5.4 (lung), and 1.0-4.7 and 1.7-14.4 (breast), respectively. Recommendations for procedures to quantify, report and reduce patient set-up errors are given based on the studies described in this review. Using these recommendations, the systematic and random set-up errors that can be achieved in routine clinical practice can be less than 2.0 mm (1 SD) for head and neck, 2.5 mm (1 SD) for prostate, 3.0 mm (1 SD) for general pelvic and 3.5 mm (1 SD) for lung cancer treatment techniques.

Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation

PURPOSE The main purpose of this work is to reduce the cardiac and lung dose by applying conformal tangential beam irradiation of the intact left breast with and without intensity modulation, instead of rectangular tangential treatment fields. The extension of the applicability of the maximum heart distance (MHD) to conformal tangential fields as a simple patient selection criterion, identifying patients for which rectangular and conformal tangential fields without intensity modulation will result in unacceptable normal tissue complication probability (NTCP) values for late cardiac mortality (e.g. >2%), was also investigated. MATERIALS AND METHODS Three-dimensional treatment planning was performed for 17 left-sided breast cancer patients. Three different tangential beam techniques were compared: (1) optimized wedges without blocks, (2) optimized wedges with conformal blocks and (3) intensity modulation. Plans were evaluated using dose-volume histograms (DVHs) for the planning target volume (PTV), the heart and the lungs. NTCPs for radiation pneumonitis and late cardiac mortality were calculated using the DVH data. The MHD was measured for all rectangular (MHD(rectangular)) and conformal (MHD(conformal)) treatment plans. RESULTS For all patients, on average, part of the PTV receiving a dose between 95 and 107% of the prescribed dose of 50Gy in 25 fractions of 2Gy was 90.8% (standard deviation (SD): 5.0%), 92.8% (SD: 3.5%) and 92.8% (SD: 3.6%) for the intensity modulation radiation therapy (IMRT), conformal and rectangular field treatment techniques, respectively. The NTCP for radiation pneumonitis was 0.3% (SD: 0.1%), 0.4% (SD: 0.4%) and 0.5% (SD: 0.6%) for the IMRT, conformal and rectangular field techniques, respectively. The NTCP for late cardiac mortality was 5.9% (SD: 2.2%) for the rectangular field technique. This value was reduced to 4.0% (SD: 2.3%) with the conformal technique. A further reduction to 2.0% (SD: 1.1%) could be accomplished with the IMRT technique. The NTCP for late cardiac mortality could be described as a second order polynomial function of the MHD. This function could be described with a high accuracy and was independent of the technique for which the MHD was determined (r(2)=0.88). In order to achieve a NTCP value for late cardiac mortality below 1, 2 or 3%, the MHD should be equal to or smaller than 11, 17 or 23 mm, respectively. If such a maximum complication probability cannot be accomplished, a treatment using the IMRT technique should be considered. CONCLUSIONS The use of conformal tangential fields decreases the NTCP for late cardiac toxicity on average by 30% compared to using rectangular fields, while the tangential IMRT technique can further reduce this value by an additional 50%. The MHD can be used to estimate the NTCP for late cardiac mortality if rectangular or conformal tangential treatment fields are used.

Cardiac and lung complication probabilities after breast cancer irradiation

PURPOSE To assess for locoregional irradiation of breast cancer patients, the dependence of cardiac (cardiac mortality) and lung (radiation pneumonitis) complications on treatment technique and individual patient anatomy. MATERIALS AND METHODS Three-dimensional treatment planning was performed for 30 patients with left-sided breast cancer and various breast sizes. Two locoregional techniques (Techniques A and B) and a tangential field technique, including only the breast in the target volume, were planned and evaluated for each patient. In both locoregional techniques tangential photon fields were used to irradiate the breast. The internal mammary (IM)-medial supraclavicular (MS) lymph nodes were treated with an anterior mixed electron/photon field (Technique A) or with an obliquely incident mixed electron/photon IM field and an anterior electron/photon MS field (Technique B). The optimal IM and MS electron field dimensions and energies were chosen on the basis of the IM-MS lymph node target volume as delineated on CT-slices. The position of the tangential fields was adapted to match the IM-MS fields. Dose-volume histograms (DVHs) and normal tissue complication probabilities (NTCPs) for the heart and lung were compared for the three techniques. In the beams eye view of the medial tangential fields the maximum distance of the heart contour to the posterior field border was measured; this value was scored as the Maximum Heart Distance. RESULTS The lymph node target volume receiving more than 85% of the prescribed dose was on average 99% for both locoregional irradiation techniques. The breast PTV receiving more than 95% of the prescribed dose was generally smaller using Technique A (mean: 90%, range: 69-99%) than using Technique B (mean: 98%, range: 82-100%) or for the tangential field technique (mean: 98%, range: 91-100%). NTCP values for excess cardiac mortality due to acute myocardial ischemia varied considerably between patients, with minimum and maximum values of 0.1 and 7.5% (Technique A), 0.1 and 5.8% (Technique B) and 0.0 and 6.1% (tangential tech.). The NTCP values were on average significantly higher (P<0.001) by 1.7% (Technique A) and 1.0% (Technique B) when locoregional breast irradiation was given, compared with irradiation of the left breast only. The NTCP values for the tangential field technique could be estimated using the Maximum Heart Distance. NTCP values for radiation pneumonitis were very low for all techniques; between 0.0 and 1.0%. CONCLUSIONS Technique B results in a good coverage of the breast and locoregional lymph nodes, while Technique A sometimes results in an underdosage of part of the target volume. Both techniques result in a higher probability of heart complications compared with tangential irradiation of the breast only. Irradiation toxicity for the lung is low in all techniques. The Maximum Heart Distance is a simple and useful parameter to estimate the NTCP values for cardiac mortality for tangential breast irradiation.

Variability in target volume delineation on CT scans of the breast

PURPOSE To determine the intra- and interobserver variation in delineation of the target volume of breast tumors on computed tomography (CT) scans in order to perform conformal radiotherapy. MATERIALS AND METHODS The clinical target volume (CTV) of the breast was delineated in CT slices by four radiation oncologists on our clinically used delineation system. The palpable glandular breast tissue was marked with a lead wire on 6 patients before CT scanning, whereas 4 patients were scanned without a lead wire. The CTV was drawn by each observer on three separate occasions. Planning target volumes (PTVs) were constructed by expanding the CTV by 7 mm in each direction, except toward the skin. The deviation in the PTV extent from the average extent was quantified in each orthogonal direction for each patient to find a possible directional dependence in the observer variations. In addition, the standard deviation of the intra- and interobserver variation in the PTV volume was quantified. For each patient, the common volumes delineated by all observers and the smallest volume encompassing all PTVs were also calculated. RESULTS The patient-averaged deviations in PTV extent were larger in the posterior (42 mm), cranial (28 mm), and medial (24 mm) directions than in the anterior (6 mm), caudal (15 mm), and lateral (8 mm) directions. The mean intraobserver variation in volume percentage (5.5%, 1 SD) was much smaller than the interobserver variation (17.5%, 1 SD). The average ratio between the common and encompassing volume for the four observers separately was 0.82, 0.74, 0.82, and 0.80. A much lower combined average ratio of 0.43 was found because of the large interobserver variations. For the observer who placed the lead wire, the intraobserver variation in volume was decreased by a factor of 4 on scans made with a lead wire in comparison to scans made without a lead wire. For the other observers, no improvement was seen. Based on these results, an improved delineation protocol was designed. CONCLUSIONS Intra- and especially interobserver variation in the delineation of breast target volume on CT scans can be rather large. A detailed delineation protocol making use of CT scans with lead wires placed on the skin around the palpable breast by the delineating observer reduces the intraobserver variation. To reduce the interobserver variation, better imaging techniques and pathology studies relating glandular breast tissue to imaging may be needed to provide more information on the extent of the clinical target volume.

CONSIDERATION OF DOSE LIMITS FOR ORGANS AT RISK OF THORACIC RADIOTHERAPY: ATLAS FOR LUNG, PROXIMAL BRONCHIAL TREE, ESOPHAGUS, SPINAL CORD, RIBS, AND BRACHIAL PLEXUS

PURPOSE To review the dose limits and standardize the three-dimenional (3D) radiographic definition for the organs at risk (OARs) for thoracic radiotherapy (RT), including the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus. METHODS AND MATERIALS The present study was performed by representatives from the Radiation Therapy Oncology Group, European Organization for Research and Treatment of Cancer, and Soutwestern Oncology Group lung cancer committees. The dosimetric constraints of major multicenter trials of 3D-conformal RT and stereotactic body RT were reviewed and the challenges of 3D delineation of these OARs described. Using knowledge of the human anatomy and 3D radiographic correlation, draft atlases were generated by a radiation oncologist, medical physicist, dosimetrist, and radiologist from the United States and reviewed by a radiation oncologist and medical physicist from Europe. The atlases were then critically reviewed, discussed, and edited by another 10 radiation oncologists. RESULTS Three-dimensional descriptions of the lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus are presented. Two computed tomography atlases were developed: one for the middle and lower thoracic OARs (except for the heart) and one focusing on the brachial plexus for a patient positioned supine with their arms up for thoracic RT. The dosimetric limits of the key OARs are discussed. CONCLUSIONS We believe these atlases will allow us to define OARs with less variation and generate dosimetric data in a more consistent manner. This could help us study the effect of radiation on these OARs and guide high-quality clinical trials and individualized practice in 3D-conformal RT and stereotactic body RT.

Intensity modulated versus non-intensity modulated radiotherapy in the treatment of the left breast and upper internal mammary lymph node chain: a comparative planning study

BACKGROUND AND PURPOSE To compare and evaluate intensity modulated (IMRT) and non-intensity modulated radiotherapy techniques in the treatment of the left breast and upper internal mammary lymph node chain. MATERIALS AND METHODS The breast, upper internal mammary chain (IMC), heart and lungs were delineated on a computed tomography (CT)-scan for 12 patients. Three different treatment plans were created: (1) tangential photon fields with oblique IMC electron-photon fields with manually optimized beam weights and wedges, (2) wide split tangential photon fields with a heart block and computer optimized wedge angles, and (3) IMRT tangential photon fields. For the IMRT technique, an inverse planning program (KonRad) generated the intensity profiles and a clinical three-dimensional treatment planning system (U-MPlan) optimized the segment weights. U-MPlan calculated the dose distribution for all three techniques. The normal tissue complication probabilities (NTCPs) for the organs at risk (ORs) were calculated for comparison. RESULTS The average root mean square deviation of the differential dose-volume histogram of the breast planning target volume was 4.6, 3.9 and 3.5% and the average mean dose to the IMC was 97.2, 108.0 and 99.6% for the oblique electron, wide split tangent and IMRT techniques, respectively. The average NTCP for the ORs (i.e. heart and lungs) were comparable between the oblique electron and IMRT techniques (<or=0.7%). The wide split tangent technique resulted in higher NTCP values (>or=2%) for the ORs. CONCLUSIONS The lowest NTCP values were found with the oblique electron and the IMRT techniques. The IMRT technique had the best breast and IMC target coverage.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/22023).

LBA1001 Background: Sentinel node biopsy (SNB) is standard in assessing axillary lymph node status for cN0 breast cancer patients. In case of a positive SNB, if treatment is advised, axillary lymph node dissection (ALND) is the current standard. Although ALND provides excellent regional control, it may give harmful side effects. Axillary radiotherapy (ART) instead of ALND was hypothesized to provide comparable regional control and less side effects. METHODS From 2001 to 2010, patients with cT1E2N0 primary breast cancer were enrolled in the EORTC phase III non-inferiority AMAROS trial. Patients were randomized between ALND and ART in case of a positive SNB. Primary endpoint was 5-year axillary recurrence rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), quality of life (QOL), shoulder movement and lymphedema at 1 and 5 years. RESULTS Of the 4,806 patients entered in the trial, 744 in the ALND-arm and 681 in the ART-arm had a positive SNB, 60% with a macrometastasis. The two treatment-arms were comparable regarding age, tumor size, grade, tumor type, and adjuvant systemic treatment. With a median follow up of 6.1 years, the 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND versus 1.03% (7/681) after ART. The planned non-inferiority test was underpowered because of the unexpectedly low number of events. The axillary recurrence rate after a negative SNB was 0.8% (25/3131). There were no significant differences between treatment arms regarding OS (5 yr estimates: 93.27% ALND, 92.52% ART, p=0.3386) and DFS (5 yr estimates: 86.90% ALND, 82.65% ART, p=0.1788). Lymphedema was found significantly more often after ALND (1yr: 40% ALND, 22% ART, p<0.0001 and 5yr: 28% ALND, 14% ART, p<0.0001). There was a nonsignificant trend toward more early shoulder movement impairment after ART. These findings were compatible with a trend in two QOL items in the arm symptom scale: swelling (ART better) and movement (ALND better). There were no other differences in QOL. CONCLUSION ALND and ART after a positive SNB provide excellent and comparable regional control. ART reduces the risk of short-term and long-term lymphedema compared to ALND. CLINICAL TRIAL INFORMATION NCT00014612.

The potential impact of treatment variations on the results of radiotherapy of the internal mammary lymph node chain: a quality-assurance report on the dummy run of EORTC Phase III randomized trial 22922/10925 in Stage I–III breast cancer

PURPOSE To present the results of the dummy run of the European Organization for Research and Treatment of Cancer (EORTC) trial investigating the role of adjuvant internal mammary and medial supraclavicular (IM-MS) irradiation in Stage I--III breast cancer. METHODS AND MATERIALS All participating institutions were asked to produce a treatment plan without (Arm 1) and with (Arm 2) simultaneous IM-MS irradiation of 1 patient after mastectomy and of 1 patient after lumpectomy. Thirty-two dummy runs have been evaluated for compliance to protocol guidelines, with respect to treatment technique and dose prescription. RESULTS A number of more or less important deviations in treatment setup and prescription have been found. The dose in the IM-MS region deviated significantly from the prescribed dose in 10% of the cases for Arm 1, and in 21% for Arm 2. Assuming a true 5% 10-year survival benefit from optimal IM-MS irradiation, an increase of only 3.8% will be found due to this suboptimal dose distribution. CONCLUSION In the dummy run, a number of potential systematic protocol deviations that might lead to false-negative results were detected. By providing recommendations to the participating institutions, we expect to improve the interinstitutional consistency and to promote a high quality irradiation in all institutions participating in the trial.

Management of radiation oncology patients with a pacemaker or ICD: A new comprehensive practical guideline in The Netherlands

Current clinical guidelines for the management of radiotherapy patients having either a pacemaker or implantable cardioverter defibrillator (both CIEDs: Cardiac Implantable Electronic Devices) do not cover modern radiotherapy techniques and do not take the patient’s perspective into account. Available data on the frequency and cause of CIED failure during radiation therapy are limited and do not converge. The Dutch Society of Radiotherapy and Oncology (NVRO) initiated a multidisciplinary task group consisting of clinical physicists, cardiologists, radiation oncologists, pacemaker and ICD technologists to develop evidence based consensus guidelines for the management of CIED patients. CIED patients receiving radiotherapy should be categorised based on the chance of device failure and the clinical consequences in case of failure. Although there is no clear cut-off point nor a clear linear relationship, in general, chances of device failure increase with increasing doses. Clinical consequences of device failures like loss of pacing, carry the most risks in pacing dependent patients. Cumulative dose and pacing dependency have been combined to categorise patients into low, medium and high risk groups. Patients receiving a dose of less than 2 Gy to their CIED are categorised as low risk, unless pacing dependent since then they are medium risk. Between 2 and 10 Gy, all patients are categorised as medium risk, while above 10 Gy every patient is categorised as high risk. Measures to secure patient safety are described for each category. This guideline for the management of CIED patients receiving radiotherapy takes into account modern radiotherapy techniques, CIED technology, the patients’ perspective and the practical aspects necessary for the safe management of these patients. The guideline is implemented in The Netherlands in 2012 and is expected to find clinical acceptance outside The Netherlands as well.