Isabelle Dumas

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy.

Image-guided brachytherapy in cervical cancer is increasingly replacing X-ray based dose planning. In image-guided brachytherapy the geometry of the applicator is extracted from the patient 3D images and introduced into the treatment planning system; a process referred to as applicator reconstruction. Due to the steep brachytherapy dose gradients, reconstruction errors can lead to major dose deviations in target and organs at risk. Appropriate applicator commissioning and reconstruction methods must be implemented in order to minimise uncertainties and to avoid accidental errors. Applicator commissioning verifies the location of source positions in relation to the applicator by using auto-radiography and imaging. Sectional imaging can be utilised in the process, with CT imaging being the optimal modality. The results from the commissioning process can be stored as library applicators. The importance of proper commissioning is underlined by the fact that errors in library files result in systematic errors for clinical treatment plans. While the source channel is well visualised in CT images, applicator reconstruction is more challenging when using MR images. Availability of commercial dummy sources for MRI is limited, and image artifacts may occur with titanium applicators. The choice of MR sequence is essential for optimal visualisation of the applicator. Para-transverse imaging (oriented according to the applicator) with small slice thickness (< or =5 mm) is recommended or alternatively 3D MR sequences with isotropic voxel sizes. Preferably, contouring and reconstruction should be performed in the same image series in order to avoid fusion uncertainties. Clear and correct strategies for the applicator reconstruction will ensure that reconstruction uncertainties have limited impact on the delivered dose. Under well-controlled circumstances the reconstruction uncertainties are in general smaller than other brachytherapy uncertainties such as contouring and organ movement.

PHYSICS CONTRIBUTIONS AND CLINICAL OUTCOME WITH 3D-MRI-BASED PULSED-DOSE-RATE INTRACAVITARY BRACHYTHERAPY IN CERVICAL CANCER PATIENTS

PURPOSE To assess the physics contributions and clinical outcome with three-dimensional magnetic resonance imaging-guided pulsed-dose-rate (PDR) intracavitary brachytherapy in cervical cancer patients. METHODS AND MATERIALS The data from 45 patients with primary locally advanced cervical carcinoma were analyzed. The median tumor cervical volume was 64.0 cm(3) (range, 3-178). Of the 45 patients, 24 (53%) had histologic and/or radiologic pelvic involvement. After pelvic with or without para-aortic concomitant chemoradiotherapy, a PDR brachytherapy boost was delivered to a three-dimensional magnetic resonance imaging-based clinical target volume, taking into account the dose-volume constraints for critical organs and optimization of the target volume coverage. RESULTS At a median follow-up of 26 months (range, 9-47), the 2-year overall survival and disease-free survival rate was 78% and 73%, respectively. At the last follow-up visit, the disease of all patients remained locally controlled. Adding external beam radiotherapy and PDR using the equivalent dose in 2-Gy fractions model, the median dose received by 100% and 90% of the target was 54.4 Gy(alpha/beta10) and 63.5 Gy(alpha/beta10) for the intermediate-risk clinical target volume and 61.6 Gy(alpha/beta10) and 74.9 Gy(alpha/beta10) for the high-risk clinical target volume, respectively. Of the 45 patients, 23 and 2 developed acute Grade 1-2 and Grade 3 complications, respectively; 21 patients presented with delayed Grade 1-2 complications. One other patient presented with Grade 3 vesicovaginal fistula. No Grade 4 or greater complications, whether acute or delayed, were observed. CONCLUSION Magnetic resonance imaging-guided PDR brachytherapy with optimization integrating the limits of tolerance to critical organs allows for excellent local control rates. Moreover, the present results have confirmed that the ability to optimize dwell times can contribute to an improvement in local control rates with a low level of late side effects.

LONG-TERM RESULTS OF BRACHYTHERAPY FOR CARCINOMA OF THE PENIS CONFINED TO THE GLANS (N- OR NX)

PURPOSE To analyze the results of exclusive interstitial low-dose-rate brachytherapy (BT) for squamous cell carcinoma (SCC) of the penis, strictly confined to the glans. METHODS AND MATERIALS A total of 144 patients with SSC of the glans penis were treated with BT. Inguinal nodal dissection was performed in 19% of patients (all N-). After circumcision, BT was performed using the hypodermic needle technique. Median iridium length per patients was 24 cm (range, 4-108) and median dose was 65 Gy (range, 37-75). Median treated volume was 22 cm(3) (range, 5-110) and median reference isodose rate was 0.4 Gy/h (range, 0.2-1.2). RESULTS Median follow-up was 5.7 years (range, 0.5-29). The 10-year penile recurrence, inguinal lymph node recurrence, and inguinal nodal metastasis rates were: 20% (CI 95%, 11-29), 11% (CI 95%, 5-17), and 6% (CI 95%, 2-10), respectively. After salvage treatment, 86% patients with local failure were in a complete remission at last follow-up. The 10-year probability of avoiding penile surgery (for complication or local recurrence) was 72% (CI 95%, 62-82). The 10-year cancer-specific survival rate was 92% (CI 95%, 87-97). Diameter of tumor significantly increased the risk of recurrence (p = 0.02). The 10-year painful ulceration and stenosis risk rates were: 26% (CI 95%, 17-35) and 29% (CI 95%, 18-40), respectively. Seven patients required excision for necrosis. Treated volume and reference isodose rate significantly increased the risk of complications. CONCLUSION BT is an effective conservative treatment for SCC confined to the glans. Salvage local treatment is effective. Dose rate should be limited to decrease toxicity.

Inter-observer comparison of target delineation for MRI-assisted cervical cancer brachytherapy: Application of the GYN GEC-ESTRO recommendations

BACKGROUND AND PURPOSE To investigate the inter-observer variation of target contouring when using the GYN GEC-ESTRO recommendations for MR image-guided brachytherapy (IGBT) for cervical cancer. MATERIALS AND METHODS Nineteen cervical cancer patients, treated by radiotherapy at the Institut Gustave Roussy (IGR) in France (n=9) or at the Medical University of Vienna (AKH) in Austria (n=10) were included in this study. IGBT was used for all patients. Two radiation oncologists, one from IGR and the other from AKH, outlined the target volumes on MRI at the time of brachytherapy according to the GYN GEC-ESTRO recommendations. The absolute, common and encompassing volumes and their conformity indices (CIs) were assessed for the GTV, HR CTV and IR CTV. D90 and D100 for each volume were assessed. Visual evaluation was made to assess the reasons for the most frequent inter-observer differences. RESULTS The mean volumes of GTV and HR CTV did not differ significantly between the observers, p>0.05. Significant differences were observed only for the mean volumes of the IR CTV of both centres, p<0.05. CIs ranged from 0.5 to 0.7. DVH-parameter analyses did not reveal any statistical differences, except for the D100 for the GTV at AKH, and the D90 for the IR CTV at IGR, p<0.05. Underlying reasons for inter-observer differences included image contrast adjustment and neglecting to consider anatomical borders. CONCLUSIONS The results of this inter-observer study show that the application of the GYN GEC-ESTRO recommendations for IGBT contouring at two different institutions with two different traditions for applicators, CTV assessment, MR image acquisition and dose prescription is feasible, and it produces acceptable inter-observer variability.

Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.

PURPOSE To report the prognostic factors for local control in patients treated for locally advanced cervical cancer with image guided pulsed-dose rate brachytherapy. MATERIALS/METHODS Patients treated with curative intent by a combination of external beam radiotherapy and pulsed-dose rate brachytherapy were selected. Local failure was defined as any relapse in the cervix, vagina, parametria, or uterus during follow-up. Prognostic factors were selected based on log rank tests and then analyzed with a Cox model. Dose/effect correlations were performed using the probit model. RESULTS Two hundred and twenty-five patients treated from 2006 to 2011 were included. According to the FIGO classification, 29% were stage IB, 58% stage II, 10% stage III, and 3% stage IVA; 95% received concomitant chemotherapy. Thirty patients were considered having incomplete response or local failure. Among the selected parameters, D90 for HR-CTV, D90 for IR-CTV, the overall treatment time, the TRAK, and the HR-CTV volume appeared significantly correlated with local control in univariate analysis. In multivariate analysis, overall treatment time >55days and HR-CTV volume >30cm(3) appeared as independent. The probit analysis showed significant correlations between the D90 for both CTVs, and the probability of achieving local control (p=0.008 and 0.024). The thresholds to reach to warrant a probability of 90% of local control were 85Gy to the D90 of the HR-CTV and 75Gy to 90% of the IR-CTV (in 2Gy equivalent, α/β=10). To warrant the same local control rate, the D90 HR-CTV should be significantly increased in stage III-IV tumors, in case of HR-CTV >30cm(3), excessive treatment time, or tumor width at diagnosis >5cm (97, 92, 105, and 92Gy respectively). CONCLUSIONS Overall treatment time and HR-CTV volume were independent prognostic factors for local control. The D90 for HR and IR CTV were significantly correlated with local control, and D90 HR-CTV should be adapted to clinical criteria.

MRI-based low dose-rate brachytherapy experience in locally advanced cervical cancer patients initially treated by concomitant chemoradiotherapy.

PURPOSE To retrospectively assess the physics contributions and the clinical outcome with preliminary 3D MRI-guided low dose-rate (LDR) intracavitary brachytherapy (BT) experience in locally advanced cervical cancer patients. PATIENTS AND METHODS Eighty-four patients with primary locally advanced cervical carcinoma were analyzed. The median tumoral cervical volume was 48.0 cc (range 1-468 cc). Twenty-four patients (53%) had histological and/or radiological pelvic involvement. After pelvic+/-paraaortic concomitant chemoradiation, a LDR BT boost was delivered to a 3D MRI-based clinical target volume taking into account dose volume constraints for critical organs and optimization of target volume coverage. RESULTS With a median follow-up of 53 months (range 31-79 months), the 4-year overall survival and disease-free survival rates were 57 (95%CI, 43-69) and 52% (95%CI, 40-64), respectively. Adding EBRT and LDR using EQD2 model, the median D(100) and D(90) for the IR-CTV were 56.5 Gy(alpha/beta10) (range 37-83 Gy(alpha/beta10)) and 69 Gy(alpha/beta10) (range 52-113 Gy(alpha/beta10)), respectively. For HR-CTV, the median D(100) and D(90) were 67 Gy(alpha/beta10) (range 47-119 Gy(alpha/beta10)) and 79 Gy(alpha/beta10) (range 53-122 Gy(alpha/beta10)), respectively. Thirty-nine late complications were observed in 28 patients (33.3%): 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others. Four grade 3 delayed complications were observed and no grade 4 complication occurred. CONCLUSIONS Applying an individual treatment planning with 3D MRI-guided LDR brachytherapy appears to be feasible and efficient for patients with locally advanced cervical cancer in routine clinical practice.

Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience

PURPOSE The aim of this study is to report the results of a conservative surgery + brachytherapy treatment for boys with prostate and/or bladder-neck rhabdomyosarcoma avoiding total cystectomy or prostatectomy and external radiotherapy. PATIENTS From 1991 to 2007, 26 boys were operated for a residual mass after chemotherapy (1 for local relapse). All patients underwent a conservative surgical procedure, with bladder-neck and urethra preservation. Surgery was never microscopically complete. Brachytherapy was systematically performed after tumor resection, as a perioperative procedure, consisting of 2 loops encompassing the prostate and the bladder-neck area. A dose of 60 Gy was delivered with low dose rate. Bladder function was evaluated clinically and with urodynamic study for boys with abnormal continence. RESULTS Median age at operation was 23 months (9 months-11 years). Seventeen boys underwent a partial prostatectomy associated in 5 with a partial cystectomy. The remaining 9 patients underwent a partial cystectomy with no procedure at the level of the prostate. At a median follow-up of 4 years (10 months-14.5 years), 24 of 26 boys are alive. Only 1 patient relapsed locally out of the brachytherapy field and died. A second boy died from metastatic relapse. Only 1 patient with bladder dysfunction after treatment underwent a total cystectomy. Four patients are too young to be evaluated for bladder function (<4 years of age). Seven patients, aged 4 to 6 years, have daytime continence, 1 has diurnal dribbling. Among 11 boys older than 6 years, 9 (82%) are normally continent (3 after temporary dribbling), 2 have diurnal dribbling treated by bladder education. CONCLUSION Even if very long-term sequelae of brachytherapy cannot be evaluated, this conservative combined treatment may allow normal continence in nearly all patients, even after temporary diurnal incontinence and should be discussed as an alternative to external radiotherapy or radical surgery.

Adaptive 3D Image-Guided Brachytherapy: A Strong Argument in the Debate on Systematic Radical Hysterectomy for Locally Advanced Cervical Cancer

PURPOSE To evaluate the outcomes of patients with locally advanced cervical cancer treated with three-dimensional image-guided brachytherapy (IGABT) after concomitant chemoradiation (CCRT). MATERIALS AND METHODS Data from patients treated with CCRT followed by magnetic resonance imaging-guided or computed tomography-guided pulsed-dose-rate brachytherapy, performed according to the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology guidelines, were reviewed. At first, stage I or II patients systematically underwent radical hysterectomy or were offered a randomized study evaluating hysterectomy. Then, hysterectomy was limited to salvage treatment. RESULTS Of 163 patients identified, 27% had stage IB, 57% had stage II, 12% had stage III, and 3% had stage IVA disease. The mean dose delivered (in 2-Gy dose equivalents) to 90% of the high-risk clinical target volume was 78.1 ± 9.6 Gy, whereas the doses delivered to organs at risk were maintained under the usual thresholds. Sixty-one patients underwent a hysterectomy. Macroscopic residual disease was found in 13 cases. With a median follow-up of 36 months (range, 5-79 months), 45 patients had relapsed. The 3-year overall survival rate was 76%. Local and pelvic control rates were 92% and 86%, respectively. According to the Common Toxicity Criteria 3.0, 7.4% of patients experienced late grade 3 or 4 toxicity. Most of those had undergone postradiation radical surgery (2.9% vs. 14.8; p = .005). CONCLUSION IGABT combined with CCRT provides excellent locoregional control rates with low treatment-related morbidity, justifying the elimination of hysterectomy in the absence of obvious residual disease. Distant metastasis remains an important first relapse and may warrant more aggressive systemic treatment.

DVH parameters and outcome for patients with early-stage cervical cancer treated with preoperative MRI-based low dose rate brachytherapy followed by surgery

BACKGROUND To our knowledge no DVH data have so far been reported for MRI-guided BT in the preoperative setting of early-stage cervical cancer. We assessed DVH parameters and clinical outcome using 3D MRI-guided preoperative intracavitary LDR BT. PATIENTS AND METHODS Thirty-nine patients with primary early cervical carcinoma (IB1 37, IIA 1 and IIB 1) were treated with preoperative MRI-based LDR BT, consisting of uterovaginal BT to a total dose of 60 Gy to the intermediate-risk CTV, followed 6 weeks later by bilateral salpingo-oophorectomy and extrafascial hysterectomy plus pelvic node dissection. Adjuvant chemoradiation was delivered to patients with pelvic lymph node involvement. RESULTS With a median follow-up of 4.4 years (range 2.6-6.6 years), local recurrence occurred in 1 patient (a lateropelvic relapse) (2.6%). The 4-year actuarial overall survival and disease-free survival were 94% (95% CI, 82-98), and 86% (95% CI, 67-95), respectively. The 2- and 4-year actuarial local relapse-free survival were 94 (95% CI, 86-100) and 91% (95% CI, 81-100), respectively. For intermediate-risk CTV, median D(100) and D(90) were 43 Gy(alpha)(/)(beta)(10) (range 2-74 Gy(alpha)(/)(beta)(10)) and 75 Gy(alpha/beta)(10), respectively (range 29-129 Gy(alpha/beta)(10)). For high-risk CTV, the median D(100) and D(90) were 69 Gy(alpha/beta)(10) (range 24-137 Gy(alpha/beta)(10)) and 109 Gy(alpha/beta)(10) (range 37-198 Gy(alpha/beta)(10)), respectively. Twenty grade 1-2 late complications were observed in 13 patients (33.3%): 10 bladder, 3 ureteral, 1 rectal, 1 small bowel, 1 vaginal, 1 pelvic fibrosis, 1 peripheral nerve, and 2 others. No grade 3 or 4 complication occurred. CONCLUSION MRI-guided brachytherapy with adaptation of the time duration and/or the length of each radioactive source allows both high local control and low toxicity in the preoperative settings of early-stage cervical cancers.

Clinical outcomes of definitive chemoradiation followed by intracavitary pulsed-dose rate image-guided adaptive brachytherapy in locally advanced cervical cancer

OBJECTIVE To report the outcomes and late toxicities of patients with locally advanced cervical cancer treated with concomitant chemoradiation (CRT) followed by intracavitary image-guided adaptive brachytherapy (IGABT). METHODS Data from consecutive patients with histologically proven stage IB-IVA cervical cancer treated with curative intent in a single institution were analyzed. After pelvic +/- para-aortic external-beam radiation therapy, they received pulsed-dose rate IGABT following GEC-ESTRO recommendations. RESULTS Two hundred and twenty-five patients were enrolled. Sixty-five percent were stage≥IIB according to FIGO classification. Ninety-five percent received CRT. Mean D90 to HR and IR-CTV were 80.4+/-10.3Gy and 67.7+/-6.1Gy. After a median follow-up of 38.8months, 3-year local control and overall survival rates were 86.4% and 76.1%, respectively. A trend for a detrimental effect of tumor stage on local control rates was observed with 3-year local control rates of 100% for stages IB1 and IIA, 90.5 for IB2, 85.8% for IIB, 50% for IIIA, 77.1 for IIIB, and 66.7% for IVA tumors (p=0.06). Local control rates at 3years were 95.6% in the group of patients with D90 of HR-CTV≥85Gy, 88.8% in those with D90 between 80 and 85Gy, and 80% when D90<80Gy (p=0.018). Eighteen severe late gastrointestinal and urinary effects affecting 14 patients were reported corresponding with a crude incidence of 6.6%. CONCLUSIONS CRT followed by IGABT provides high local control rates with limited toxicity. Reaching high doses is mandatory to achieve local control and interstitial brachytherapy is necessary in advanced diseases.