PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer.

BACKGROUND: Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics. PRIMARY OBJECTIVES: To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs. TRIAL DESIGN: A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm). MAJOR INCLUSION/EXCLUSION CRITERIA: Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1). ENDPOINTS: The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs. SAMPLE SIZE: 500 eligible and evaluable patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).

Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.

OBJECTIVE: To evaluate the efficacy and toxicity of primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer and to identify predictors of treatment failure and toxicity. METHODS: Retrospective analysis of 155 stage IB-IVA cervical cancer patients treated from 2008 to 2016 with chemoradiation and image-guided adaptive brachytherapy. Treatment consisted of external beam radiotherapy (45 - 48.6 Gy in 1.8 - 2 Gy fractions) with concurrent weekly cisplatin (40 mg/m2, 5 - 6 cycles) and image-guided adaptive brachytherapy (3-4 × 7 Gy high dose rate) using intracavitary or combined intracavitary-interstitial techniques according to GEC-ESTRO (Group Européen de Curiethérapie and the European Society for Radiotherapy and Oncology) recommendations. Incidences of all outcomes were calculated using Kaplan-Meier's methodology. Risk factors for treatment failure and toxicity were identified using Cox's proportional hazards model and the Kruskal-Wallis H-test respectively. RESULTS: Median follow-up was 57 months. Five-year local control was 90.4 %. Five-year para-aortic lymph node metastasis-free and distant metastasis-free survival were 85.3 % and 70.2 % respectively. Tumor size and lymph node metastasis were independent risk factors for treatment failure. Cumulative incidences of severe late bladder, rectal, bowel, and vaginal toxicity were 0.8%, 3.3%, 3.6%, and 1.4% respectively at 5 years of follow-up. Combined intracavitary-interstitial brachytherapy techniques were associated with less vaginal morbidity. CONCLUSIONS: Primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer is a highly effective local and loco-regional treatment. However, survival is compromised by the occurrence of distant metastasis. Patients with large tumors and nodal involvement at diagnosis are at increased risk and may benefit from intensified treatment. Severe late gastrointestinal and urogenital toxicity is limited and may be further reduced by increasing conformity, using combined intracavitary-interstitial techniques and lowering doses to organs at risk.

Optimal source position for irradiation of coronary bifurcations in endovascular brachytherapy with catheter based beta or iridium-192 sources.

BACKGROUND AND PURPOSE: Intracoronary brachytherapy after percutaneous transluminal coronary angioplasty (PTCA) is usually performed with catheter-based treatment techniques in a straight vessel segment. There is a growing interest for treatment of bifurcations, which requires consecutive positioning of the source in main vessel and side branch. MATERIALS AND METHODS: In-house developed software (IC-BT doseplan) is used to explore the optimal positioning of the source in modelled bifurcations with different shape for the source types available in our hospital, i.e. (90)Sr/(90)Y, (32)P and (192)Ir. The results were summarised in look-up tables. The usefulness of these look-up tables was tested on various clinical examples. RESULTS: Tabulated results for the modelled bifurcations yield an estimation of the distance between the sources (gap width) in relation to the geometry and source type: (90)Sr/(90)Y gap range 3-8.5 mm, (32)P gap range 2-7 mm and (192)Ir gap range 3.5-8 mm. The average dose relative to 2 mm from the source axis is: (90)Sr/(90)Y, (mean+/-SD) 120+/-40%; (32)P, 125+/-50% and (192)Ir, 120+/-22%. The look-up tables also provide the coarse location and value of maximum and minimum dose: (90)Sr/(90)Y, 220-60%, (32)P, 230-55% and (192)Ir, 170-85%. It appeared that the look-up tables provide a good approximation of the optimal gap width in the clinical examples. CONCLUSIONS: Tabulated optimal gap widths are very useful for quick estimation of the required gap width for a given bifurcation and source type, in case the prescribed dose in both vessels is the same. In unfavourable geometries there is a risk of local underdosage. Individual treatment planning using a program such as IC-BT doseplan is then recommended.

High dose rate brachytherapy for the palliation of malignant dysphagia.

BACKGROUND AND PURPOSE: High dose rate (HDR) brachytherapy is a commonly used palliative treatment for esophageal carcinoma. We evaluated the outcome of HDR brachytherapy in patients with malignant dysphagia. MATERIAL AND METHODS: A retrospective analysis over a 10-year period was performed of 149 patients treated with HDR brachytherapy, administered in one or two sessions, at a median dose of 15Gy. Patients were evaluated for functional outcome, complications, recurrent dysphagia, and survival. RESULTS: At 6 weeks after HDR brachytherapy, dysphagia scores had improved from a median of 3 to 2 (n=104; P<0.001), however, dysphagia had not improved in 51 (49%) patients. Procedure-related complications occurred in seven (5%) patients. Late complications, including fistula formation or bleeding, occurred in 11 (7%) patients. Twelve (8%) patients experienced minor retrosternal pain. Median survival of the patients was 160 days with a 1-year survival rate of 15%. Procedure-related mortality was 2%. At follow-up, 55 (37%) patients experienced recurrent dysphagia. In 34 (23%) patients a metal stent was placed to relieve persistent or recurrent dysphagia. CONCLUSION: HDR brachytherapy is a moderately effective treatment for the palliation of malignant dysphagia. The incidence of early major complications is low, however, persistent and recurrent dysphagia occur frequently, and require often additional treatment.

Inaccuracy in manual multisegmental irradiation in coronary arteries.

PURPOSE: Retrospective evaluation of the accuracy of manual multisegmental irradiation with a source train for irradiation of long (re)stenotic lesions in coronary arteries, following percutaneous transluminal coronary angioplasty (PTCA). MATERIAL AND METHODS: Thirty-six patients were treated with intracoronary irradiation following PTCA with manual multisegmental irradiation. These patients were included in the multicenter, multinational 'European Surveillance Registry with the Novoste Beta-Cath system' (RENO). In all 36 patients the target length (i.e. PTCA length plus 5-mm margin at each side) was too long for the available source train lengths (30 and 40 mm). In 33 patients the radiation delivery catheter was manually positioned twice and in three patients three times in series, trying to avoid any gap or overlap. The total number of junctions was 39. Following a successful PTCA procedure the site of angioplasty was irradiated using the Novoste Beta-Cath afterloader with a 5-F non-centered catheter which accommodates the sealed beta-emitting (90)Sr/(90)Y source train or dummy source train. Radiation was delivered first to the distal part of the target length. Fluoroscopic images of this source position were stored in the computer memory. For irradiation of the proximal part of the target length, the delivery catheter had to be retracted over a distance equal to the source length used for the distal part. This was done by a continuous overlay video loop with ECG-gated replay of the image stored in the computer memory. The dummy source was used to position the delivery catheter so that the junction between both source positions was as precise as possible. Measurements of gap or overlap between the source positions were performed retrospectively on printed images. Doses were calculated, in accordance with the Novoste study protocol, at a distance of 2 mm from the source axis (=dose prescription distance) in several points along the irradiated length. RESULTS: Interventional or PTCA length varied between 33 and 95 mm. The lesion sites were in the left anterior descending artery, (n=6), right coronary artery (n=20), left circumflex artery (n=6) and one vein graft. The administered radiation dose was determined by the vessel diameter and the presence of a stent. This dose, prescribed at a distance of 2 mm from the source axis, varied between 16 and 22 Gy. No gap or overlap was seen between the two source trains in only two out of 39 cases. In 16 cases there was a gap ranging between 0.6 and 9.6 mm and 18 cases showed an overlap of 0.5-14.4 mm. In three patients the measurement was not possible. In case of a gap the minimal dose calculated at 2 mm from the source axis varies between 0 and 87% of the prescribed dose, depending on the distance between both sources. In case of overlap the maximal dose varies between 110 and 200% of the prescribed dose at 2 mm from the source axis. CONCLUSIONS: The results show the inaccuracy of manual multisegmental irradiation using a source train in coronary arteries, causing unacceptable dose inhomogeneities at a distance of 2 mm from the source axis at the junction between both source positions. Moreover, a perfect junction will never be possible due to movement of the non-centered radiation delivery catheter in the vessel lumen, as applied in this study. Manual multisegmental irradiation is therefore not recommended. Using longer line sources or source trains or preferably an automated stepping source is a more reliable and safer technique for treatment of long lesions.