Jacob Christian Lindegaard

Impact of Patient Selection on Real-World Outcomes by Using the EMBRACE-II Treatment Protocol in Locally Advanced Cervical Cancer

External beam radiation therapy (EBRT), concomitant cisplatin, and magnetic resonance image guided adaptive brachytherapy performed according to the EMBRACE-II study protocol (IntErnational study on MRI-guided BRAchytherapy in locally advanced CErvical cancer) is considered state-of-the-art for the treatment of locally advanced cervical cancer. The aim of the present study was to evaluate the possibilities for realizing the planning aims and to assess the clinical outcome of using the EMBRACE-II treatment principles in real-world patients. The EMBRACE-II treatment protocol was implemented in 2015 at Aarhus University Hospital as standard for all patients. The present analysis comprises a consecutive cohort treated from 2015 to 2019. In total 209 of 215 (97%) patients completed radiation therapy according to EMBRACE-II. Compared with 96 of 209 (46%) patients recruited in EMBRACE, major patient and disease related prognostic factors, were all significantly in disfavor for 113 of 209 (54%) patients treated according to EMBRACE-II, but not included in the trial. Nonetheless, the planning aims for EBRT and image guided adaptive brachytherapy were largely fulfilled in all patients. In contrast, the completion rate of 5 courses of concomitant cisplatin was reduced from 69% to 27% according to ± trial participation (P < .001) and was significantly influenced by age, comorbidity, performance status, and local tumor stage (P < .001). Overall 5-year local control was high (89%) and the rate of severe radiation-related side effects was low (7%). Advanced local tumor stage was a negative prognostic factor for loco-regional control, systemic control, and survival (P < .001), whereas concomitant cisplatin was important for EBRT-target control (P < .002). The dose-volume planning aims derived from EMBRACE-II for combining EBRT and brachytherapy are achievable in real-world patients while delivery of concomitant cisplatin is challenging. The use of carboplatin or increasing the dose of EBRT in patients unfit for concomitant cisplatin may be relevant for adjusting EMBRACE-II to the real world. In addition, wider indications for elective paraortic EBRT may be appropriate for patients with large primary tumors, irrespective of nodal status.

Are we making progress in curing advanced cervical cancer—again?

Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.

Evaluation of a New Prognostic Tumor Score in Locally Advanced Cervical Cancer Integrating Clinical Examination and Magnetic Resonance Imaging

The integral results of clinical examination and magnetic resonance imaging (MRI) of patients with locally advanced cervical cancer may provide prognostic information that cannot readily be placed in current staging systems, such as proximal versus distal parametrial invasion, unilateral versus bilateral involvement, or organ infiltration on MRI. The aim was to develop and investigate the performance of a simple but comprehensive tumor score for reporting and prognostication. In the present study, 400 consecutive patients with locally advanced cervical cancer treated 2005 to 2018 with chemoradiation and image guided adaptive brachytherapy (IGABT) were analyzed. The diagnostic workup included clinical examination, positron emission tomography/computed tomography, and MRI. International Federation of Gynecology and Obstetrics 2009 stage distribution was IB to IIA 9%, IIB 61%, and III to IV 30%. Involvement of 8 anatomic locations (cervix, left parametrium, right parametrium, vagina, bladder, ureter, rectum, and uterine corpus) was scored according to a ranked ordinal scale with 0 to 3 points. The total sum of points constituted the tumor score (T-score). The median T-score was 6 (range, 0-20). Based on the frequency distribution of the T-score, 4 equally sized groups were formed: 0 to 4, 5 to 6, 7 to 9, and >9 points. The T-score grouping was highly significant in both univariate and multivariable analysis and outperformed International Federation of Gynecology and Obstetrics stage for both survival and local control enabling also intrastage prognostication. Used as a linear variable, the T-score was correlated with IGABT target volume (high-risk clinical target volume, CTV The T-score is a simple instrument for combining clinical findings and imaging into a powerful prognostic factor for survival and local control with capabilities surpassing traditional staging. In addition, the T-score may already at diagnosis predict essential IGABT parameters and may be used for audit and comparison of results in multicenter settings.

Characterization of combined intracavitary/interstitial brachytherapy including oblique needles in locally advanced cervix cancer

To characterize and report on dosimetric outcomes of image guided adaptive brachytherapy (IGABT) using intracavitary and interstitial (IC/IS) applicators including oblique needles (O-needles) in locally advanced cervical cancer (LACC). Twenty LACC patients treated with radio-chemotherapy and offered IC/IS-IGABT including O-needles were analyzed. An in-house 3D-printed vaginal template was used to steer the needles parallel and obliquely in relation to the tandem, supplemented with free-hand needles if needed. Implant characteristics and loading patterns were analyzed. Using the equivalent dose in 2Gy-fractions (EQD2) concept, cumulative (EBRT+BT) V85, V75, V60Gy, targets/OARs doses and high dose volumes (150%, 200% and 300% (100% = 85 Gy EQD2 Median(range) tumor width at diagnosis was 5.5(3.6; 7.5)cm; CTV The use of O-needles in patients with large and/or unfavorable tumors resulted in excellent target coverage and OARs sparing. Intrauterine and vaginal loadings were reduced compared to standard loading and almost half of the loading was shifted into IS needles. This was achieved with gentle loading in the majority of dwell positions.

Hypoxic gene expression is a prognostic factor for disease free survival in a cohort of locally advanced squamous cell cancer of the uterine cervix

Tumour hypoxia in locally advanced squamous cervical cancer (LACC) has been shown to be of substantial prognostic importance. The aims of the present study were therefore to investigate if hypoxia could be identified by a newly validated hypoxic gene expression classifier and used as a prognostic factor for disease free survival (DFS). Paraffin embedded biopsies were obtained from 190 patients with LACC with squamous cell carcinoma treated 2005-2016 with chemo-radiation and image guided adaptive brachytherapy. Analysis of hypoxia was successful in 183 patients (96%). Hypoxic classification of tumours into 'more' or 'less' hypoxic was based on 15 genes using the same method as in a prospective head and neck cancer trial (NCT02661152). HPV was genotyped using INNO-LiPA. Local tumour invasion was evaluated by the T-score. Primary endpoint was DFS analysed by Kaplan-Meier and Cox regression. Events were death of any cause, persistent disease, or recurrence. The FIGO Hypoxic gene expression is a prominent prognostic factor for DFS in LACC with SCC histology and should be considered for treatment stratification in clinical trials.

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis

To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D

The Diagnostic Value of Circulating Cell-Free HPV DNA in Plasma from Cervical Cancer Patients

Circulating cell-free HPV DNA (ccfHPV DNA) may serve as a marker for cervical cancer. In this study, we used digital droplet PCR (ddPCR) to detect and quantify ccfHPV DNA in plasma from patients with HPV16- or HPV18-associated cervical cancer. Blood samples from 60 patients diagnosed with cervical cancer (FIGO IA1-IVA) at Aarhus or Odense University Hospital (June 2018 to March 2020) were collected prior to treatment, and patients were subdivided into an early stage (n = 30) and a late-stage subgroup (n = 30) according to disease stage. Furthermore, blood samples from eight women with HPV16- or 18-associated premalignant conditions (CIN3), and 15 healthy controls were collected. ddPCR was used to analyze plasma from all participants. ccfHPV DNA was detected in 19 late-stage patients (63.33%), 3 early stage patients (10.00%), and none of the CIN3 patients or controls. Quantitative evaluation showed significant correlations between ccfHPV DNA level and stage, tumor score, and tumor size. Thus, our results indicate that ccfHPV DNA may not be a useful marker for early detection of cervical cancer. However, for patients with advanced stage cervical cancer, ccfHPV DNA level represents a promising tool to establish tumor burden, making it useful for establishing treatment response and monitoring the disease.

Prognostic Implications of Uterine Cervical Cancer Regression During Chemoradiation Evaluated by the T-Score in the Multicenter EMBRACE I Study

A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation. EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TS Median TS TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity.

A Clinical Trial to Assess the Effectiveness of NRF2 Activator (Oral Sodium-copper- Chlophyllin ) in Locally Advanced Cervical Cancer to Reduce Late Radiotherapy Toxicity.

Cervical cancer is the second most common cancer in Indian women, and most patients are diagnosed at advanced stages. The standard treatment for these stages is concurrent chemoradiotherapy, but this can cause long-term side effects such as bladder inflammation, strictures, ulcers, and tissue damage, which negatively impact patients' quality of life. Previous studies have shown that oral sodium-copper-chlorophyllin can help reduce radiation-related side effects in rectal, prostate, and cervical cancer patients. However, no study has compared side effects between patients receiving standard follow-up care and those taking sodium-copper-chlorophyllin during follow-up. We hypothesize that the use of sodium-copper-chlorophyllin as a short-duration adjuvant is associated with reduced incidence of late grade 2 or higher gastrointestinal and genitourinary toxicities compared to patients receiving standard-of-care follow-up.

MRI-based Signatures for Survival Prediction in Cervical Cancer With Radiotherapy

This study aims to validate the value of tumor involvement features based on MRI in cervical cancer, facilitate the development of a more appropriate model for risk stratification, and help patients with varying risk profiles make appropriate decisions in treatment selection and follow-up plans.