Dose-intensified stereotactic body radiotherapy for painful vertebral metastases: A randomized phase 3 trial.

BACKGROUND: The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment. METHODS: This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis. RESULTS: Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p = .02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups. CONCLUSIONS: Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months.

Randomized self-controlled study comparing open-face vs. closed immobilization masks in fractionated cranial radiotherapy.

PURPOSE: To compare patient discomfort and immobilisation performance of open-face and closed immobilization masks in cranial radiotherapy. MATERIAL AND METHODS: This was a single-center randomized self-controlled clinical trial. At CT simulation, an open-face and closed mask was made for each patient and treatment plans with identical dose prescription were generated for each mask. Patients were randomised to start treatment with an open-face or closed mask. Masks were switched halfway through the treatment course; every patient was their own control. Patients self-reported discomfort, anxiety and pain using the visual analogue scale (VAS). Inter- and intrafraction set-up variability was measured with planar kV imaging and a surface guided radiotherapy (SGRT) system for the open-face masks. RESULTS: 30 patients with primary or metastatic brain tumors were randomized - 29 completed radiotherapy to a median total dose of 54 Gy (range 30-60 Gy). Mean discomfort VAS score was significantly lower with open-face masks (0.5, standard deviation 1.0) vs. closed masks (3.3, standard deviation 2.9), P < 0.0001. Anxiety and pain VAS scores were significantly lower with open-face masks (P < 0.0001). Closed masks caused more discomfort in infraorbital (P < 0.001) and maxillary (P = 0.02) areas. Two patients and 27 patients preferred closed or open-face masks, respectively. Interfraction longitudinal shifts and roll and yaw rotations were significantly smaller and lateral shifts were significantly larger with closed masks in combination with the laser system (P < 0.05) compared to open masks in combination with a SGRT system. Intrafraction variability did not differ between the masks. CONCLUSIONS: Open-face masks are associated with decreased patient discomfort without compromising patient positioning and immobilisation accuracy.

Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial.

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.

Stereotactic Body Radiation Therapy for Metastases in Long Bones.

PURPOSE: To evaluate the cumulative incidence of fracture and local failure and associated risk factors after stereotactic body radiation therapy (SBRT) for long bone metastases. METHODS AND MATERIALS: Data from 111 patients with 114 metastases in the femur, humerus, and tibia treated with SBRT in 7 international centers between October 2011 and February 2021 were retrospectively reviewed and analyzed using a competing risk regression model. RESULTS: The median follow-up was 21 months (range, 6-91 months). All but 1 patient had a Karnofsky performance status ≥70. There were 84 femur (73.7%), 26 humerus (22.8%), and 4 tibia (3.5%) metastases from prostate (45 [39.5%]), breast (22 [19.3%]), lung (15 [13.2%]), kidney (13 [11.4%]), and other (19 [16.6%]) malignancies. Oligometastases accounted for 74.8% of metastases and 28.1% were osteolytic. The most common total doses were 30 to 50 Gy in 5 daily fractions (50.9%). Eight fractures (5 in the femur, 2 in the tibia, and 1 in the humerus) were observed with a median time to fracture of 12 months (range, 0.8-33 months). In 6 out of 8 patients, fracture was not associated with local failure. The cumulative incidence of fracture was 3.5%, 6.1%, and 9.8% at 1, 2, and 3 years, respectively. The cumulative incidence of local failure (9/110 metastases with imaging follow-up) was 5.7%, 7.2%, and 13.5% at 1, 2, and 3 years, respectively. On multivariate analysis, extraosseous disease extension was significantly associated with fracture (P = .001; subhazard ratio, 10.8; 95% confidence interval, 2.8-41.9) and local failure (P = .02; subhazard ratio, 7.9; 95% confidence interval, 1.4-44.7). CONCLUSIONS: SBRT for metastases in long bones achieved high rates of durable local metastasis control without an increased risk of fracture. Similar to spine SBRT, patients with extraosseous disease extension are at higher risk of local failure and fracture.

Long-Term Results of Dose-Intensified Fractionated Stereotactic Body Radiation Therapy (SBRT) for Painful Spinal Metastases.

PURPOSE: To report long-term outcome of fractionated stereotactic body radiation therapy (SBRT) for painful spinal metastases. METHODS AND MATERIALS: This prospective, single-arm, multicenter phase 2 clinical trial enrolled 57 patients with 63 painful, unirradiated spinal metastases between March 2012 and July 2015. Patients were treated with 48.5 Gy in 10 SBRT fractions (long life expectancy [Mizumoto score ≤4]) or 35 Gy in 5 SBRT fractions (intermediate life expectancy [Mizumoto score 5-9]). Pain response was defined as pain improvement of a minimum of 2 points on a visual analog scale, and net pain relief was defined as the sum of time with pain response (complete and partial) divided by the overall follow-up time. RESULTS: All 57 patients received treatment per protocol; 32 and 25 patients were treated with 10- and 5-fraction SBRT, respectively. The median follow-up of living patients was 60 months (range, 33-74 months). Of evaluable patients, 82% had complete or partial pain response (responders) at 3 months' follow-up (primary endpoint), and pain response remained stable over 5 years. Net pain relief was 74% (95% CI, 65%-80%). Overall survival rates of 1, 3, and 5 years were 59.6% (95% CI, 47%-72%), 33.3% (95% CI, 21%-46%), and 21% (95% CI, 10%-32%), respectively. Freedom from local spinal-metastasis progression was 82% at the last imaging follow-up. Late grade-3 toxicity was limited to pain in 2 patients (nonresponders). There were no cases of myelopathy. SBRT resulted in long-term improvements of all dimensions of the 5-level EuroQol 5-Dimension Questionnaire except anxiety/depression. CONCLUSIONS: Fractionated SBRT achieved durable pain response and improved quality of life at minimum late toxicity.

Inter-observer variability in target delineation increases during adaptive treatment of head-and-neck and lung cancer.

Introduction: Inter-observer variability (IOV) in target volume delineation is a well-documented source of geometric uncertainty in radiotherapy. Such variability has not yet been explored in the context of adaptive re-delineation based on imaging data acquired during treatment. We compared IOV in the pre- and mid-treatment setting using expert primary gross tumour volume (GTV) and clinical target volume (CTV) delineations in locoregionally advanced head-and-neck squamous cell carcinoma (HNSCC) and (non-)small cell lung cancer [(N)SCLC]. Material and methods: Five and six observers participated in the HNSCC and (N)SCLC arm, respectively, and provided delineations for five cases each. Imaging data consisted of CT studies partly complemented by FDG-PET and was provided in two separate phases for pre- and mid-treatment. Global delineation compatibility was assessed with a volume overlap metric (the Generalised Conformity Index), while local extremes of IOV were identified through the standard deviation of surface distances from observer delineations to a median consensus delineation. Details of delineation procedures, in particular, GTV to CTV expansion and adaptation strategies, were collected through a questionnaire. Results: Volume overlap analysis revealed a worsening of IOV in all but one case per disease site, which failed to reach significance in this small sample (p-value range .063-.125). Changes in agreement were propagated from GTV to CTV delineations, but correlation could not be formally demonstrated. Surface distance based analysis identified longitudinal target extent as a pervasive source of disagreement for HNSCC. High variability in (N)SCLC was often associated with tumours abutting consolidated lung tissue or potentially invading the mediastinum. Adaptation practices were variable between observers with fewer than half stating that they consistently adapted pre-treatment delineations during treatment. Conclusion: IOV in target volume delineation increases during treatment, where a disparity in institutional adaptation practices adds to the conventional causes of IOV. Consensus guidelines are urgently needed.

Dose-intensified hypofractionated stereotactic body radiation therapy for painful spinal metastases: Results of a phase 2 study.

BACKGROUND: The objective of this study was to prospectively evaluate dose-intensified hypofractionated stereotactic body radiation therapy (SBRT) in patients with painful spinal metastases in a multicenter, single-arm, phase 2 study. METHODS: Patients with 2 or fewer distinct, noncontiguous, painful, mechanically stable, unirradiated spinal metastases from a solid tumor with a Karnofsky performance status ≥ 60 were eligible. Patients with a long (Mizumoto score ≤ 4) or intermediate overall survival expectancy (Mizumoto score = 5-9) received 48.5 Gy in 10 fractions or 35 Gy in 5 fractions, respectively, with SBRT. The primary outcome was the overall (complete and partial) pain response as measured with international consensus guidelines 3 months after SBRT. RESULTS: There were 57 patients enrolled between 2012 and 2015, and 54 of these patients with 60 painful vertebral metastases were analyzed. The 3-month pain response was evaluated in 42 patients (47 lesions). An overall pain response was observed in 41 lesions (87%), and the pain response remained stable for at least 12 months. The mean maximum pain scores on a visual analogue scale significantly improved from the baseline of 6.1 (standard deviation, 2.5) to 2.0 (standard deviation, 2.3) 3 months after treatment (P < .001). The 5-level EuroQol 5-Dimension Questionnaire quality-of-life (QOL) dimensions (self-reported mobility, usual activities, and pain/discomfort) significantly improved from the baseline to 3 months after treatment. The 12-month overall survival and local control rates were 61.4% (95% confidence interval [CI], 48%-74.8%) and 85.9% (95% CI, 76.7%-95%), respectively. Grade 3 toxicity was limited to acute pain in 1 patient (2%). No patient experienced radiation-induced myelopathy. Six patients (11%) developed progressive vertebral compression fractures (VCFs), and 8 patients (15%) developed new VCFs. CONCLUSIONS: Dose-intensified SBRT achieved durable local metastasis control and resulted in pronounced and long-term pain responses and improved QOL. Cancer 2018;124:2001-9. © 2018 American Cancer Society.

Long-term outcome of 18 F-fluorodeoxyglucose-positron emission tomography-guided dose painting for head and neck cancer: Matched case-control study.

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.

Variations in target volume definition and dose to normal tissue using anatomic versus biological imaging (18 F-FDG-PET) in the treatment of bone metastases: results from a 3-arm randomized phase II trial.

INTRODUCTION: To report the impact on target volume delineation and dose to normal tissue using anatomic versus biological imaging (18 F-FDG-PET) for bone metastases. 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 (ConvRT-8 Gy) or 8 Gy in a single fraction with dose-painting-by-numbers (DPBN) dose range between 6 and 10 Gy) (DPBN-8 Gy) or 16 Gy in a single fraction with DPBN (dose range between 14 and 18 Gy) (DPBN-16 Gy). The primary endpoint was overall pain response at 1 month. Volumes of the gross tumour volume (GTV) - both biological (GTVPET ) and anatomical (GTVCT ) -, planning target volume (PTV), dose to the normal tissue and maximum standardized-uptake values (SUVMAX ) were analysed (secondary endpoint). RESULTS: Sixty-three percent of the GTVCT volume did not show 18 F-FDG-uptake. On average, 20% of the GTVPET volume was outside GTVCT . The volume of normal tissue receiving 4 Gy, 6 Gy and 8 Gy was at least 3×, 6× and 13× smaller in DPBN-8 Gy compared to ConvRT-8 Gy and DPBN-16 Gy (P < 0.05). CONCLUSION: Positron emitting tomography-information potentially changes the target volume for bone metastases. DPBN between 6 and 10 Gy significantly decreases dose to the normal tissue compared to conventional radiotherapy.

Intensity modulated arc therapy implementation in a three phase adaptive (18)F-FDG-PET voxel intensity-based planning strategy for head-and-neck cancer.

BACKGROUND: This study investigates the implementation of a new intensity modulated arc therapy (IMAT) class solution in comparison to a 6-static beam step-and-shoot intensity modulated radiotherapy (s-IMRT) for three-phase adaptive (18)F-FDG-PET-voxel-based dose-painting-by-numbers (DPBN) for head-and-neck cancer. METHODS: We developed (18)F-FDG-PET-voxel intensity-based IMAT employing multiple arcs and compared it to clinically used s-IMRT DPBN. Three IMAT plans using (18)F-FDG-PET/CT acquired before treatment (phase I), after 8 fractions (phase II) and CT acquired after 18 fractions (phase III) were generated for each of 10 patients treated with 3 s-IMRT plans based on the same image sets. Based on deformable image registration (ABAS, version 0.41, Elekta CMS Software, Maryland Heights, MO), doses of the 3 plans were summed on the pretreatment CT using validated in-house developed software. Dosimetric indices in targets and organs-at-risk (OARs), biologic conformity of treatment plans set at ≤5 %, treatment quality and efficiency were compared between IMAT and s-IMRT for the whole group and for individual patients. RESULTS: Doses to most organs-at-risk (OARs) were significantly better in IMAT plans, while target levels were similar for both types of plans. On average, IMAT ipsilateral and contralateral parotid mean doses were 14.0 % (p = 0.001) and 12.7 % (p < 0.001) lower, respectively. Pharyngeal constrictors D50% levels were similar or reduced with up to 54.9 % for IMAT compared to s-IMRT for individual patient cases. IMAT significantly improved biologic conformity by 2.1 % for treatment phases I and II. 3D phantom measurements reported an agreement of ≥95 % for 3 % and 3 mm criteria for both treatment modalities. IMAT delivery time was significantly shortened on average by 41.1 %. CONCLUSIONS: IMAT implementation significantly improved the biologic conformity as compared to s-IMRT in adaptive dose-escalated DPBN treatments. The better OAR sparing and faster delivery highly improved the treatment efficiency.

Intensity-modulated radiotherapy for early-stage glottic cancer.

BACKGROUND: The purpose of this study was to report on treatment outcome of intensity-modulated radiotherapy (IMRT) for early-stage (cT1-2 cN0 M0) squamous cell carcinoma of the glottis, as compared with patients treated with conventional radiotherapy. METHODS: Between November 2007 and December 2011, 40 consecutive patients were treated with IMRT with daily cone-beam CT position verification. The median prescription to the planning target volume (PTV) was 63 Gy/28 fractions and 67.5 Gy/30 fractions for T1 and T2 tumors, respectively. The historical control comprised 81 consecutive patients treated with conventional radiotherapy to total doses of 66 Gy/33 fractions (66 patients) and 70 Gy/35 fractions (15 patients) for T1 and T2 tumors, respectively. RESULTS: The median follow-up of living patients was 3.8 years (range, 1.0-5.0 years) in the IMRT group and 9.0 years, (range, 5.2-12.7 years) in the conventional group. Five-year actuarial local control was equal compared to the conventional group: 83% versus 74% (p = .64). Five-year actuarial ultimate local control was 100% in the IMRT group and 95% in the conventional group (p = .17). Five-year actuarial overall and disease-specific survival was 85% after IMRT versus 65% after conventional radiotherapy (p = .15) and 97% versus 89% (p = .31), respectively. Incidence and severity of acute dermatitis was significantly less during IMRT than in the control group (p < .001). Two patients receiving IMRT had late grade 3 hoarseness. CONCLUSION: IMRT is as efficient as conventional radiotherapy in terms of disease control and overall survival. It has the potential to reduce toxicity as compared to conventional radiotherapy. © 2015 Wiley Periodicals, Inc. Head Neck 38: E179-E184, 2016.

Biological 18[F]-FDG-PET image-guided dose painting by numbers for painful uncomplicated bone metastases: A 3-arm randomized phase II trial.

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 8Gy in a single fraction with conventionally planned radiotherapy (arm A) or 8Gy in a single fraction with DPBN (dose range between 610Gy and 10Gy) (arm B) or 16Gy in a single fraction with DPBN (dose range between 1410Gy and 18Gy) (arm C). The primary endpoint was overall pain response at 1month. 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 8Gy with DPBN will be further evaluated in a phase III-trial.

Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma.

BACKGROUND: Newly diagnosed WHO grade II-III or any WHO grade recurrent meningioma exhibit an aggressive behavior and thus are considered as high- or intermediate risk tumors. Given the unsatisfactory rates of disease control and survival after primary or adjuvant radiation therapy, optimization of treatment strategies is needed. We investigated the potential of dose-painting intensity-modulated proton beam-therapy (IMPT) for intermediate- and high-risk meningioma. MATERIAL AND METHODS: Imaging data from five patients undergoing proton beam-therapy were used. The dose-painting target was defined using [68]Ga-[1,4,7,10-tetraazacyclododecane tetraacetic acid]- d-Phe(1),Tyr(3)-octreotate ([68]Ga-DOTATATE)-positron emission tomography (PET) in target delineation. IMPT and photon intensity-modulated radiation therapy (IMRT) treatment plans were generated for each patient using an in-house developed treatment planning system (TPS) supporting spot-scanning technology and a commercial TPS, respectively. Doses of 66 Gy (2.2 Gy/fraction) and 54 Gy (1.8 Gy/fraction) were prescribed to the PET-based planning target volume (PTVPET) and the union of PET- and anatomical imaging-based PTV, respectively, in 30 fractions, using simultaneous integrated boost. RESULTS: Dose coverage of the PTVsPET was equally good or slightly better in IMPT plans: dose inhomogeneity was 10 ± 3% in the IMPT plans vs. 13 ± 1% in the IMRT plans (p = 0.33). The brain Dmean and brainstem D50 were small in the IMPT plans: 26.5 ± 1.5 Gy(RBE) and 0.002 ± 0.0 Gy(RBE), respectively, vs. 29.5 ± 1.5 Gy (p = 0.001) and 7.5 ± 11.1 Gy (p = 0.02) for the IMRT plans, respectively. The doses delivered to the optic structures were also decreased with IMPT. CONCLUSIONS: Dose-painting IMPT is technically feasible using currently available planning tools and resulted in dose conformity of the dose-painted target comparable to IMRT with a significant reduction of radiation dose delivered to the brain, brainstem and optic apparatus. Dose escalation with IMPT may improve tumor control and decrease radiation-induced toxicity.

High-dose reirradiation with intensity-modulated radiotherapy for recurrent head-and-neck cancer: disease control, survival and toxicity.

PURPOSE: To evaluate disease control, survival and severe late toxicity after high-dose fractionated reirradiation using intensity-modulated radiotherapy (IMRT) for recurrent head-and-neck cancer. MATERIALS AND METHODS: Sixty consecutive patients were reirradiated with IMRT between 1997 and 2011. The median prescribed dose was 70 Gy in 35 daily fractions until 2004 and 69.12 Gy in 32 daily fractions thereafter. The median cumulative dose was 132 Gy. Sixty-seven percent of patients had non-metastatic stage IV disease. Surgery prior to reirradiation and concomitant systemic therapy was performed in 13 (22%) and 20 (33%) patients, respectively. RESULTS: Median follow-up in living patients was 18.5 months. Actuarial 1-, 2- and 5-year locoregional control was 64%, 48% and 32%, respectively. Median overall (OS) and disease-free survival was 9.6 and 6.7 months, respectively. Actuarial 1-, 2- and 5-year OS was 44%, 32% and 22%, respectively. Seventeen (27%) and 2 (3%) patients had grade 3 and 4 acute toxicity, respectively. Cumulative incidence of late grade≥3 toxicity was 23%, 27% and 66% at 1, 2 and 5 years, respectively. In 4 patients, death was attributed to toxicity: fatal bleeding (n=2), aspiration pneumonia (n=1) and skin necrosis (n=1). CONCLUSIONS: High-dose fractionated reirradiation with IMRT offers 5-year disease control and OS in recurrent head-and-neck cancer for 1/3 and 1/4 patients, respectively. Severe late toxicity after 1-2 and 5 years occurs in 1/4 and 2/3 patients, respectively.

Comparative dosimetry of three-phase adaptive and non-adaptive dose-painting IMRT for head-and-neck cancer.

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.

Reduction of the dose to the elective neck in head and neck squamous cell carcinoma, a randomized clinical trial using intensity modulated radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity.

BACKGROUND AND PURPOSE: A randomized trial was initiated to investigate whether a reduction of the dose to the elective nodal sites and the swallowing apparatus delivered by IMRT would result in a reduction of acute and late side effects without compromising tumor control. The aim of this paper is to report on dosimetrical analysis and acute toxicity. MATERIALS & METHODS: Two-hundred patients were randomized. In the standard arm, elective nodal volumes (PTVelect) were irradiated up to an equivalent dose of 50Gy. In the experimental arm an equivalent dose of 40Gy was prescribed to the PTVelect. The dose to the swallowing apparatus was kept as low as possible without compromising therapeutic PTV (PTVther) coverage. RESULTS: No significant difference was seen between both arms concerning PTVther coverage. The median D95 of the PTVelect was significantly lower in the experimental arm (39.5 vs 49.8Gy; p<0.001). Concerning the organs at risk, the dose to swallowing structures and spinal cord was significantly reduced. There was no significant difference in acute toxicity. Three months after radiotherapy there was significantly less grade ⩾3 dysphagia in the experimental arm (2% vs 11%; p=0.03). With a median follow-up of 6months no significant differences were observed in locoregional control, disease free survival or overall survival. CONCLUSIONS: Using IMRT we were able to significantly reduce the dose to the PTVelect and several organs at risk without compromising PTVther coverage. This resulted in a significant reduction of severe dysphagia 3months after radiotherapy. Further follow-up is necessary to investigate whether these observations translate into a benefit on late treatment related dysphagia without affecting treatment outcome.

Deformation field validation and inversion applied to adaptive radiation therapy.

Development and implementation of chronological and anti-chronological adaptive dose accumulation strategies in adaptive intensity-modulated radiation therapy (IMRT) for head-and-neck cancer. An algorithm based on Newton iterations was implemented to efficiently compute inverse deformation fields (DFs). Four verification steps were performed to ensure a valid dose propagation: intra-cell folding detection finds zero or negative Jacobian determinants in the input DF; inter-cell folding detection is implemented on the resolution of the output DF; a region growing algorithm detects undefined values in the output DF; DF domains can be composed and displayed on the CT data. In 2011, one patient with nonmetastatic head and neck cancer selected from a three phase adaptive DPBN study was used to illustrate the algorithms implemented for adaptive chronological and anti-chronological dose accumulation. The patient received three (18)F-FDG-PET/CTs prior to each treatment phase and one CT after finalizing treatment. Contour propagation and DF generation between two consecutive CTs was performed in Atlas-based autosegmentation (ABAS). Deformable image registration based dose accumulations were performed on CT1 and CT4. Dose propagation was done using combinations of DFs or their inversions. We have implemented a chronological and anti-chronological dose accumulation algorithm based on DF inversion. Algorithms were designed and implemented to detect cell folding.

Whole breast radiotherapy in prone and supine position: is there a place for multi-beam IMRT?

BACKGROUND: Early stage breast cancer patients are long-term survivors and finding techniques that may lower acute and late radiotherapy-induced toxicity is crucial. We compared dosimetry of wedged tangential fields (W-TF), tangential field intensity-modulated radiotherapy (TF-IMRT) and multi-beam IMRT (MB-IMRT) in prone and supine positions for whole-breast irradiation (WBI). METHODS: MB-IMRT, TF-IMRT and W-TF treatment plans in prone and supine positions were generated for 18 unselected breast cancer patients. The median prescription dose to the optimized planning target volume (PTVoptim) was 50 Gy in 25 fractions. Dose-volume parameters and indices of conformity were calculated for the PTVoptim and organs-at-risk. RESULTS: Prone MB-IMRT achieved (p<0.01) the best dose homogeneity compared to WTF in the prone position and WTF and MB-IMRT in the supine position. Prone IMRT scored better for all dose indices. MB-IMRT lowered lung and heart dose (p<0.05) in supine position, however the lowest ipsilateral lung doses (p<0.001) were in prone position. In left-sided breast cancer patients population averages for heart sparing by radiation dose was better in prone position; though non-significant. For patients with a PTVoptim volume ≥600 cc heart dose was consistently lower in prone position; while for patients with smaller breasts heart dose metrics were comparable or worse compared to supine MB-IMRT. Doses to the contralateral breast were similar regardless of position or technique. Dosimetry of prone MB-IMRT and prone TF-IMRT differed slightly. CONCLUSIONS: MB-IMRT is the treatment of choice in supine position. Prone IMRT is superior to any supine treatment for right-sided breast cancer patients and left-sided breast cancer patients with larger breasts by obtaining better conformity indices, target dose distribution and sparing of the organs-at-risk. The influence of treatment techniques in prone position is less pronounced; moreover dosimetric differences between TF-IMRT and MB-IMRT are rather small.

Three-phase adaptive dose-painting-by-numbers for head-and-neck cancer: initial results of the phase I clinical trial.

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.

A predictive model for dysphagia following IMRT for head and neck cancer: introduction of the EMLasso technique.

BACKGROUND AND PURPOSE: Design a model for prediction of acute dysphagia following intensity-modulated radiotherapy (IMRT) for head and neck cancer. Illustrate the use of the EMLasso technique for model selection. MATERIAL AND METHODS: Radiation-induced dysphagia was scored using CTCAE v.3.0 in 189 head and neck cancer patients. Clinical data (gender, age, nicotine and alcohol use, diabetes, tumor location), treatment parameters (chemotherapy, surgery involving the primary tumor, lymph node dissection, overall treatment time), dosimetric parameters (doses delivered to pharyngeal constrictor (PC) muscles and esophagus) and 19 genetic polymorphisms were used in model building. The predicting model was achieved by EMLasso, i.e. an EM algorithm to account for missing values, applied to penalized logistic regression, which allows for variable selection by tuning the penalization parameter through crossvalidation on AUC, thus avoiding overfitting. RESULTS: Fifty-three patients (28%) developed acute ≥ grade 3 dysphagia. The final model has an AUC of 0.71 and contains concurrent chemotherapy, D2 to the superior PC and the rs3213245 (XRCC1) polymorphism. The model's false negative rate and false positive rate in the optimal operation point on the ROC curve are 21% and 49%, respectively. CONCLUSIONS: This study demonstrated the utility of the EMLasso technique for model selection in predictive radiogenetics.