PURPOSE:Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT). METHODS AND MATERIALS:This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent. PRIMARY OUTCOMES:1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. RESULTS:Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity. CONCLUSIONS:A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers.

BACKGROUND AND PURPOSE Local recurrence remains the main cause of death in stage III-IV non-metastatic head-and-neck cancer (HNC) with relapse-prone regions within high 18F-FDG-PET-signal gross tumor volume. We investigated if dose-escalation within this subvolume combined with a 3-phase treatment-adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET-voxel-intensity-based dose-painting-by-numbers (A-DPBN) with non-adaptive standard intensity-modulated radiotherapy (S-IMRT). MATERIALS AND METHODS This two-center randomized controlled phase II trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: non-metastatic HNC of oral cavity, oro-/hypopharynx or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS≥70; ≥18 years and informed consent. Primary outcomes: 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in two steps to an absolute dose-volume limit (≤1.75cm3 can receive >84Gy and normalized isoeffective dose >96Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. RESULTS Ninety-five patients were randomized (A-DPBN: 47; S-IMRT: 48). Median follow-up amounts 31 months (IQR: 14-48 months); 29 patients died (17 of cancer progression). A-DPBN results in superior LC compared to S-IMRT with 1- and 2-year LC of 91% and 88% vs. 78% and 75%, respectively (hazard ratio, 3.13; 95% confidence interval, 1.13-8.71; p=0.021). RC and overall survival are comparable between arms, as is overall grade (G) ≥3 late toxicity (36% vs. 20%, p=0.1). More ≥G3 late mucosal ulcers are observed in active smokers (29% vs. 3%, p=0.005) and alcohol users (33% vs. 13%, p=0.02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients that smoked at diagnosis developed ≥G3 (46% vs. 12%, p=0.005) and ≥G4 (29% vs. 8%, p=0.048) mucosal ulcers. One arterial blowout occurred following a G5 mucosal toxicity. CONCLUSION A-DPBN resulted in superior 1- and 2-year LC for HNC compared to S-IMRT. This supports further exploration in multicenter phase III trials. It will however be challenging to recruit a substantial patient sample for such trials as concerns have arisen on the association of late mucosal ulcers when escalating the dose in continuing smokers.

Advanced stage HL patients achieving a complete metabolic response after ABVD regimen may benefit from the addition of consolidation RT to bulky lesions at baseline, regardless of the maximum diameter of the mass, with a PFS benefit ranging from 7% to 10% at 3 and 5 years.

Introduction: In view of the limited incremental benefit between whole breast irradiation (WBI), accelerated partial breast irradiation (APBI) and omission of radiotherapy in favorable early-stage breast cancer (ESBC), APBI can only be justified if it combines adequate target coverage with the lowest achievable toxicity. Interobserver exercises demonstrated the difficulty of precise target delineation, especially in prone position; information on accuracy is even scarcer. We tested the impact of inserting an additional indicator clip, marking the depth of the tumor in the breast, and the added value of a preoperative CT in treatment position on precision and accuracy.Material and methods: In 12 patients, tumor bed delineation was performed by four radiation oncologists, with CTVstandard (clinical target volume) based on standard delineation guidelines, CTVclip resulting from a 1-2-cm symmetrical expansion with the indicator clip as center and CTVclip_CT expanding from the midpoint between the indicator clip and preoperative gross tumor volume (GTV) as center. Precision was measured as the mean pairwise Jaccard index (JI(pairs)) between observers, accuracy as the mean overlap between GTV and respective CTVs.Results: JI(pairs) was 0.38 for CTVstandard, 0.75 for CTVclip and 0.59 for CTVclip_CT. Overlap rate of GTV with CTVs was respectively 0.48, 0.67 and improved further to 0.88 for CTVclip_CT. High-dose coverage of GTV (D95 and D90) improved with an indicator clip, but the most optimal result was reached when preoperative CT was added.Conclusions: If EB-APBI in prone position is aimed for, an indicator clip intended to mark the depth of the tumor increases the probability of accurate target coverage, but cannot entirely replace the added value of a preoperative CT in treatment position. Avoiding the cost and effort of such CT implies a risk of missing the target, especially when small volumes are aimed for. Increasing target volumes to reduces this risk, questions the concept of APBI.

BACKGROUND:The purpose of this study was to report the long-term outcome of 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET)-guided dose painting for head and neck cancer in comparison to conventional intensity-modulated radiotherapy (IMRT) in a matched case-control study. METHODS:Seventy-two patients with nonmetastatic head and neck cancer treated with dose painting were compared with 72 control patients matched on tumor site and T classification. Either 18 F-FDG-PET-guided dose painting by contour (DPBC) or voxel intensity-based dose painting by number (DPBN) was performed; control patients underwent standard IMRT. A total median dose to the dose-painted target was 70.2-85.9 Gy/30-32 fractions versus 69.1 Gy/32 fractions with conventional IMRT. In 31 patients, dose painting was adapted to per-treatment changes in the tumor and organs-at-risk (OAR). RESULTS:Median follow-up in living dose-painting and control patients was 87.7 months (range 56.1-119.3) and 64.8 months (range 46.3-83.4), respectively. Five-year local control rates in the dose-painting patients were 82.3% against 73.6% in the control (P = .36); in patients treated to normalized isoeffective doses >91 Gy (NID2Gy) local control reached 85.7% at 5 years against 73.6% in the control group (P =.39). There was no difference in regional (P = .82) and distant control (P = .78). Five-year overall and disease-specific survival rates were 36.3% versus 38.1% (P = .50) and 56.5% versus 51.7% (P = .72), respectively. A half of the dose-painting patients developed acute grade ≥3 dysphagia (P = .004). Late grade 4 mucosal ulcers at the site of dose escalation in 9 of 72 patients was the most common severe toxicity with dose painting versus 3 of 72 patients with conventional IMRT (P = .11). Patients in the dose-painting group had increased rates of acute and late dysphagia (P = .004 and P = .005). CONCLUSION:Dose-painting strategies can be used to increase dose to specific tumor subvolumes. Five-year local, regional, and distant control rates are comparable with patients treated with conventional IMRT. Volume and intensity of dose escalation should be further tailored, given the possible increase in severe acute and chronic toxicity. Adapting treatment and decreasing dose to the swallowing structures might contribute to lower toxicity rates when applied in smaller tumor volumes. Whether adaptive DPBN can significantly improve outcomes is currently being investigated in a novel clinical trial.

________________________________________________________________________________collimator angle.The results are based on the value of GAI: when the value is lower than 95%, the error is detected.Introduced errors are smaller and smaller in order to characterize error detection limits of each method.For Portal Dosimetry, it is possible to detect errors of collimator angle up to 4° and errors of Monitor Units up to 3%.For Delta4, it is possible to detect errors of collimator angle up to 2° and errors of Monitor Units up to 2 %.For Epiqa, it is possible to detect errors of collimator angle up to 2° and errors of Monitor Units up to 3%. Conclusion:In spite of their differences, the three pretreatment verification methods are able to detect different sort of errors in dose distributions.The comparative study gives us concordant results.Therefore, these data suggest the possibility of using only one routinely and complete the analysis with one of the other in case of problems.

Implementation of in-house software for simultaneous optimization of multiple treatment plans per patient. Objectives are defined on individual treatment plans, their dose distributions, and on dose distributions resulting from the summation of individual treatment plan doses. Simultaneous optimization of multiple linked treatment plans (SOLTP) was developed as a module to the GRATIS treatment planning system. All treatment planning CTs are linked by rigid transform matrices or by deformation fields. Dose objectives and constraints are defined on the individual treatment plans and on one or more accumulated dose distributions. During the optimization, the dose per treatment plan as well as the accumulated dose distribution is updated according to the changes in leaf positions and monitor units. The combined objective function value of each treatment plan and each accumulated dose distribution is used in the optimization. To demonstrate the possibilities of SOLTP, a cadaver was scanned 5 times on CT. Five CT scans with different bladder fillings (0, 60, 120, 180, and 240 mL) were obtained. On each CT, a treatment plan was created. The dose prescribed to 50% of the gross tumor volume (GTV) and clinical target volume was 62.5 and 40 Gy, respectively. To avoid late grade ≥2 rectal toxicity, the rectum and sigmoid volumes receiving 34.3 Gy and 34.4 Gy were constrained to 64% and 35%, respectively. Two sets of optimizations were performed separately. The first optimization was performed with objectives defined on individual treatment plans only. The second optimization had objectives defined on the individual treatment plans, as well as on the accumulated dose distribution from all 5 treatments plans on the 120-mL CT. Dose computations were performed with the collapsed cone convolution/superposition algorithm of a treatment planning system. The minimum dose to the GTV on the dose distribution accumulated on the 120-mL CT was higher in SOLTP (D98% : 58.74 Gy) than in the individually optimized treatment plans (IOTP) (D98% : 55.30 Gy). The V34.3Gy and V34.4Gy for the rectum with IOTP was respectively 3.20 and 3.12% while with SOLTP it was reduced to 1.65 and 1.56%. The V34.3Gy and V34.4Gy for the sigmoid with IOTP was respectively 0.279 and 0.278% while with SOLTP it was 0.279 and 0.269%. The D2% in IOTP for the femoral head left and right was respectively 29.70 and 31.29 Gy, while for SOLTP the D2% was respectively 29.03 and 29.61 Gy. The small intestine received a higher D2% using SOLTP (39.01 Gy) than using IOTP (36.78 Gy). A better target coverage was obtained with the optimization taking into account the objectives defined on the accumulated dose distribution. SOLTP reached all clinical constraints on the individual treatment plans and on the accumulated dose distribution.

This study aims to establish target physical and biological effective dose (BED) thresholds to prevent the occurrence of late grade 4 mucosal ulcers in adapted dose escalated head and neck cancer treatments. 39 patients included in three phase I and one phase II dose escalation clinical trials with non-metastatic, non-resected, histologically confirmed squamous cell carcinoma of head and neck were considered. All patients were treated in a 3-phase adaptive radiation therapy scheme. 18F-FDG-PET/CT based dose painting by numbers (DPBN) was used for the first 2 phases (10 fractions each), while phase 3 (10 or 12 fractions) was planned with either DPBN or conventional IMRT, depending on the protocol. The physical dose distribution was converted into a BED distribution (α/β = 3) for each treatment. Both types of dose distributions were summed on the CT scan taken before the start of the treatment using deformable image registration and validated in-house developed software. The dose levels on dose-volume histograms above which lay 2% (D2%) and 1.75 cc (D1.75cc) of the gross tumor volume (GTVT) were calculated. Inspired by the ICRU report 50, the 1.75 cc target volume receiving the highest doses was analyzed with the purpose of finding a threshold above which the probability of developing grade 4 mucosal ulcer was higher. Clinical cofactors (concomitant chemotherapy, continuation of smoking and alcohol habits) were analyzed. The four patient groups included 21 oropharynx, 7 hypopharynx, 3 oral cavity and 8 larynx cases. 29 patients developed a late mucosal ulcer with grades between 1 and 4. From the 9 patients that developed grade 4 mucosal ulcer, 6 received chemotherapy. Smoking and alcohol drinking was continued after radiation therapy by 6 and 3 of them, respectively. Grade 4 occurred between 3 and 10.5 months after therapy. Table 1 presents the median dose levels for GTVT. The analyzed thresholds for D1.75cc and BED1.75cc were 86.5 Gy and 100 Gy3, respectively. The sensitivity and specificity of these criteria were 55.6% and 85.2%, respectively for D1.75cc and 55.6% and 81.5%, respectively for BED1.75cc. When smoking and alcohol abuse after therapy were added as extra criteria to the above thresholds, the sensitivity and specificity became 100.0% and 90.0%, respectively for both physical dose and BED. This study allowed the determination of dosimetrical thresholds to prevent the occurrence of late grade 4 mucosal ulcers. For these thresholds to be efficient, the smoking and alcohol drinking habits after therapy should also be taken into account.Abstract 2815; Table 1.D2%BED2%D1.75ccBED1.75ccGrade 487.9102.786.6100.0Grade 1-384.697.082.192.1 Open table in a new tab

To report the impact on target volume delineation and dose to normal tissue using anatomic versus biological imaging (18F‐FDG‐PET) for bone metastases.

Background: Antalgic radiotherapy for bone metastases might be improved by implementing biological information in the radiotherapy planning using 18 F-FDG-PET-CT based dose painting by numbers (DPBN).Materials and methods: Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8 Gy in a single fraction with conventionally planned radiotherapy (arm A) or 8 Gy in a single fraction with DPBN (dose range between 610 Gy and 10 Gy) (arm B) or 16 Gy in a single fraction with DPBN (dose range between 1410 Gy and 18 Gy) (arm C).The primary endpoint was overall pain response at 1 month.The phase II trial was designed to select the experimental arm with sufficient promise of efficacy to continue to a phase III trial.Results: Forty-five patients were randomized.Eight (53%), 12 (80%) and 9 patients (60%) had an overall response to treatment in arm A, B and C, respectively.The estimated odds ratio of overall response for arm B vs. A is 3.5 (95% CI: 0.44-17.71,p = 0.12).The estimated odds ratio of arm C vs. A is 1.31 (95% CI: 0.31-5.58,p = 0.71).Conclusion: A single fraction of 8 Gy with DPBN will be further evaluated in a phase III-trial.

Purpose/Objective: Adjuvant RT after quadrantectomy or lumpectomy plays an essential role in breast conserving therapy for early stage carcinoma and 60 Gy delivered in 30 fractions in 6 weeks is generally considered the standard dose.The present study aims to evaluate acute, sub-acute and short term late side effects in patients with early stage breast cancer treated with adjuvant radiotherapy (RT) using concomitant boost.Materials and Methods: Between June 2010 and October 2013, 586 patients (median age 60 years, range 27-96 years) with early-stage breast cancer were treated with a hypofractionated schedule of external beam RT after conserving surgery; 143 patients underwent post-operative chemotherapy before starting RT.RT was delivered as follow: 45 Gy in 20 fractions (225 cGy/fr) in 4 weeks to the whole breast and a daily concomitant boost dose (5Gy) to the lumpectomy cavity (25 cGy/fr).The cumulative nominal dose was 50 Gy.The technique used was 3D-conformational RT with 2 tangential fields for the whole breast and 2 oblique fields for the boost.The surgical bed was primarily defined with clips.Toxicity was scored according to LENT-SOMA scale.Results: Twenty-five patients experienced grade 3 skin toxicity within one week from the end of the RT course (eight after adjuvant chemotherapy administered before breast RT).After 19-month median follow-up (range 12-52 months), no grade 4 toxicity were detected; only 5 patients experienced grade 3 skin toxicity and thirty-nine patients reported grade 2 breast pain.Concerning cosmetic results, one patients developed scar retraction; the others 585 patients showed excellent or good cosmetic results.Disease recurrences were recorded in 4 patients: one of them with local relapse, the others three with systemic spread.Conclusions: The explored regimen seems to be feasible providing consistent clinical results with excellent toxicity profile.

PURPOSE:The anatomical changes, which occur during the radiotherapy treatment for head-and-neck cancer, may compromise the effectiveness of the treatment. This study compares dosimetrical effects of adaptive (ART) and non-adaptive (RT) dose-painted radiotherapy. MATERIALS AND METHODS:For 10 patients, three treatment phases were preceded by a planning PET/CT scan. In ART, phases II and III were planned using PET/CT2 and PET/CT3, respectively. In RT, phases II and III were planned on PET/CT1 and recalculated on PET/CT2 and PET/CT3. Deformable image co-registration was used to sum the dose distributions and to propagate regions-of-interest (ROIs) drawn on PET/CT1 to PET/CT2, PET/CT3 and a last-treatment-day CT-scan. RESULTS:Re-adjusted dose-painting ART provided higher minimum and lower maximum doses in target ROIs in comparison to RT. On average, ART reduced the parotids' median dose and swallowing structures mean dose by 4.6-7.1% (p>0.05) and 3% (p=0.06), respectively. Dose differences for targets were from -1.6% to 6.6% and for organs-at-risk from -7.1% to 7.1%. Analysis of individual patient data showed large improvements of ROI dose/volume metrics by ART, reaching a 24.4% minimum-dose increase in the elective neck planning target volume and 21.1% median-dose decrease in swallowing structures. CONCLUSION:Compared to RT, ART readjusts dose-painting, increases minimum and decreases maximum doses in target volumes and improves dose/volume metrics of organs-at-risk. The results favored the adaptive strategy, but also revealed considerable heterogeneity in patient-specific benefit. Reporting population-average effects underestimates the patient-specific benefits of ART.

PURPOSE:To evaluate feasibility of using deformable image co-registration in three-phase adaptive dose-painting-by-numbers (DPBN) for head-and-neck cancer and to report dosimetrical data and preliminary clinical results. MATERIAL AND METHODS:Between November 2010 and October 2011, 10 patients with non-metastatic head-and-neck cancer enrolled in this phase I clinical trial where treatment was adapted every ten fractions. Each patient was treated with three DPBN plans based on: a pretreatment 18[F]-FDG-PET scan (phase I: fractions 1-10), a per-treatment 18[F]-FDG-PET/CT scan acquired after 8 fractions (phase II: fractions 11-20) and a per-treatment 18[F]-FDG-PET/CT scan acquired after 18 fractions (phase III: fractions 21-30). A median prescription dose to the dose-painted target was 70.2 Gy (fractions 1-30) and to elective neck was 40 Gy (fractions 1-20). Deformable image co-registration was used for automatic region-of-interest propagation and dose summation of the three treatment plans. RESULTS:All patients (all men, median age 68, range 48-74 years) completed treatment without any break or acute G≥4 toxicity. Target volume reductions (mean (range)) between pre-treatment CT and CT on the last day of treatment were 72.3% (57.9-98.4) and 46.3% (11.0-73.1) for GTV and PTV(high_dose), respectively. Acute G3 toxicity was limited to dysphagia in 3/10 patients and mucositis in 2/10 patients; none of the patients lost ≥20% weight. At median follow-up of 13, range 7-22 months, 9 patients did not have evidence of disease. CONCLUSIONS:Three-phase adaptive 18[F]-FDG-PET-guided dose painting by numbers using currently available tools is feasible. Irradiation of smaller target volumes might have contributed to mild acute toxicity with no measurable decrease in tumor response.