External validation of a prediction model for timely implementation of innovations in radiotherapy.

BACKGROUND AND PURPOSE: The aim of this study was to externally validate a model that predicts timely innovation implementation, which can support radiotherapy professionals to be more successful in innovation implementation. MATERIALS AND METHODS: A multivariate prediction model was built based on the TRIPOD (Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis) criteria for a type 4 study (1). The previously built internally validated model had an AUC of 0.82, and was now validated using a completely new multicentre dataset. Innovation projects that took place between 2017-2019 were included in this study. Semi-structured interviews were performed to retrieve the prognostic variables of the previously built model. Projects were categorized according to the size of the project; the success of the project and thepresence of pre-defined success factors were analysed. RESULTS: Of the 80 included innovation projects (32.5% technological, 35% organisational and 32.5% treatment innovations), 55% were successfully implemented within the planned timeframe. Comparing the outcome predictions with the observed outcomes of all innovations resulted in an AUC of the external validation of the prediction model of 0.72 (0.60-0.84, 95% CI). Factors related to successful implementation included in the model are sufficient and competent employees, desirability and feasibility, clear goals and processes and the complexity of a project. CONCLUSION: For the first time, a prediction model focusing on the timely implementation of innovations has been successfully built and externally validated. This model can now be widely used to enable more successful innovation in radiotherapy.

EUS-guided fiducial marker placement for radiotherapy in rectal cancer: feasibility of two placement strategies and four fiducial types.

Background and study aims To facilitate image guidance during radiotherapy of rectal cancer, we investigated the feasibility of fiducial marker placement. This study aimed to evaluate technical success rate and safety of two endoscopic ultrasound (EUS)-guided placement strategies and four fiducial types for rectal cancer patients. Patients and methods This prospective multicenter study included 20 participants who were scheduled to undergo rectal cancer treatment with neoadjuvant short-course radiotherapy or chemoradiation. EUS-guided endoscopy was used for fiducial placement at the tumor site (n = 10) or in the mesorectal fat and in the tumor (n = 10). Four fiducial types were used (Visicoil 0.75 mm, Visicoil 0.50 mm, Cook, Gold Anchor). The endpoints were technical success rate and retention of fiducials, the latter of which was evaluated on cone-beam computed tomography scans during the first five radiotherapy fractions. Results A total of 64 fiducials were placed in 20 patients. For each fiducial type, at least three fiducials were successfully placed in all patients. Technical failure consisted of fiducial blockage within the needle (n = 2) and ejection of two preloaded fiducials at once (n = 4). No serious adverse events were reported. In three patients, one of the fiducials was misplaced without clinical consequences; two in the prostate and one in the intraperitoneal cavity. After a median time of 17 days after placement (range 7 - 47 days), a total of 42/64 (66 %) fiducials were still present (24/44 intratumoral vs. 18/20 mesorectal fiducials, P  = 0.009). Conclusions Placement of fiducials in rectal cancer patients is feasible, however, retention rates for intratumoral fiducials were lower (55 %) than for mesorectal fiducials (90 %).

Predictive factors for response and toxicity after brachytherapy for rectal cancer; results from the HERBERT study.

PURPOSE: The HERBERT study was a dose-finding feasibility study of a high-dose rate endorectal brachytherapy (HDREBT) boost after external beam radiotherapy (EBRT) in elderly patients with rectal cancer who were unfit for surgery. This analysis evaluates the association of patient, tumor and dosimetric parameters with tumor response and toxicity after HDREBT in definitive radiotherapy for rectal cancer. PATIENTS AND METHODS: The HERBERT study included 38 inoperable patients with T2-3N0-1 rectal cancer. Thirteen fractions of 3 Gy EBRT were followed by three weekly HDREBT applications of 5-8 Gy per fraction. Clinical and dosimetric parameters were tested for correlation with clinical complete response (cCR), sustained partial/complete response (SR), patient reported bowel symptoms, physician reported acute and late proctitis (CTCAE v3) and endoscopically scored toxicity. RESULTS: Thirty-five patients completed treatment and were included in the current analyses. Twenty of 33 evaluable patients achieved a cCR, the median duration of a sustained response was 32 months. Tumor volume at diagnosis showed a strong association with clinical complete response (OR 1.15; p = 0.005). No dose-response correlation was observed in this cohort. Prescribed dose to the brachytherapy CTV (D90) correlated with acute and late physician reported proctitis while CTV volume, CTV width and high dose regions in the CTV (D1cc/D2cc) were associated with endoscopic toxicity at the tumor site. CONCLUSION: Tumor volume is the most important predictive factor for tumor response and a higher dose to the brachytherapy CTV increases the risk of severe clinically and endoscopically observed proctitis after definitive radiotherapy in elderly patients with rectal cancer.

Ruthenium-106 brachytherapy for iris and iridociliary melanomas.

BACKGROUND AND PURPOSE: To evaluate ruthenium-106 (Ru106) brachytherapy as eye-conserving treatment of iris melanomas (IMs) and iridociliary melanomas (ICMs). MATERIALS AND METHODS: Eighty-eight patients received Ru106 brachytherapy between 2006 and 2016. Primary outcome was local control, and secondary outcomes were metastasis, survival, eye preservation, complications and visual acuity (VA). RESULTS: Overall median follow-up was 36 months. Of 88 patients, 58 (65.9%) had IM and 30 (34.1%) had ICM. ICM were on average larger and more advanced than IM. Local failure-free survival at 3years was 98.9% (SE 1.2%). Metastasis-free survival was 98.2% (SE 1.8%) at 3years; no deaths due to melanoma occurred during follow-up. Eye preservation rate was 97.7%. Treatment-related toxicities were mostly mild and observed in 80.7% of the patients. Common toxicities were worsening of pre-existing or new cataract (51.1%), dry eyes (29.5%) and glaucoma (20.5%). VA was not affected by Ru106 brachytherapy, with only 2.3% having VA <0.33 (low vision) at follow-up. CONCLUSIONS: Ru106 for IM and ICM yielded excellent local control (98.9%) and eye preservation (97.7%). Toxicities were common, but mostly mild and transient. Moreover, Ru106 did not affect visual acuity.

Benefit of adaptive CT-based treatment planning in high-dose-rate endorectal brachytherapy for rectal cancer.

PURPOSE: In this planning study, we investigated the dosimetric benefit of repeat CT-based treatment planning at each fraction vs. the use of a single CT-based treatment plan for all fractions for high-dose-rate endorectal brachytherapy (HDREBT) for rectal cancer. METHODS AND MATERIALS: We included 11 patients that received a CT scan with applicator in situ for all three fractions. The treatment plan of the first fraction was projected on the repeat CT scans to simulate the use of a single treatment plan. In addition, replanning was performed on the repeat CT scans, and these were compared to the corresponding projected treatment plans. RESULTS: Repeat CT-based treatment planning resulted on average in a 21% higher (p = 0.01) conformity index compared to single CT-based treatment planning. Projecting the initial treatment plan to the repeat CT scans of fraction two and three, 12/22 fractions reached a CTV D98 of 85% of the prescribed dose of 7 Gy, which increased to 14/22 using replanning. For the remaining fractions, median CTV D98 was 4.2 Gy, and an intervention would be necessary to correct applicator balloon setup or to remove remaining air and/or feces between the CTV and the applicator. CONCLUSIONS: Using a single CT-based treatment plan for all fractions may result in a suboptimal treatment at later fractions. Therefore, repeat CT imaging should be the minimal standard practice in HDREBT for rectal cancer to determine whether an intervention would be necessary. Replanning based on repeat CT imaging resulted in more conformal treatment plans and is therefore recommended.

Endorectal Brachytherapy Boost After External Beam Radiation Therapy in Elderly or Medically Inoperable Patients With Rectal Cancer: Primary Outcomes of the Phase 1 HERBERT Study.

PURPOSE: To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer. METHODS AND MATERIALS: A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13 × 3 Gy) followed by 3 weekly brachytherapy applications 6 weeks later. The HDREBT dose started at 5 Gy per fraction, increasing with 1 Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis <6 weeks after HDREBT) occurred in ≤2 patients per dose level. The primary endpoint was the maximum tolerated dose, defined as 1 dose level below the dose at which 3 patients experienced DLT. Secondary endpoints were toxicity, clinical tumor response, freedom from local progression, and local progression-free and overall survival (L-PFS and OS). RESULTS: Thirty-eight patients with a median age of 83 years were included in the study. Thirty-two were evaluable for DLT and late toxicity and 33 for response evaluation. Maximum delivered dose was 8 Gy per fraction, resulting in a recommended dose of 7 Gy per fraction. Response occurred in 29 of 33 patients (87.9%), with 60.6% complete response (CR). The L-PFS and OS rates were 42% and 63%, respectively, at 2 years. Patients with CR showed a significantly improved L-PFS (60% at 2 years, P=.006) and a trend in improved OS (80% at 2 years, P=.11). Severe late toxicity occurred in 10 of 32 patients. CONCLUSION: We found that HDREBT after EBRT results in a high overall response rate, with improved L-PFS for patients with a CR. The high observed rate of severe late toxicity requires further evaluation of the risks and benefits of an HDREBT boost.

Ruthenium-106 brachytherapy for choroidal melanoma without transpupillary thermotherapy: Similar efficacy with improved visual outcome.

PURPOSE: To evaluate efficacy and toxicity of two different protocols for eye-conserving treatment of patients with small to intermediate-sized choroidal melanomas; the current ruthenium-106 (Ru106) brachytherapy protocol and the preceding protocol of Ru106-brachytherapy with transpupillary thermotherapy (Ru106/TTT). METHODS AND MATERIALS: Long-term outcomes of 449 consecutive patients, of whom 196 (43.6%) treated using Ru106/TTT and 253 (56.3%) treated using Ru106, were compared in terms of local control, survival, eye preservation and visual outcome. RESULTS: Median follow-up was 82.8 months. Patients in the Ru106-group had smaller, less centrally located tumours and better pre-treatment visual acuity (VA). Five-year cumulative incidence of local failure was 11.2% for Ru106/TTT and 5.2% for Ru106, which was not statistically significant after correction for differences in baseline characteristics (hazard ratio for Ru106 = 0.57, p = 0.14). Cumulative incidence of distant metastases was 11.2 versus 6.2%, and cumulative incidence of cause-specific death was 22.4 versus 5.5% for Ru106/TTT and Ru106 respectively. Enucleation was performed in 9.2 versus 4.0% for Ru106/TTT versus Ru106; 5.1 versus 3.2% for local failure and 2.6 versus 0.8% for complications. At one year of follow-up, significantly more patients had lost useful vision (VA < 0.33) in the Ru106/TTT-group than in the Ru106-group (50.0 versus 24.5%). After two and three years, the differences decreased (54.6 versus 34.0% and 61.7 versus 45.8%, respectively) and lost statistical significance. CONCLUSIONS: Both the current Ru106 and the preceding Ru106/TTT-protocols provided excellent tumour control, cosmetic and functional eye preservation and vital prognosis. The Ru106-protocol yielded prolonged preservation of VA and should be regarded the current standard of treatment.

Multicentre treatment planning study of MRI-guided brachytherapy for cervical cancer: comparison between tandem-ovoid applicator users.

BACKGROUND AND PURPOSE: To compare MRI-guided treatment planning approaches between four centres that use tandem-ovoid applicators. MATERIAL AND METHODS: Four centres generated three treatment plans for four patients: standard, optimised intracavitary, and optimised intracavitary/interstitial. Prescribed D90 High-Risk CTV (HR-CTV) was 85 Gy EQD2 (external-beam radiotherapy and brachytherapy), while the D(2cc) OAR limit was 90 Gy EQD2 for bladder and 75 Gy EQD2 for rectum, sigmoid, and bowel, respectively. DVH-parameters, source loading patterns and spatial dose distributions of the three treatment plans were compared. RESULTS: The standard plans of the different centres were comparable with respect to the D90 HR-CTV, but differed in OAR doses. MRI-guided intracavitary optimisation resulted in organ sparing and smaller variation in DVH parameters between the centres. Adding interstitial needles led to target dose escalation while respecting the OAR constraints. However, substantial differences in relative weights of the applicator parts resulted in an increased variation in DVH parameters and locations of high dose regions. CONCLUSIONS: MRI-guided brachytherapy treatment planning optimisation provides the possibility to increase the dose to the HR-CTV and spare the OARs. Depending on the degree of conformity the centres make different choices in relative weighting of applicator parts, leading to different dose distributions.

Ruthenium plaque radiation therapy for iris and iridociliary melanomas.

PURPOSE: To determine the long-term effects of ruthenium-106 plaque radiation therapy for iris and iridociliary melanomas in terms of tumour regression and complications. METHODS: Between 1 November 1997 and 31 December 2007, 36 patients with an iris or iridociliary melanoma were treated with Ruthenium-106 (Ru-106) ophthalmic plaque radiation therapy. The median follow-up was 6.5 years with a range of 2-11 years. The mean tumour apex dose was 151.5 Gy. Main outcome measures were local tumour control and radiation-related ocular complications. RESULTS: The mean age of the patients at the time of treatment was 54 years (range 14-82). The tumours had a median largest basal dimension of 4.8 mm (range 3-11) and a prominence of 2.3 mm (range 0.8-5), with a median involvement of three clock hours (range 1-6). The tumours were confined to the iris in 14 patients (39%), extended into the anterior ciliary body in 12 (33%), while the anterior ciliary body tumour extended into the iris in ten patients (28%). Tumours regressed in all patients (100%) with a mean regression of 80% of the original tumour size at 7 years of follow-up. Radiation-related complications included corneal erosions on the first postoperative day in nine patients (25%), cataract in four of 11 patients free of cataract before treatment (36%) and postradiation glaucoma in one patient (3%). Visual acuity of 20/200 or worse was present in one of 20 patients (5%) at 6 years of follow-up. Local recurrences occurred in two patients (5%), 2 and 5 years after the radiation therapy respectively, and both underwent enucleation. Distant metastases occurred in one of these enucleated patients (3%) 2 years after treatment. CONCLUSION: Ru-106 plaque radiation therapy for iris and iridociliary melanoma resulted in good local tumour control and preservation of visual acuity with few and treatable side-effects.

Long-term outcomes of eye-conserving treatment with Ruthenium(106) brachytherapy for choroidal melanoma.

PURPOSE: To evaluate long-term outcomes of eye-conserving treatment using Ruthenium-106 plaque brachytherapy with or without transpupillary thermotherapy (TTT) for small to intermediate size choroidal melanomas. METHODS: Outcomes of 425 consecutive patients were analysed. The median basal tumour diameter was 10.9 mm (range 4.8-15.9 mm), and the median apical height 4.2 mm (range 1.2-9.3 mm). Brachytherapy doses ranged from 400 to 600Gy with TTT (86%), or from 600 to 800Gy without TTT (14%), specified at the scleral surface. Kaplan-Meier survival curves, log-rank tests and Cox regression analysis were used for analysis. RESULTS: Median follow-up was 50 months. Five-year actuarial local control was 96%. Five-year overall and metastases-free survival rates were 79.6% and 76.5%. Prognostic factors for metastasis-free survival were peripheral location (p=0.02) and smaller basal diameter (p<0.001). No dose effect relationships were found. Radiation side effects were frequent, with 2- and 5-year rates free of radiation complications of 60% and 35%. Five-year enucleation rate was 4.4% (10 for local recurrence, 7 for complications). Cosmetic and functional (visual acuity >0.10) eye preservation rates were 96% and 52% at 5 years. CONCLUSIONS: Ruthenium-106 brachytherapy for choroidal melanoma provides excellent rates of local control and eye preservation.

Probing the electronic structure and conformational flexibility of individual light-harvesting 3 complexes by optical single-molecule spectroscopy.

We present fluorescence-excitation spectra of individual light-harvesting 3 (LH3 or B800-820) complexes of Rhodopseudomonas acidophila at 1.2 K. The optical single-molecule studies were employed to investigate the electronic structure as well as the conformational flexibility of the individual pigment-protein complexes. The optical spectra resemble those of individual light-harvesting 2 (LH2) complexes, in agreement with the structural similarity of both types of complexes. Although variations among the LH3 spectra are large, there is a distinct difference in the spectral features of the 800 and 820 nm region that appears in all the complexes studied. In the B800 region 4-6 narrow bands are present whereas in the B820 region a limited number of relatively broad bands are observed. These observations can generally be interpreted in terms of localized excitations in the 800 nm region and delocalized excitations in the 820 nm region. The observed heterogeneous spectral behavior, especially in the B820 band, indicates that the B820 pigments of LH3 are sensitive to light-induced local conformational changes. It is suggested that a rotation of the C(3)-acetyl chain of a BChl a pigment bound to the beta-subunit of the light-harvesting complex is the origin of the conformational flexibility and affects the optical properties of the whole pigment-protein complex.

Conventional, conformal, and intensity-modulated radiation therapy treatment planning of external beam radiotherapy for cervical cancer: The impact of tumor regression.

PURPOSE: Investigating the impact of tumor regression on the dose within cervical tumors and surrounding organs, comparing conventional, conformal, and intensity-modulated radiotherapy (IMRT) and the need for repeated treatment planning during irradiation. METHODS AND MATERIALS: Fourteen patients with cervical cancer underwent magnetic resonance (MR) imaging before treatment and once during treatment, after about 30 Gy. Target volumes and critical organs were delineated. First conventional, conformal, and IMRT plans were generated. To evaluate the impact of tumor regression, we calculated dose-volume histograms for these plans, using the delineations of the intratreatment MR images. Second conformal and IMRT plans were made based on the delineations of the intratreatment MR images. First and second plans were compared. RESULTS: The average volume receiving 95% of the prescribed dose (43 Gy) by the conventional, conformal, and IMRT plans was, respectively, for the bowel 626 cc, 427 cc, and 232 cc; for the rectum 101 cc, 90 cc, and 60 cc; and for the bladder 89 cc, 70 cc, and 58 cc. The volumes of critical organs at this dose level were significantly reduced using IMRT compared with conventional and conformal planning (p < 0.02 in all cases). After having delivered about 30 Gy external beam radiation therapy, the primary gross tumor volumes decreased on average by 46% (range, 6.1-100%). The target volumes on the intratreatment MR images remained sufficiently covered by the 95% isodose. Second IMRT plans significantly diminished the treated bowel volume, if the primary gross tumor volumes decreased >30 cc. CONCLUSIONS: Intensity-modulated radiation therapy is superior in sparing of critical organs compared with conventional and conformal treatment, with adequate coverage of the target volumes. Intensity-modulated radiation therapy remains superior after 30 Gy external beam radiation therapy, despite tumor regression and internal organ motion. Repeated IMRT planning can improve the sparing of the bowel and rectum in patients with substantial tumor regression.

Single-molecule study of the electronic couplings in a circular array of molecules: light-harvesting-2 complex from Rhodospirillum molischianum.

Applying single-molecule spectroscopic techniques allowed us to determine the mutual angles between the transition-dipole moments associated with optical transitions of the eight bacteriochlorophyll a molecules which form the so-called B800 ring of the light-harvesting-2 complex from Rhodospirillum molischianum. The orientation of the transition-dipole moment is a sensitive probe for the strength of the local intermolecular interactions because of the well-defined arrangement of the individual molecules within the B800 ring. Our data reveal that the strength of the electronic coupling between individual molecules in the ring is subjected to spatial as well as temporal variations.

Spectroscopy on individual light-harvesting 1 complexes of Rhodopseudomonas acidophila.

In this paper the fluorescence-excitation spectra of individual LH1-RC complexes (Rhodopseudomonas acidophila) at 1.2 K are presented. All spectra show a limited number of broad bands with a characteristic polarization behavior, indicating that the excitations are delocalized over a large number of pigments. A significant variation in the number of bands, their bandwidths, and polarization behavior is observed. Only 30% of the spectra carry a clear signature of delocalized excited states of a circular structure of the pigments. The large spectral variety suggests that besides site heterogeneity also structural heterogeneity determines the optical spectrum of the individual LH1-RC complexes. Further research should reveal if such heterogeneity is a native property of the complex or induced during the experimental procedures.