In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of ...cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.
A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).
In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).
Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved.
This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).
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Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target ...concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up.
In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed.
At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported.
Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Summary Introduction Tongue metastasis of renal cell carcinoma (RCC) is rare. Treatment is hindered by the proximity of anatomic structures involved in swallowing, speech and mastication. It is, ...moreover, radioresistant. Case report We report a case of inaugural isolated tongue metastasis, where biopsy redirected diagnosis to RCC. To avoid potentially mutilating excision in a metastatic disease of poor prognosis, treatment was local, consisting in interstitial brachytherapy, enabling a high dose (65 Gy) to be delivered. Despite initially complete response, recurrence at 10.5 months required salvage surgery. Discussion and conclusion Brachytherapy allowed a higher dose to be delivered than with external beam radiation therapy, previously reported for similar cases. This dose, which can usually be expected to ensure local control in 90% of squamous cell carcinomas of the tongue, obtained 10 months’ response, insufficient to avoid salvage surgery.
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Image-guided Adaptive Radiotherapy in Cervical Cancer Tan MBBS, MRCP, FRCR, MD, Li Tee; Tanderup PhD, Kari; Kirisits PhD, Christian ...
Seminars in radiation oncology,
July 2019, 2019-07-00, 20190701, Volume:
29, Issue:
3
Journal Article
Peer reviewed
This paper reviews the conceptual, methodological, and technical innovations underpinning strategies for adaptive target volume selection and risk-adapted dose prescription in cervical cancer. An ...adaptive target volume concept has been developed which reflects tumor shrinkage at the end of initial chemo-radiation, which serves for an image-guided boost delivered through brachytherapy, with a risk-adapted dose prescription to different gross tumor- and clinical target volumes defined at diagnosis and after 40-50Gy external beam radiotherapy, and adaptation of the treatment technique according to the topography of the tumor after response and adjacent organs at risk. Clinical results of these innovations are presented based on prospective and retrospective multi-center trials (IntErnational study on MRI-based BRachytherapy in locally Advanced CErvical cancer EMBRACE, retroEMBRACE) with large patient cohorts (n = 1416, n = 731). The potential benefit of applying these strategies and using a specific multi-parametric dose prescription protocol are explored (EMBRACE-II) and overall current and future research strategies are outlined. The challenges of dissemination and implementation of these complex new techniques into clinical practice are discussed.
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The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and ...radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.
Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for
exonuclease domain were done to classify tumors as p53 abnormal (p53abn),
ultramutated (
mut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis.
Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%),
mut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for
mut EC, 72% for MMRd EC, and 74% for NSMP EC (
< .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% (
= .019); 100% versus 97% for patients with
mut EC (
= .637); 68% versus 76% (
= .428) for MMRd EC; and 80% versus 68% (
= .243) for NSMP EC.
Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with
mut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.
To report the application of the global risk analysis (GRA) in the pulsed-dose rate (PDR) brachytherapy workflow.
Analyses were led by a multidisciplinary working group established within the unit ...with the guidance of a quality engineer. First, a mapping of hazardous situations was developed as a result of interactions between the patient workflow for a treatment using PDR brachytherapy split into 51 sub-phases with a comprehensive list of the hazards that he/she faces (44). Interactions, when relevant, were sorted by level of priority: to be treated immediately, secondarily (the group is not entitled to treat the situation), or later (safe situation). Secondly, for each high priority dangerous situation, scenarios were developed to anticipate their potential consequences. Criticality was assessed, using likelihood and severity scales and a matrix, which allocated risks into categories: acceptable (C1), tolerable under control (C2) and unacceptable (C3). Then, corrective actions were proposed and planned when relevant, after assessment of their feasibility with a scale of effort. Finally, the criticality of the scenarios was reevaluated, taking into account the implementation of these actions, leading to a residual risk mapping, which could trigger additional proposals of actions.
Two thousand one hundred and eighty-four potential interactions between the list of hazards and the workflow were analyzed. Mapping of dangerous situations identified 213 relevant interactions, from which 61 were considered with high priority. One hundred and twenty-six scenarios were generated: 68 with a low criticality (74.3%), 58 with an intermediate score (25.7%). No scenario with the highest criticality was individualized. Twenty-one corrective actions were planned. Mapping of residual risk resulted in the disappearance of most C2 risks, leaving 5 C2 scenarios (4%), for which four monitoring indicators were implemented in addition to the corrected actions decided on.
The implementation of the GRA appeared feasible, and led to implement 21 corrective actions, based on scenarios and not on incidents.
Rapporter l’expérience et les résultats de l’application de l’analyse globale des risques en curiethérapie de débit pulsé.
Les analyses ont été menées par un groupe de travail pluridisciplinaire mis en place au sein de l’unité de curiethérapie et encadré par un ingénieur détaché par la direction qualité de l’établissement. Tout d’abord, une cartographie des situations dangereuses a été élaborée, correspondant aux interactions entre le circuit du patient dont le traitement est une curiethérapie de débit pulsé, divisé en 51 sous-phases, et une liste exhaustive des risques auxquels il fait face (44). Ces interactions, quand jugées pertinentes, ont été classés par niveaux de priorité : à traiter immédiatement, secondairement (le groupe n’est pas apte à traiter de la situation), ou plus tard (situation sécurisée). Dans un second temps, pour chaque situation dangereuse prioritaire, des scénarii ont été élaborés afin d’anticiper leurs conséquences potentielles. Leur criticité a été évaluée en utilisant des échelles de probabilité et de gravité et une matrice a permis de classer ces risques en trois catégories : acceptables (C1), tolérables sous contrôle (C2) et inacceptables (C3). Des mesures correctives ont ensuite été proposées par le groupe et planifiées quand elles étaient pertinentes, après évaluation de leur faisabilité à l’échelle de l’effort. Enfin, la criticité des scénarii a été réévaluée, prenant en compte la mise en œuvre de ces actions, conduisant à une cartographie des risques résiduels. Cette dernière pouvait justifier de nouvelles propositions d’actions si nécessaire.
Deux mille cent quatre-vingt-quatre interactions potentielles entre la liste des risques et le circuit patient ont été analysées. La cartographie des situations dangereuses a permis d’identifier 213 interactions pertinentes, dont 61 ont été considérées prioritaire. Cent vingt-six scénarii ont été générés : 68 avec une criticité faible (74,3 %) et 58 avec un score intermédiaire (25,7 %). Aucun scénario de criticité inacceptable n’a été individualisé. Vingt et un des mesures correctives ont été planifiées. L’analyse de la cartographie des risques résiduels a montré la disparition de la plupart des risques classés C2, laissant cinq scénarii de criticité intermédiaire (4 %), pour lesquels quatre indicateurs de surveillance ont été mis en place.
La mise en œuvre de l’analyse globale des risques est apparue réalisable, et a conduit à la mise en œuvre de 21 mesures correctives, basées sur des scénarii et non sur les incidents.
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To investigate the expression of a new fibrogenic cytokine the connective tissue growth factor (CTGF) in intestinal radiation fibrosis and to characterize the mesenchymal cell subtypes involved in ...CTGF synthesis and collagen deposition.
Sixteen patients with radiation enteritis that occurred after radiotherapy for pelvic malignancies and 6 with histologically normal bowel entered the study. Immunohistochemistry, Western blot analysis, and real-time reverse transcriptase–polymerase chain reaction were performed to study CTGF expression, along with other known markers of radiation fibrosis: the pro-fibrogenic cytokine transforming growth factor (TGF)-β1 and phenotypic markers of the fibroblast differentiation the α-sm actin (A), vimentin (V), and desmin (D). Finally, the collagen accumulation was measured by Sirius red staining and colorimetric assay.
Radiation enteritis was characterized by increased collagen content within the intestinal wall. CTGF immunoreactivity, protein, and mRNA level were increased in radiation enteritis compared with the healthy bowel. On the contrary, no increase of the TGF-β1 mRNA level was observed in radiation enteritis compared with healthy bowel, and the level of TGF-β protein was slightly increased in radiation enteritis. A co-localization of CTGF immunoreactivity and collagen deposition was found in the extracellular matrix and subtypes of activated mesenchymal cells with a fibroblast phenotype (V
+/D
−/A
−) and myofibroblast phenotype (V
+/D
−/+/A
+).
The increased level of CTGF protein and mRNA associated with the accumulation of fibroblasts/myofibroblasts and collagen deposition were parts of the fibrogenic signals involved in the persistence of late intestinal radiation fibrosis.
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The end of the production of 192 iridium wires terminates low dose rate brachytherapy and requires to move towards pulsed-dose rate or high-dose rate brachytherapy. In the case of gynecological ...cancers, technical alternatives exist, and many teams have already taken the step of pulsed-dose rate for scientific reasons. Using a projector source is indeed a prerequisite for 3D brachytherapy, which gradually installs as a standard treatment in the treatment of cervical cancers. For other centers, this change implies beyond investments in equipment and training, organizational consequences to ensure quality.
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To report the results of a conservative multimodal approach in girls with nonmetastatic rhabdomyosarcoma (RMS) of the genital tract, treated in International Society of Pediatric Oncology (SIOP) ...Malignant Mesenchymal Tumors 84 and 89 protocols.
From 1984 to 1994, 38 girls with RMS of the genital tract (vulva, vagina, uterus) were treated in SIOP protocols. With the exception of patients with rare small tumors, which were resected at the start of the studies, all patients received initial chemotherapy (CHT) (ifosfamide, vincristine, and actinomycin D). Local treatment including surgery, brachytherapy (BT), and external-beam radiotherapy (ERT) was given only to girls who did not achieve complete remission (CR) with CHT or who subsequently relapsed.
The primary tumor originated in the vulva or vagina in 27 girls and in the uterus in 11. The overall survival rate (+/- SE) was 91% +/- 6% at 5 years, and the event-free survival rate was 78% +/- 7%. At a median follow-up of 5 years, 30 girls were alive and in first CR and five were alive and in second CR. Four patients treated with complete resection of the tumor at diagnosis received less CHT. Thirteen patients were treated with CHT alone. In 17 patients, local treatment was necessary to achieve complete local control, for a residual mass after initial CHT (10 patients), for viable tumor on biopsy (three patients), or for local relapse (four patients). The local treatment used was radiotherapy (RT) (ERT in three patients, BT in seven), radical surgery with uterine ablation (three patients), RT and radical surgery (three patients), and conservative surgery with RT (one patient).
Girls with nonmetastatic RMS of the genital tract have an excellent prognosis. We found no difference in outcome between uterine and vulvovaginal RMS. Local treatment does not seem necessary in patients who have a complete response to CHT. When a local treatment is needed, BT may be an alternative to radical surgery or ERT.
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