External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Reducing radiation risks to staff for patients with permanently implanted radioactive sources requiring unrelated surgery.

Permanent implant of sealed radioactive sources is an effective technique for treating cancer. Typically, the radioactive sources are implanted in and near the disease, depositing radiation absorbed dose locally over several months. There may be instances where these patients must undergo unrelated surgical procedures when the radioactive material remains active enough to pose risks. This work explores these risks, discusses strategies to mitigate those risks, and describes a case study for a permanent iodine-125 (I-125) prostate brachytherapy implant patient who developed colorectal cancer and required surgery six months after brachytherapy. The first consideration is identifying the radiological risk to the patient and staff before, during, and after the surgical procedure. The second is identifying the risk the surgical procedure may have on the efficacy of the brachytherapy implant. Finally, there are considerations for controlling the radioactive substances from a regulatory perspective. After these risks are defined, strategies to mitigate those risks are considered. We summarize this experience with some guidelines: If the surgical procedure is near (e.g., within 5-10 cm of) the implant; and, the surgical intervention may dislodge sources enough to compromise treatment or introduces radiation safety risks; and, the radioactivity has not sufficiently decayed to background levels; and, the surgery cannot be postponed, then a detailed analysis of risk is advised.

Simultaneous couch and gantry dynamic arc rotation (CG-Darc) in the treatment of breast cancer with accelerated partial breast irradiation (APBI): a feasibility study.

The purpose of this study was to compare the dosimetry of CG-Darc with three-dimensional conformal radiation therapy (3D CRT) and volumetric-modulated arc therapy (RapidArc) in the treatment of breast cancer with APBI. CG-Darc plans were generated using two tangential couch arcs combined with a simultaneous noncoplanar gantry arc. The dynamic couch arc was modeled by consecutive IMRT fields at 10° intervals. RapidArc plans used a single partial arc with an avoidance sector, preventing direct beam exit into the thorax. CG-Darc and RapidArc plans were compared with 3D CRT in 20 patients previously treated with 3D CRT (group A), and in 15 additional patients who failed the dosimetric constraints of the Canadian trial and of NSABP B-39/RTOG 0413 for APBI (group B). CG-Darc resulted in superior target coverage compared to 3D CRT and RapidArc (V95%: 98.2% vs. 97.1% and 95.7%). For outer breast lesions, CG-Darc and RapidArc significantly reduced the ipsilateral breast V50% by 8% in group A and 15% in group B (p < 0.05) as compared with 3D CRT. For inner and centrally located lesions, CG-Darc resulted in significant ipsilateral lung V10% reduction when compared to 3D CRT and RapidArc (10.7% vs. 12.6% and 20.7% for group A, and 15.1% vs. 25.2% and 27.3% for group B). Similar advantage was observed in the dosimetry of contralateral breast where the percent maximum dose for CG-Darc, 3D CRT, and RapidArc were 3.9%, 6.3%, and 5.8% for group A and 4.3%, 9.2%, and 6.3% for group B, respectively (p < 0.05). CG-Darc achieved superior target coverage while decreasing normal tissue dose even in patients failing APBI dose constraints. Consequently, this technique has the potential of expanding the use of APBI to patients currently ineligible for such treatment. Modification of the RapidArc algorithm will be necessary to link couch and gantry rotation with variable dose rate and, therefore, enable the use of CG-Darc in clinical practice.

Understanding the impact of RapidArc therapy delivery errors for prostate cancer.

The purpose of this study is to simulate random and systematic RapidArc delivery errors for external beam prostate radiotherapy plans in order to determine the dose sensitivity for each error type. Ten prostate plans were created with a single 360° arc. The DICOM files for these treatment plans were then imported into an in-house computer program that introduced delivery errors. Random and systematic gantry position (0.25°, 0.5°, 1°), monitor unit (MU) (1.25%, 2.5%, 5%), and multileaf collimator (MLC) position (0.5, 1, 2 mm) errors were introduced. The MLC errors were either random or one of three types of systematic errors, where the MLC banks moved in the same (MLC gaps remain unchanged) or opposing directions (increasing or decreasing the MLC gaps). The generalized equivalent uniform dose (gEUD) was calculated for the original plan and all treatment plans with errors introduced. The dose sensitivity for the cohort was calculated using linear regression for the gantry position, MU, and MLC position errors. Because there was a large amount of variability for systematic MLC position errors, the dose sensitivity of each plan was calculated and correlated with plan MU, mean MLC gap, and the percentage of MLC leaf gaps less than 1 and 2 cm for each individual plan. We found that random and systematic gantry position errors were relatively insignificant (< 0.1% gEUD change) for gantry errors up to 1°. Random MU errors were also insignificant, and systematic MU increases caused a systematic increase in gEUD. For MLC position errors, random MLC errors were relatively insignificant up to 2 mm as had been determined in previous IMRT studies. Systematic MLC shift errors caused a decrease of approximately -1% in the gEUD per mm. For systematic MLC gap open errors, the dose sensitivity was 8.2%/mm and for MLC gap close errors the dose sensitivity was -7.2%/mm. There was a large variability for MLC gap open/close errors for the ten RapidArc plans which correlated strongly with MU, mean gap width, and percentage of MLC gaps less than 1 or 2cm. This study evaluates the magnitude of various simulated RapidArc delivery errors by calculating gEUED on various prostate plans.

Comparing planning time, delivery time and plan quality for IMRT, RapidArc and Tomotherapy.

The purpose of this study is to examine plan quality, treatment planning time, and estimated treatment delivery time for 5- and 9-field sliding window IMRT, single and dual arc RapidArc, and tomotherapy. For four phantoms, 5- and 9-field IMRT, single and dual arc RapidArc and tomotherapy plans were created. Plans were evaluated based on the ability to meet dose-volume constraints, dose homogeneity index, radiation conformity index, planning time, estimated delivery time, integral dose, and volume receiving more than 2 and 5 Gy. For all of the phantoms, tomotherapy was able to meet the most optimization criteria during planning (50% for P1, 67% for P2, 0% for P3, and 50% for P4). RapidArc met less of the optimization criteria (25% for P1, 17% for P2, 0% for P3, and 0% for P4), while IMRT was never able to meet any of the constraints. In addition, tomotherapy plans were able to produce the most homogeneous dose. Tomotherapy plans had longer planning time, longer estimated treatment times, lower conformity index, and higher integral dose. Tomotherapy plans can produce plans of higher quality and have the capability to conform dose distributions better than IMRT or RapidArc in the axial plane, but exhibit increased dose superior and inferior to the target volume. RapidArc, however, is capable of producing better plans than IMRT for the test cases examined in this study.

Analysis of RapidArc optimization strategies using objective function values and dose-volume histograms.

RapidArc is a novel treatment planning and delivery system that has recently been made available for clinical use. Included within the Eclipse treatment planning system are a number of different optimization strategies that can be employed to improve the quality of the final treatment plan. The purpose of this study is to systematically assess three categories of strategies for four phantoms, and then apply proven strategies to clinical head and neck cases. Four phantoms were created within Eclipse with varying shapes and locations for the planning target volumes and organs at risk. A baseline optimization consisting of a single 359.8 degrees arc with collimator at 45 degrees was applied to all phantoms. Three categories of strategies were assessed and compared to the baseline strategy. They include changing the initialization parameters, increasing the total number of control points, and increasing the total optimization time. Optimization log files were extracted from the treatment planning system along with final dose-volume histograms for plan assessment. Treatment plans were also generated for four head and neck patients to determine whether the results for phantom plans can be extended to clinical plans. The strategies that resulted in a significant difference from baseline were: changing the maximum leaf speed prior to optimization ( p < 0.05), increasing the total number of segments by adding an arc ( p < 0.05), and increasing the total optimization time by either continuing the optimization ( p < 0.01) or adding time to the optimization by pausing the optimization ( p < 0.01). The reductions in objective function values correlated with improvements in the dose-volume histogram (DVH). The addition of arcs and pausing strategies were applied to head and neck cancer cases, which demonstrated similar benefits with respect to the final objective function value and DVH. Analysis of the optimization log files is a useful way to intercompare treatment plans that have the same dose-volume objectives and importance values. The results for clinical head and neck plans were consistent with phantom plans.

Is multibeam IMRT better than standard treatment for patients with left-sided breast cancer?

PURPOSE: When treatment intent is to include breast and internal mammary lymph nodes (IMNs) in the clinical target volume (CTV), a significant volume of the heart may receive radiation, which may result in late morbidity. The value of conformal intensity-modulated radiation therapy (IMRT) to avoid heart dose was studied. METHODS AND MATERIALS: Breast, IMNs, and normal tissues were contoured for 30 consecutive patients previously treated with RT after lumpectomy for left-sided breast cancer. Eleven-beam, conformal, inverse-planned IMRT plans were developed and compared with best standard plans. Conformity Index (CI), Homogeneity Index (HI), and doses to normal tissues were compared. RESULTS: Intensity-modulated RT significantly improved (two-sided paired t test) HI (0.95 vs. 0.74), CI (0.91 vs. 0.48), volume of the heart receiving more than 30 Gy (V30-heart) (1.7% vs. 12.5%), and volume of lung receiving more than 20-Gy (V20-left lung) (17.1% vs. 26.6%), all p < 0.001. The mean Healthy Tissue Volume (HTV = CT set - PTV) dose was similar between IMRT and best standard plans (6.0 and 6.9 Gy, respectively), but IMRT increased the volume of normal tissues receiving low-dose RT: V5-right lung (13.7% vs. 2.0%), V5-right breast (29.2% vs. 7.9%), and V5-HTV (31.7% vs. 23.6%), all p < 0.001. IMRT plans were generated in less than 60 min and treatment delivered in approximately 20 min, suggesting that this technique is clinically applicable. CONCLUSIONS: IMRT significantly improved conformity and homogeneity for plans when the breast + IMNs were in the CTV. Heart and lung volume receiving high doses were decreased, but more healthy tissue received low doses. A simple algorithm based on amount of heart included in the standard plan showed limited ability to predict the benefit from IMRT.

Target volume delineation for partial breast radiotherapy planning: clinical characteristics associated with low interobserver concordance.

PURPOSE: To examine variability in target volume delineation for partial breast radiotherapy planning and evaluate characteristics associated with low interobserver concordance. METHODS AND MATERIALS: Thirty patients who underwent planning CT for adjuvant breast radiotherapy formed the study cohort. Using a standardized scale to score seroma clarity and consensus contouring guidelines, three radiation oncologists independently graded seroma clarity and delineated seroma volumes for each case. Seroma geometric center coordinates, maximum diameters in three axes, and volumes were recorded. Conformity index (CI), the ratio of overlapping volume and encompassing delineated volume, was calculated for each case. Cases with CI

Inverse-planned, dynamic, multi-beam, intensity-modulated radiation therapy (IMRT): a promising technique when target volume is the left breast and internal mammary lymph nodes.

The purpose of this study was to determine the optimum beam number and orientation for inverse-planned, dynamic intensity-modulated radiation therapy (IMRT) for treatment of left-sided breast cancer and internal mammary nodes (IMNs) to improve target coverage while reducing cardiac and ipsilateral lung irradiation. Computed tomography (CT) data was used from 5 patients with left-sided breast cancer in whom the heart was close to the chest wall. The planning target volume (PTV) was the full breast plus ipsilateral IMNs. Two geometric beam arrangements were investigated, 240 degrees and 190 degrees sector angles, and the number of beams was increased from 7 to 9 to 11. Dose comparison metrics included: PTV homogeneity and conformity indices (HI, CI), heart V30, left lung V20, and mean doses to surrounding structures. To assess clinical application, the IMRT plans with 11 beams equally spaced in a 190 degrees sector angle were compared to conventional plans. Treatment times were modeled. The 190 degrees IMRT plans improved PTV HI and CI and reduced mean dose to the heart, lungs, contralateral breast, and total healthy tissue (all p < 0.05) compared to a 240 degrees sector angle. The 11-beam plan significantly improved PTV HI and CI, heart V30, left lung V20, and healthy tissue V5 compared to a 7-beam plan (all p < 0.05). The 11-beam plan reduced heart V30 and left lung V20 (p < 0.05) without compromising PTV coverage, compared to a 9-beam plan. Compared to a conventional plan, the IMRT class solution significantly improved PTV HI and CI (both p < 0.01), heart V30 (p = 0.01), and marginally reduced left lung V20 (p = 0.07) but increased contralateral breast and lung mean dose (p < 0.001) and healthy tissue V5 (p < 0.001). An 11-beam 190 degrees sector angle IMRT technique as a class solution is clinically feasible.

Correction of systematic setup errors in prostate radiation therapy: how many images to perform?

The purpose of this study was to develop an evidence-based off-line setup correction protocol for systematic errors in prostate radiation therapy. Daily orthogonal electronic portal images were acquired from 30 patients. Field displacements were measured in the medial-lateral (ML), superior-inferior (SI), and anterior-posterior (AP) directions for each treatment fraction. The off-line protocol corrects the mean field displacement found from n consecutive images, starting at a particular fraction of treatment, with a fixed tolerance level. Simulations were performed with the measured data to determine (1) how many images (n) should be averaged to determine the systematic error; (2) on which treatment fraction should the protocol be initiated; and (3) what tolerance level should be applied to determine whether the patient position should be corrected. Uncorrected systematic errors in the ML, SI, and AP directions were (mean position +/- 1 standard deviation [SD]): -0.7 +/- 2.2 mm, -1.5 +/- 1.3 mm, and 1.4 +/- 2.6 mm, respectively. Random errors (1 SD and range) were 1.9 mm (1.3 - 3.3), 1.5 mm (0. - 4.1), and 1.8 mm (1.0-2.6), respectively. A correction based on a single image taken on the first fraction actually increased the systematic errors in the ML and SI directions compared with no correction. More accurate correction of systematic errors was achieved with increasing number of images averaged, with only small benefit after 5 images. With fewer images averaged, delaying the start of the protocol resulted in more accurate correction because of the influence of unrepresentative positions at early fractions. The number of corrections made on patients with small (< 2 mm) systematic errors was minimized for tolerance values of 2 mm and n > or = 5 images averaged. The optimal off-line setup correction protocol would be to shift the patient by the mean displacement of the first 5 portal images of a radical course of radiation therapy. A small tolerance level should be utilized with 2 mm giving good accuracy with minimal unnecessary shifts.

Improving the resolution of dynamic intensity modulated radiation therapy delivery by reducing the multileaf collimator sampling distance.

The conformality of a dose distribution delivered by a multileaf collimator (MLC) for intensity modulated radiation therapy (IMRT) is limited in the direction perpendicular to leaf motion by the finite leaf width. Two methods of improving the resolution of IMRT intensity maps in this direction were investigated. In the first, the desired fluence distribution is considered to be sampled by the MLC, with the sampling distance being the center-to-center distance between the MLC leaves. The sampling distance is reduced below the leaf width by combining separate irradiations with a couch shift between them. This has been applied to static field therapy [Galvin et al., Int. J. Radiat. Oncol., Biol., Phys. 35, 89-94 (1996)], and was proposed for IMRT by Bortfeld et al. [Med. Phys. 27, 2494-2502 (2000)]. In the second method, two MLC component fluences, with leaf width L = 2deltay and offset by deltay, are combined to reproduce desired intensity bins with deltay width. The effect of MLC leaf sampling distance on dose resolution was quantified for both 1.0 and 0.5 cm MLC leaf widths, utilizing a high resolution bar-pattern fluence, an annular shaped fluence, and an intensity step-edge. Improvement in resolution was found for the 1.0 cm leaf width at a sampling distance of 0.5 cm, with only a small benefit for further reduction. For the 0.5 cm leaf width, a sampling distance of 0.25 cm resulted in a dose resolution that was nearly independent of direction.

Volumetric modulated arc therapy improves dosimetry and reduces treatment time compared to conventional intensity-modulated radiotherapy for locoregional radiotherapy of left-sided breast cancer and internal mammary nodes.

PURPOSE: Volumetric modulated arc therapy (VMAT) is a novel extension of conventional intensity-modulated radiotherapy (cIMRT), in which an optimized three-dimensional dose distribution may be delivered in a single gantry rotation. VMAT is the predecessor to RapidArc (Varian Medical System). This study compared VMAT with cIMRT and with conventional modified wide-tangent (MWT) techniques for locoregional radiotherapy for left-sided breast cancer, including internal mammary nodes. METHODS AND MATERIALS: Therapy for 5 patients previously treated with 50 Gy/25 fractions using nine-field cIMRT was replanned with VMAT and MWT. Comparative endpoints were planning target volume (PTV) dose homogeneity, doses to surrounding structures, number of monitor units, and treatment delivery time. RESULTS: For VMAT, two 190 degrees arcs with 2-cm overlapping jaws were required to optimize over the large treatment volumes. Treatment plans generated using VMAT optimization resulted in PTV homogeneity similar to that of cIMRT and MWT. The average heart volumes receiving >30 Gy for VMAT, cIMRT, and MWT were 2.6% +/- 0.7%, 3.5% +/- 0.8%, and 16.4% +/- 4.3%, respectively, and the average ipsilateral lung volumes receiving >20 Gy were 16.9% +/- 1.1%, 17.3% +/- 0.9%, and 37.3% +/- 7.2%, respectively. The average mean dose to the contralateral medial breast was 3.2 +/- 0.6 Gy for VMAT, 4.3 +/- 0.4 Gy for cIMRT, and 4.4 +/- 4.7 Gy for MWT. The healthy tissue volume percentages receiving 5 Gy were significantly larger with VMAT (33.1% +/- 2.1%) and IMRT (45.3% +/- 3.1%) than with MWT (19.4% +/- 3.7%). VMAT reduced the number of monitor units by 30% and the treatment time by 55% compared with cIMRT. CONCLUSIONS: VMAT achieved similar PTV coverage and sparing of organs at risk, with fewer monitor units and shorter delivery time than cIMRT.

Does a three-field electron/minitangent photon technique offer dosimetric advantages to a multifield, photon-only technique for accelerated partial breast irradiation?

PURPOSE: To determine whether 3-field electron/minitangent photons (mixed-modality) technique improved dosimetry compared with a multifield, photon-only technique for accelerated partial breast irradiation (APBI). MATERIALS AND METHODS: Subjects were 20 breast cancer patients previously treated with photon-only APBI as part of a clinical trial to a dose of 38.5Gy/10 fractions in 5 days. Mixed-modality replans were compared with the photon-only plans with regards to planning target volume (PTV) coverage, conformity, homogeneity, and doses to normal tissues. RESULTS: The mixed-modality plans had similar PTV coverage, with more conformality, and reduced the volume of the ipsilateral breast receiving > or =95% and > or =50% doses, but had the pitfalls of less homogeneity and increased exposure of the ipsilateral lung and heart receiving low-dose radiation because of the exit dose of the electron beam. Factors associated with this increase were medial/deep-seated tumor beds, large tumor beds with PTV/Ipsilateral Breast ratio >20%, and use of high energy electrons. CONCLUSIONS: The three-field electron/minitangent photon APBI technique was more conformal and reduced the dose to the ipsilateral breast but had the disadvantage of exposing increased volumes of heart and ipsilateral lung to low-dose radiation compared with the photon-only technique.