Recommendations from gynaecological (GYN) GEC-ESTRO working group - ACROP: Target concept for image guided adaptive brachytherapy in primary vaginal cancer.

BACKGROUND AND AIM: External beam radiotherapy (EBRT) combined with brachytherapy has an essential role in the curative treatment of primary vaginal cancer. EBRT is associated with significant tumour shrinkage, making primary vaginal cancer suitable for image guided adaptive brachytherapy (IGABT). The aim of these recommendations is to introduce an adaptive target volume concept for IGABT of primary vaginal cancer. METHODS: In December 2013, a task group was initiated within GYN GEC-ESTRO with the purpose to introduce an IGABT target concept for primary vaginal cancer. All participants have broad experience in IGABT and vaginal cancer brachytherapy. The target concept was elaborated as consensus agreement based on an iterative process including target delineation and dose planning comparison, retrospective analysis of clinical data and expert opinions. RESULTS: Gynaecological examination and MR imaging are the modalities of choice for local tumour assessment. A specific template for standardised documentation with clinical drawings for vaginal cancer was developed. The adaptive target volume concept comprises different response-related target volumes. For EBRT these are related to the primary tumour and the lymph nodes, while for IGABT these are related to the primary tumour and are consisting of the residual gross tumour volume (GTV-Tres) and the high-, and intermediate risk clinical target volumes (CTV-THR, CTV-TIR). CONCLUSION: This target concept for IGABT of primary vaginal cancer defines adaptive target volumes for volumetric dose prescription and should improve comparability of different radiotherapy schedules of this rare disease. A prospective evaluation of the target volume concept within a multicentre study is planned.

Risk Factors for Pelvic Insufficiency Fractures in Locally Advanced Cervical Cancer Following Intensity Modulated Radiation Therapy.

PURPOSE: To investigate the incidence of and risk factors for pelvic insufficiency fracture (PIF) after definitive chemoradiation therapy for locally advanced cervical cancer (LACC). METHODS AND MATERIALS: We analyzed 101 patients with LACC treated from 2008-2014. Patients received weekly cisplatin and underwent external beam radiation therapy with 45 Gy in 25 fractions (node-negative patients) or 50 Gy in 25 fractions with a simultaneous integrated boost of 60 Gy in 30 fractions (node-positive patients). Pulsed dose rate magnetic resonance imaging guided adaptive brachytherapy was given in addition. Follow-up magnetic resonance imaging was performed routinely at 3 and 12 months after the end of treatment or based on clinical indication. PIF was defined as a fracture line with or without sclerotic changes in the pelvic bones. D50% and V55Gy were calculated for the os sacrum and jointly for the os ileum and pubis. Patient- and treatment-related factors including dose were analyzed for correlation with PIF. RESULTS: The median follow-up period was 25 months. The median age was 50 years. In 20 patients (20%), a median of 2 PIFs (range, 1-3 PIFs) were diagnosed; half were asymptomatic. The majority of the fractures were located in the sacrum (77%). Age was a significant risk factor (P<.001), and the incidence of PIF was 4% and 37% in patients aged ≤50 years and patients aged >50 years, respectively. Sacrum D50% was a significant risk factor in patients aged >50 years (P=.04), whereas V55Gy of the sacrum and V55Gy of the pelvic bones were insignificant (P=.33 and P=.18, respectively). A dose-effect curve for sacrum D50% in patients aged >50 years showed that reduction of sacrum D50% from 40 GyEQD2 to 35 GyEQD2 reduces PIF risk from 45% to 22%. CONCLUSIONS: PIF is common after treatment of LACC and is mainly seen in patients aged >50 years. Our data indicate that PIFs are not related to lymph node boosts but rather to dose and volume associated with irradiation of the elective pelvic target. Reducing the prescribed elective dose from 50 to 45 Gy may reduce the risk of PIF considerably.

Parecoxib is neuroprotective in spontaneously hypertensive rats after transient middle cerebral artery occlusion: a divided treatment response?

BACKGROUND: Anti-inflammatory treatment affects ischemic damage and neurogenesis in rodent models of cerebral ischemia. We investigated the potential benefit of COX-2 inhibition with parecoxib in spontaneously hypertensive rats (SHRs) subjected to transient middle cerebral artery occlusion (tMCAo). METHODS: Sixty-four male SHRs were randomized to 90 min of intraluminal tMCAo or sham surgery. Parecoxib (10 mg/kg) or isotonic saline was administered intraperitoneally (IP) during the procedure, and twice daily thereafter. Nineteen animals were euthanized after 24 hours, and each hemisphere was examined for mRNA expression of pro-inflammatory cytokines and COX enzymes by quantitative RT-PCR. Twenty-three tMCAo animals were studied with diffusion and T2 weighted MRI within the first 24 hours, and ten of the SHRs underwent follow-up MRI six days later. Thirty-three SHRs were given 5-bromo-2'-deoxy-uridine (BrdU) twice daily on Day 4 to 7 after tMCAo. Animals were euthanized on Day 8 and the brains were studied with free-floating immunohistochemistry for activated microglia (ED-1), hippocampal granule cell BrdU incorporation, and neuronal nuclei (NeuN). Infarct volume estimation was done using the 2D nucleator and Cavalieri principle on NeuN-stained coronal brain sections. The total number of BrdU+ cells in the dentate gyrus (DG) of the hippocampus was estimated using the optical fractionator. RESULTS: We found a significant reduction in infarct volume in parecoxib treated animals one week after tMCAo (p < 0.03). Cortical ADC values in the parecoxib group were markedly less increased on Day 8 (p < 0.01). Interestingly, the parecoxib treated rats were segregated into two subgroups, suggesting a responder vs. non-responder phenomenon. We found indications of mRNA up-regulation of IL-1beta, IL-6, TNF-alpha and COX-2, whereas COX-1 remained unaffected. Hippocampal granule cell BrdU incorporation was not affected by parecoxib treatment. Presence of ED-1+ activated microglia in the hippocampus was related to an increase in BrdU uptake in the DG. CONCLUSION: IP parecoxib administration during tMCAo was neuroprotective, as evidenced by a large reduction in mean infarct volume and a lower cortical ADC increment. Increased pro-inflammatory cytokine mRNA levels and hippocampal granule cell BrdU incorporation remained unaffected.

Single photon emission computed tomography (SPECT) and SPECT/low-dose computerized tomography did not increase sensitivity or specificity compared to planar bone scintigraphy for detection of bone metastases in advanced breast cancer.

PURPOSE: To evaluate and compare the diagnostic performance of whole-body planar bone scintigraphy (WBS), single photon emission computed tomography (SPECT), SPECT/low-dose computerized tomography (SPECT/ldCT) and SPECT/contrast enhanced diagnostic CT (SPECT/cdCT) in the staging of patients with advanced breast cancer. METHODS: Seventy-eight patients with recurrence of biopsy-proven breast cancer and suspicion of disseminated disease were investigated with WBS, SPECT, SPECT/ldCT, SPECT/cdCT and MRI performed on the same day in this prospective study. Images were separately analysed in a blinded fashion by radiologists and nuclear medicine physicians regarding the presence of pathological findings. MRI served as reference standard. RESULTS: According to reference standard, 38 of 73 patients had bone metastases. The sensitivity was 87%, 87%, 79%, and 84% and specificity 63%, 71%, 63% and 83% for WBS, SPECT, SPECT/ldCT and SPECT/cdCT. A significantly increased specificity of SPECT/cdCT compared to WBS and SPECT/ldCT was found, and other parameters did not differ significantly between modalities. Additional two patients had bone metastases solely located outside the MRI scan field and seven patients had soft tissue metastases, but no skeletal changes on MRI. CONCLUSION: WBS, SPECT and SPECT/ldCT were less sensitive than MRI and equally specific for the detection of bone metastases in patients with advanced breast cancer. Based on our findings, we suggest that initial staging include WBS, MRI of the spine and CT for soft tissue evaluation. Further studies may clarify the potential benefits of whole-body MRI and 18F-NaF PET/CT or 18F-FDG PET/CT.

Toward four-dimensional image-guided adaptive brachytherapy in locally recurrent endometrial cancer.

PURPOSE: To evaluate clinical outcome and feasibility of a four-dimensional image-guided adaptive brachytherapy concept in patients with locally recurrent endometrial cancer. METHODS AND MATERIALS: Forty-three patients with locally recurrent endometrial cancer were included. Treatment consisted of conformal external beam radiotherapy followed by a boost using pulsed-dose-rate brachytherapy (BT). Large tumors were treated with MRI-guided interstitial BT. Small tumors were treated with CT-guided intracavitary BT. The planning aim (total external beam radiotherapy and BT) for high-risk clinical target volume was D90 > 80 Gy, whereas constraints for organs at risk were D2cc ≤ 90 Gy for bladder and D2cc ≤ 70 Gy for rectum, sigmoid, and bowel in terms of equivalent dose in 2 Gy fractions. RESULTS: Median high-risk clinical target volume was 18 cm(3) (range, 0-91). D90 was 82 Gy (range, 77-88). D2cc to bladder, rectum, and sigmoid were 67 Gy (range, 50-81), 67 Gy (range, 51-77), and 55 Gy (range, 44-68), respectively. Median followup was 30 months (6-88). Two-year local control rate was 92% (standard error [SE], 5). Disease-free survival rate and overall survival rate was 59% (SE, 8) and 78% (SE, 7), respectively. Patients with low- to intermediate-risk for recurrence had a 2-year disease-free survival rate of 72% (SE, 9) compared with 42% (SE, 12) in patients with high risk for recurrence (p = 0.04). Late morbidity Grade 3 was recorded in 5 (12%) patients. CONCLUSIONS: Four-dimensional image-guided adaptive brachytherapy is feasible in locally recurrent endometrial cancer. Local control rate is good. Systemic control remains a problem in patients with high risk for recurrence.

Clinical feasibility of combined intracavitary/interstitial brachytherapy in locally advanced cervical cancer employing MRI with a tandem/ring applicator in situ and virtual preplanning of the interstitial component.

PURPOSE: To investigate the reproducibility of virtually planned needles, changes in DVH parameters and clinical feasibility of combined intracavitary/interstitial (IC/IS) pulsed dose rate brachytherapy (PDR-BT) for locally advanced cervical cancer based on 3D MRI preplanning. MATERIAL AND METHODS: Fifty-eight consecutively patients accrued in the EMBRACE study were included. Treatment was initiated with external beam radiotherapy and cisplatin. Three BT implants and MRI with the applicator in situ were performed in all patients, i.e. week 5 (BT0), week 6 (BT1) and week 7 (BT2) of the treatment. BT0 was only used for preplanning of subsequent implantations, whereas BT1 and BT2 comprised 2 equal sized fractions of PDR BT. RESULTS: Based on BT0, 24 patients (41%) were selected for a combined IC/IS implant at BT1 and BT2. Patients treated with IC/IS BT had significantly larger tumours compared with patients treated with IC BT only (p<0.03). Additional time in general anaesthesia for the IC/IS component was on average 16 min. The number of preplanned virtual needles was 5.3±2.7 compared to 5.3±2.9 and 5.4±3.0 needles implanted at BT1 and BT2, respectively (p=0.72). Planned needle implantation depth was 33±15 mm compared to 30±10 mm at BT1 and 29±11 mm at BT2 (p=0.04). In the 24 patients selected for IC/IS BT both the virtual IC/IS plan (BT0) and the actually delivered plan (BT1+BT2) significantly increased D90 and D100 for HR CTV (p<0.01) and reduced D2cc for sigmoid (p<0.01) and bowel (p=0.04) compared to the optimised IC preplan (BT0). IC/IS BT was only associated with minor morbidity, which was resolved at a 3-month follow up. CONCLUSION: Combined IC/IS BT based on full 3D MRI preplanning is clinically feasible. The virtual preplanned needle positions are reproducible at subsequent BT applications leading to significantly improved DVH parameters and a clinically feasible and fast implant procedure.

[Ovarian metastases from ventricular cancer diagnosed using diffusion-weighted 3T magnetic resonance imaging]. / Ovariemetastaser fra ventrikelcancer diagnosticeret med diffusionsvægtet 3T-magnetisk resonans-skanning.

A 58-year-old female with a non-resectable ventricular cancer was followed by conventional 3.0 T magnetic resonance imaging (MRI) of the pelvis and abdomen including diffusion-weighted MR imaging (DWI). B-values were 0 and 1,000 seconds/mm2, and the apparent diffusion coefficient was calculated. At one control, ovarian metastases were detected by DWI, but did not show on conventional T2 and T1. The ovarian metastases were surgically removed and histologically verified - even though metastasectomy is controversial. In conclusion, DWI at 3.0 T is feasible and can improve the detection of metastatic disease compared with conventional MRI.

Image and laparoscopic guided interstitial brachytherapy for locally advanced primary or recurrent gynaecological cancer using the adaptive GEC ESTRO target concept.

PURPOSE: To retrospectively assess treatment outcome of image and laparoscopic guided interstitial pulsed dose rate brachytherapy (PDR-BT) for locally advanced gynaecological cancer using the adaptive GEC ESTRO target concept. MATERIALS AND METHODS: Between June 2005 and December 2010, 28 consecutive patients were treated for locally advanced primary vaginal (nine), recurrent endometrial (12) or recurrent cervical cancer (seven) with combined external beam radiotherapy (EBRT) and interstitial PDR-BT. Treatment was initiated with whole pelvic EBRT to a median dose of 45 Gy followed by PDR-BT using the Martinez Universal Perineal Interstitial Template (MUPIT). All implants were virtually preplanned using MRI of the pelvis with a dummy MUPIT in situ. The GEC ESTRO high risk clinical target volume (HR CTV), intermediate risk clinical target volume (IR CTV) and the organs at risk (OAR) were contoured and a preplan for implantation was generated (BrachyVision, Varian). The subsequent implantation was performed under laparoscopic visualisation. Final contouring and treatment planning were done using a post-implant CT. Planning aim of PDR-BT was to deliver 30 Gy in 50 hourly pulses to HR CTV. Manual dose optimisation was performed with the aim of reaching a D90>80 Gy in the HR CTV calculated as the total biologically equivalent to 2 Gy fractions of EBRT and BT (EQD2). Dose to the OAR were evaluated using dose volume constraints for D(2cc) of 90 Gy for bladder and 70 Gy for rectum and sigmoid. RESULTS: For HR CTV the median volume was 26 cm(3) (7-91 cm(3)). Coverage of the HR CTV was 97% (90-100%) and D90 was 82 Gy (77-88 Gy). The D(2cc) for bladder, rectum, and sigmoid were 65 Gy (47-81 Gy), 61 Gy (50-77 Gy), and 52 Gy (44-68 Gy), respectively. Median follow up was 18 months (6-61 months). The actuarial 2 years local control rate was 92% (SE 5), while disease-free survival and overall survival were 59% (SE 11) and 74%, respectively (SE 10). No complications to the laparoscopic guided implantation were encountered. Late grade 2 (CTC v 3.0) complications were recorded in nine (32%) patients. One patient had a grade 3 vaginal complication. No grade 4-5 complications have been recorded so far. CONCLUSION: Image and laparoscopic guided interstitial PDR-BT using the GEC ESTRO target concept is applicable for locally advanced primary vaginal or recurrent endometrial and cervical cancer resulting in an excellent local control rate and limited morbidity.

From point A to the sculpted pear: MR image guidance significantly improves tumour dose and sparing of organs at risk in brachytherapy of cervical cancer.

BACKGROUND AND PURPOSE: Brachytherapy in locally advanced cervical cancer is still widely based on 2D standard dose planning, although 3D image guidance is available. The purpose of this study was to compare point doses to 3D dose volume parameters for tumour and organs at risk (OARs), and to evaluate the improvement of dose parameters with MR image guided adaptive brachytherapy (IGABT). MATERIAL AND METHODS: MRI-based IGABT was performed in 72 consecutive patients. HR-CTV, IR-CTV, bladder, rectum and sigmoid were contoured according to GEC-ESTRO recommendations. BT standard dose planning was compared to MRI-based dose optimisation. RESULTS: HR-CTV dose (D90) was highly variable in standard plans with point A dose prescription. In small tumours (<31 cc) HR-CTV was well covered by standard plans in 94% of patients, while OAR constraints were exceeded in 72% of patients. Optimisation decreased violation of OAR constraints to only 6% of patients while maintaining excellent target coverage. In large tumours (>31 cc) the dose optimisation improved the HR-CTV D90 by a mean of 7 Gy resulting in full coverage in 72% of patients as compared to 25% for standard plans, even while reducing violation of OAR constraints. CONCLUSION: Point A dose is a poor surrogate of HR-CTV dose, and the use of 3D image-based dose planning is encouraged. MRI-based IGABT significantly improves target coverage and OAR dose.

Magnetic resonance imaging determination of extraocular eye muscle volume in patients with thyroid-associated ophthalmopathy and proptosis.

PURPOSE: Recent studies concerning the association between extraocular muscle (EOM) enlargement in thyroid-associated ophthalmopathy (TAO) and immunological and clinical activity have not been conclusive, probably due to a lack of uniform imaging methods (ultrasonography, computer tomography [CT] or magnetic resonance imaging [MRI]) and difficulties in the determination of EOM volume. The aim of the present study was to examine the significance of EOM enlargement as established by MRI-based volume determination, with reference to proptosis and the presence of autoantibodies, clinical activity and the duration of active disease. METHODS: We determined EOM volume using MRI in 15 patients concomitantly with the determination of TSH, thyroid hormones, thyrotropin receptor antibodies (TRab) thyroid peroxidase antibodies (TPOab) and clinical activity score (CAS) at entry. We also established the duration until cessation of clinically active TAO. RESULTS: All 15 patients had bilateral EOM enlargement, but swelling of orbital fatty tissue was absent. Significant correlations between thickness of musculi rectales and proptosis, values of TRab, CAS, and duration of activity were observed. CONCLUSION: Our results support the hypothesis of a role of thyrotropin receptor antibodies in the pathogenesis of TAO and suggest that only EOM enlargement is responsible for proptosis in TAO.

Ischemic injury detected by diffusion imaging 11 minutes after stroke.

A 78-year-old woman suffered a stroke inside a magnetic resonance scanner while being imaged because of a brief transient ischemic attack 2 hours earlier. Diffusion-weighted images obtained 11 minutes after stroke showed tissue injury not found on initial images. The data show early, abrupt diffusion changes in hypoperfused tissue, adding to our understanding of the progression of microstructural abnormalities in the hyperacute phase of stroke.

Final infarct size after acute stroke: prediction with flow heterogeneity.

PURPOSE: To compare acute measurements of flow heterogeneity (FH) and mean transit time (MTT) with follow-up data to determine which method yields better predictive measures of final infarct volumes. MATERIALS AND METHODS: Twenty-three patients with symptoms of stroke underwent magnetic resonance (MR) imaging during the acute stage, and the tissue at risk was estimated from MTT maps and maps generated by means of detecting abnormal FH. Final infarct volumes were calculated from T2-weighted follow-up MR image measurement. The Wilcoxon signed rank test was performed to compare the two predictive maps (MTT and FH) with T2-weighted follow-up maps. RESULTS: Eleven (48%) patients experienced infarct growth. Both the MTT and the FH maps enabled prediction of 10 of these cases. There were five false-positive cases with MTT measurement but three with FH measurement. In terms of predicting final infarct volumes, the final infarct size on the MTT maps was overestimated by 75%. The final infarct size on the FH maps also was overestimated, but by only 15%. MTT map measurements were significantly different from follow-up MR image measurements (P =.005), but FH map measurements were not (P =.059). CONCLUSION: FH maps may enable more precise prediction of final infarct volume in stroke patients.

Time evolution of cerebral perfusion and apparent diffusion coefficient measured by magnetic resonance imaging in a porcine stroke model.

PURPOSE: To demonstrate the feasibility of sequential diffusion-weighted (DW) and perfusion-weighted (PW) magnetic resonance imaging (MRI) of a recently developed porcine stroke model and to evaluate the evolution of cerebral perfusion and the apparent diffusion coefficient (ADC) over time. Materials and Methods In five pigs, DW imaging (DWI) and PW imaging (PWI) was carried out for 7 hours after stroke onset, starting 1 hour after middle cerebral artery occlusion (MCAO). RESULTS: The DWI lesion volume increased significantly with time, and final DWI lesion volume correlated well with lesion area on histological sections (r = 0.910). T2 changes could be recognized 3 hours after stroke onset. At 1 hour the ADC ratio (ischemic lesion/contralateral side) was reduced to 0.81 in the caudate-putamen and to 0.87 in the cortex, and the cerebral blood flow ratio was reduced to 0.40 in the caudate-putamen and 0.51 in the cortex. CONCLUSION: The level of flow reduction in the caudate-putamen and the cortex after 1 hour is in good correlation with human thresholds of irreversible and reversible ischemic damage, and accordingly, this model might be a model for mechanisms of infarct evolution and therapeutic intervention.