Management of Nodal Disease in Advanced Cervical Cancer.

During the last decade the adoption of image-guided adaptive brachytherapy has dramatically improved local control in patients with locally advanced cervical cancer (LACC) treated with radiotherapy and concomitant chemotherapy; however, nodal failure remains an obstacle. Metastatic lymph nodes can be detected by surgical and imaging approaches with different sensitivities and specificities, that improve the definition of relevant targets for macroscopic and microscopic nodal disease, and that influence our understanding of dose levels of external beam radiotherapy. Systematic use of modern radiotherapy techniques including intensity modulated radiotherapy and simultaneously integrated nodal boosts in combination with daily position verification is emerging as increasingly important for obtaining nodal control in LACC. This review summarizes published and ongoing efforts for optimizing nodal disease treatment in LACC, elaborates the state of the art approach for nodal disease detection, radiotherapy planning and delivery, and discusses future investigational efforts needed for precise optimization.

Implementation of state-of-the-art (chemo)radiation for advanced cervix cancer in the Netherlands: A quality improvement program.

PURPOSE: To report on the "Dutch Quality Improvement Project" regarding external beam (EBRT) and brachytherapy (BT) contouring and treatment planning for locally advanced cervical cancer (LACC). MATERIAL AND METHODS: Two rounds of three workshops were organized. Data from two patients with LACC were made available for homework exercises. Contouring and treatment planning was asked for according to the EMBRACE-II protocol. The submissions were analysed and the results were addressed during the workshops. RESULTS: Almost all invited centres participated. EBRT contouring guidelines were followed within acceptable range, with major effort needed with regard to the ITV concept. BT contouring was of good quality, with especially small discrepancies for centres already participating in EMBRACE.EBRT treatment planning results improved between workshops with more centres being able to fulfil the planning aims. Guidance was especially necessary to improve the coverage probability planning for affected nodes.For BT planning prioritizing between target coverage and OAR sparing improved over time; the variation in dose to vaginal points remained considerable, as did variation in loading patterns and spatial dose distribution.The project was highly appreciated by all participants. CONCLUSION: Homework and workshop activities provide a suitable platform for discussion, exchange of experience and improvement of quality and conformity. Due to this project, radiotherapy for LACC can be administered with better and more comparable quality throughout the Netherlands.

Risk Factors for Ureteral Stricture After Radiochemotherapy Including Image Guided Adaptive Brachytherapy in Cervical Cancer: Results From the EMBRACE Studies.

PURPOSE: Ureteral stricture is a rare but severe side effect of radiation therapy for locally advanced cervical cancer. This report describes the incidence and risk factors for ureteral stricture in a large patient cohort treated with 3-dimensional image guided adaptive brachytherapy and radiochemotherapy within the EMBRACE studies. METHODS AND MATERIALS: A total of 1860 patients were included. Treatment consisted of external beam radiation therapy (45-50 Gy in 25-30 fractions), concomitant cisplatin, and image guided adaptive brachytherapy. Grade 3 to 4 ureteral strictures were assessed with Common Terminology Criteria for Adverse Events v. 3.0. Risk factors for grade 3 to 4 ureteral stricture were analyzed. These factors included age, hydronephrosis on imaging at time of diagnosis, TNM stage, high-risk clinical target volume, laparoscopic staging, chemotherapy, radiation therapy doses to targets and organs at risk, applicator type, intracavitary versus intracavitary/interstitial technique, and dose rate. RESULTS: At a median follow-up of 34 months (range, 2-163), 31 patients received diagnoses of grade 3 to 4 ureteral stricture. Actuarial 3- and 5-year risk for ureteral stricture grade 3 to 4 was 1.7% and 2.1%, respectively, for all patients. Advanced tumor stage T3-4 with hydronephrosis at diagnosis was the only independent risk factors for ureteral stricture (P = .01). Patients with TNM stage T1 (n = 359) had a low risk of 0.4% and 1.0% at 3 and 5 years, and those with T2 (n = 1085) had a low risk of 1.0% and 1.0% at 3 and 5 years, respectively. Patients (n = 274) with T3-T4 without hydronephrosis at diagnosis had a 3- and 5-year risk of 2.2% and 4.8%, respectively, compared with 11.5% and 11.5%, respectively, in those with baseline hydronephrosis (n = 142). CONCLUSIONS: Severe to life-threatening ureteral stricture occurs rarely in patients with locally advanced cervical cancer with T1-2 tumors. The risk for ureteral stricture is significantly increased in patients with T3-T4 tumors with hydronephrosis at diagnosis.

Bowel morbidity following radiochemotherapy and image-guided adaptive brachytherapy for cervical cancer: Physician- and patient reported outcome from the EMBRACE study.

BACKGROUND/PURPOSE: This study describes late bowel morbidity prospectively assessed in the multi-institutional EMBRACE study on MRI-guided adaptive brachytherapy in locally advanced cervical cancer (LACC). MATERIALS/METHODS: A total of 1176 patients were analyzed. Physician reported morbidity (CTCAE v.3.0) and patient reported outcome (PRO) (EORTC QLQ C30/CX24) were assessed at baseline and at regular follow-up. RESULTS: At 3/5 years the actuarial incidence of bowel morbidity grade 3-4 was 5.0%/5.9%, including incidence of stenosis/stricture/fistula of 2.0%/2.6%. Grade 1-2 morbidity was pronounced with prevalence rates of 28-33% during follow-up. Diarrhea and flatulence were most frequently reported, significantly increased after 3 months and remained elevated during follow-up. Incontinence gradually worsened with time. PRO revealed high prevalence rates. Diarrhea ≥"a little" increased from 26% to 37% at baseline to 3 months and remained elevated, difficulty in controlling bowel increased from 11% to 26% at baseline to 3 months gradually worsening with time. Constipation and abdominal cramps improved after treatment. CONCLUSION: Bowel morbidity reported in this large cohort of LACC patients was limited regarding severe/life-threatening events. Mild-moderate diarrhea, flatulence and incontinence were prevalent after treatment with PROs indicating a considerable and clinically relevant burden. Critical knowledge based on the extent and manifestation pattern of treatment-related morbidity will serve future patient management.

Physician assessed and patient reported urinary morbidity after radio-chemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer.

BACKGROUND AND PURPOSE: The EMBRACE study is a prospective multi-institutional study on MRI guided adaptive brachytherapy (IGABT) in locally advanced cervix cancer (LACC). This analysis describes early to late urinary morbidity assessed by physicians and patients (PRO). MATERIAL AND METHODS: A total of 1176 patients were analysed. Median follow up (FU) was 27 (1-83) months. Morbidity (CTCAE v.3) and PRO (EORTC QLQ-C30&CX24) was prospectively assessed at baseline (BL), and during FU. RESULTS: The most frequent symptoms were frequency/urgency, incontinence, and cystitis with grade 2-4 prevalence rates of 4.3%, 5.0% and 1.7% and grade 1-4 prevalence rates of 24.5%, 16.1% and 5.8% at 3-years. The most frequent PRO endpoints were "urinary frequency" and "leaking of urine". Prevalence of "Quite a bit" or "very much" bother fluctuated from 14.0% to 21.5% for "frequency", while "leaking of urine" increased from 4.6% at BL to 9.3% at 3-years. Actuarial 3-year incidence of grade 3-4 urinary morbidity was 5.3% with most events being urinary frequency, incontinence and ureteral strictures. Grade 3-4 fistula, bleeding, spasm and cystitis were all <1.0% at 3/5-years. No grade 5 toxicity occurred. CONCLUSION: Urinary grade 3-4 morbidity with IGABT was limited. Urinary morbidity grade 2-4 comprises mainly frequency/urgency, incontinence and cystitis and has considerable prevalence in PRO. Various urinary morbidity endpoints have different patterns of manifestation and time course.

A volumetric analysis of GTVD and CTVHR as defined by the GEC ESTRO recommendations in FIGO stage IIB and IIIB cervical cancer patients treated with IGABT in a prospective multicentric trial (EMBRACE).

PURPOSE: To quantify the gross tumor volume at diagnosis (GTVD) and high-risk clinical target volume (CTVHR) at brachytherapy (BT) and describe subgroups of patients with different patterns of response to chemoradiotherapy (CRT) in patients with FIGO stage IIB and IIIB cervical cancer treated with image-guided adaptive brachytherapy (IGABT). Additionally, to evaluate the feasibility of IGABT achieving adequate target coverage in these groups. MATERIALS AND METHODS: Patients with FIGO stage IIB and IIIB cervical cancer enrolled in the EMBRACE study were analyzed. T2-weighted MRI scans were obtained at diagnosis and at BT. GTVD and CTVHR were defined as per the GEC ESTRO recommendations. Patients were classified taking into account that initial tumor volume and response to CRT represented by the volume of residual disease (CTVHR) and extent of residual parametrial disease are all major factors determining local dose delivery by BT, local control, and overall disease outcome. These factors were quantified applying the following criteria: (1) volume of the GTVD relative to the median volume of the GTVD; (2) the ratio (R) of CTVHR to GTVD for each patient; (3) the extent of residual parametrial disease at the time of BT. Accordingly, patients were classified into six groups (G1-G6): stage IB1-like tumors (G1), tumors with good response and any size (G2), small tumors with moderate response (G3), large tumors with moderate response (G4), tumors with poor response (G5) and those with progressive disease (G6). Tumor and treatment characteristics were then compared among the first five groups (only 3 patients were allocated to G6). RESULTS: A total of 481 patients were evaluated. The number of patients in the 6 groups were 55, 78, 123, 147, 75 and 3, respectively. The mean (SD) GTVD was 43.6 (32.8)cm3 and the mean (SD) CTVHR was 31.6 (16.1)cm3. The mean GTVD and CTVHR were 12.6cm3 and 23.7cm3 in G1 (R>1.1), 47.5cm3 and 25.3cm3 in G2 (R<0.9), 23.9 cm3 and 29.9cm3 in G3 (R 0.9-1.1), 73.4cm3 and 38.5cm3 in G4 (R 0.9-1.1), 79.4cm3 and 59.5cm3 in G5 (R>1.1), respectively. Parametrial disease extent at BT was as follows: no involvement in G1 and G2, proximal at most in G3 and G4, distal or to the pelvic wall in G5, progressive in G6. The use of interstitial needles was progressively higher among the groups (mean 0, 0, 2, 3, 6 in G1-5, P<0.001). The mean GTVBT D100 in G1-5 was 103.1Gy, 91.8Gy, 93.5Gy, 88.3Gy and 87.1Gy. The mean CTVHR D90 in G1-5 was 95.1Gy, 92.1Gy, 92.6Gy, 87.6Gy and 88.4Gy. CONCLUSIONS: In patients with FIGO stage IIB and IIIB disease, intra-FIGO stage heterogeneity and overlap between the two stages exist with respect to tumor volume, treatment response and extent of parametrial disease at BT. Taking into account GTVD, parametrial disease at BT and the ratio of CTVHR/GTVD, five major groups exist. These enable prediction of GTVBT and CTVHR dose coverage through BT. IGABT, as performed in EMBRACE, accommodates to a considerable degree for the different variants of tumor regression in these groups through adaptation of the treatment technique including the use of needles. However, major variations remain at present with regard to dose to GTVBT and to CTVHR, which are most pronounced in G4 and G5. This new classification will be validated in future in regard to clinical outcome in EMBRACE.

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study.

PURPOSE: Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS: From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS: Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION: IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

Clinical outcome and dosimetric parameters of chemo-radiation including MRI guided adaptive brachytherapy with tandem-ovoid applicators for cervical cancer patients: a single institution experience.

PURPOSE: To evaluate dosimetric parameters and clinical outcome for cervical cancer patients treated with chemo-radiation and MR-image guided adaptive brachytherapy (MR-IGABT) using tandem-ovoid applicators for intracavitary or combined intracavitary/interstitial approaches. METHOD: This retrospective analysis includes 46 patients treated between 2006 and 2008. Dose-volume parameters D90 HR-CTV (high-risk clinical target volume) and D(2cc) OARs (organs at risk) were determined and converted into biologically equivalent doses in 2 Gy fractions (EQD2). Clinical outcome parameters (local control (LC), progression free survival (PFS) and overall survival (OS)) were analysed actuarially and late morbidity crude rates were scored using CTCAEv3.0. RESULTS: Mean D90 HR-CTV was 84 (SD9) Gy EQD2 for HR-CTV volumes of mean 57 (SD37) cm(3) at time of first brachytherapy (BT). Median follow-up was 41 (range, 4-67) months. Three year LC, PFS, and OS rates were 93, 71, and 65%, respectively. Node negative patients had significantly higher 3-year survival rates compared to node positive ones (PFS 85 versus 53% (p=0.013), OS 77 versus 50% (p=0.032), respectively) with an even larger difference for patients with FIGO stages IB-IIB (PFS 87 versus 42% (p=0.002), OS 83 versus 46% (p=0.007), respectively). Late grade 3-4 mainly gastrointestinal or vaginal morbidity was observed in 4 patients (9.5%). No correlations were seen between morbidity and D(2cc) OAR values. CONCLUSION: (Chemo-) radiation and MR-IGABT with tandem-ovoid applicators result in high LC and promising survival rates with reasonable morbidity.

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.

Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer.

PURPOSE: The aims of this study were to investigate the benefit of the Utrecht interstitial CT/MR applicator for combined intracavitary/interstitial (IC/IS) approach, using magnetic resonance imaging-guided brachytherapy, over the intracavitary approach alone in patients with locally advanced cervical cancer and to analyze the clinical use of needles. METHODS AND MATERIALS: This study includes the first 20 patients treated with the new applicator. Brachytherapy consisted of two pulsed dose rate applications, and the second application was performed with the IC/IS approach. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the dose distribution and dosimetric shortcomings of the first application (IC alone). We investigated the dosimetric gain by comparing the clinical interstitial optimized plan (IC/IS(clinical)) with an additionally generated optimized plan without needle use (IC(study)). Furthermore, we studied the relation of the inserted needles and their source loading patterns with the high-risk clinical target volume (HR-CTV). RESULTS: A total of 54 needles (range, 1-6 per application) were applied with an average depth of 25 mm. The chosen needle positions corresponded with the location of the HR-CTV extensions. The total and individual needle treatment times per application were on average 19% (range, 4-35%) and 7% (range, 2-14%) of the implant treatment time, respectively. The total (external-beam radiotherapy + brachytherapy) D90 HR-CTV for the IC(study) and the IC/IS(clinical) were on average 79.5 (SD 7.4) Gy(α/ß10) and 83.9 (SD 6.7) Gy(α/ß10), respectively, with an average gain of 4.4 (SD 2.3) Gy(α/ß10) for the second application. CONCLUSIONS: Needle placement was feasible in all patients and resulted in a gain in dose and better coverage of HR-CTV. Defining the location of HR-CTV protrusions and analyzing the associated needles has given us deeper understanding of the possibilities in magnetic resonance imaging-guided (pre)treatment planning with the IC/IS Utrecht applicator.

Determining DVH parameters for combined external beam and brachytherapy treatment: 3D biological dose adding for patients with cervical cancer.

PURPOSE: To compare two methods of DVH parameter determination for combined external beam and brachytherapy treatment of cervical cancer. MATERIALS AND METHODS: Clinical treatment plans from five patients were used in this study. We simulated two applications given with PDR (32 x 60 cGy per application, given hourly) or HDR (4 x 7 Gy in two applications; each application of two fractions of 7 Gy, given within 17 h) standard and optimised treatment plans, all combined with IMRT (25 x 1.8 Gy). Additionally, we simulated an external beam (EBRT) boost to pathological lymph nodes or the parametrium (7 x 2 Gy). We determined D90 of the high-risk CTV (HR-CTV) and D(2 cc) of bladder and rectum in EQD2 in two ways. (1) 'Parameter adding': assuming a uniform contribution of the EBRT dose distribution and adding the values of DVH parameters for the two brachytherapy insertions, and (2) 'distributions adding': summing 3D biological dose distributions of IMRT and brachytherapy plans and subsequently determining the values of the DVH parameters. We took alpha/beta=10 Gy for HR-CTV, alpha/beta=3 Gy otherwise and half-time of repair 1.5 h. RESULTS: Without EBRT boost, 'parameter adding' yielded a good approximation. With an EBRT boost to lymph nodes, the total D90 HR-CTV was underestimated by 2.6 (SD 1.3)% for PDR and 2.8 (SD 1.4)% for HDR. This was even worse with a parametrium boost: 9.1 (SD 6.2)% for PDR and 9.9 (SD 6.2)% for HDR. CONCLUSION: Without an EBRT boost 'parameter adding', as proposed by the GEC-ESTRO, yielded accurate results for the values for DVH parameters. If an EBRT boost is given 'distributions adding' should be considered.