Clinical outcomes using a 3D printed tandem-needle-template and the EMBRACE-II planning aims for image guided adaptive brachytherapy in locally advanced cervical cancer.

BACKGROUND: Extensive local disease or narrow vagina may compromise brachytherapy (BT) in patients with cervical cancer. This is the first study to analyze long-term outcomes of using 3D printed vaginal tandem-needle templates (3DP TNT) for transvaginal insertion of needles in parallel (P) or parallel and oblique (P&O) direction to the tandem. MATERIAL AND METHODS: All patients treated with BT using 3DP TNT from 2015-2020 were included. Decision to use a 3DP TNT and preplanning were made after 4-5 weeks of external beam radiotherapy, based on gynecological examination and MRI with a tandem-ring applicator in situ. The TNT was 3D-printed in house consisting of a circular template with P&O holes for guidance of plastic needles and a shaft fitting the uterine tandem. Thus, the radioactive source was never in direct contact with the 3DP TNT. The TNT was 3D printed in a standard or personalized configuration. Planning aims were based on the Embrace II protocol. RESULTS: 101 patients (median age of 63 years) were included: 49 with P needles only and 52 with P&O needles. Personalized TNT was used in 19 patients in the P&O group. Performance status (WHO) was > 0 in 48%. FIGO2018 stage III-IV was present in 77%. T-score at diagnosis and BT was 9.1 and 6.3 respectively, with a significantly higher T-score in the P&O compared to P group. The mean high-risk CTV D90 was 93 Gy with no significant difference between the two groups. Three-year local control rates were 85%, 95%, 75% for the overall, P- and P&O group respectively and 68%, 80% and 56% for cancer specific survival. Grade ≥3 treatment related complications were observed in 10 (10%) patients. CONCLUSIONS: 3DP TNT for BT in cervical cancer provides successful management of very extensive local disease and/or unfavorable anatomy with the possibility for treatment individualization.

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

INTRODUCTION: 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). MATERIAL AND METHODS: 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. RESULTS: The FIGO2009 stage distribution was IB-IIA 9%, IIB 64%, and III-IVA 27%, and mean T-score was 7.2. Pathological nodes were present in 53%. Median observation time was 5.2 years. Local control rate at 5 years was 96%, and pelvic (loco-regional) control 91%. Overall, 36% of the tumours were classified as 'more' hypoxic. The frequency of 'more' hypoxic tumours increased with local tumour intrusion (30% for T-score 0-9 vs. 55% for T-score ≥10, p = 0.004). Hypoxia was associated with decreased DFS in univariate, HR 1.71 (1.04-2.82), and multivariate analysis, HR 1.75 (1.04-2.92), and the effect was particularly observed among tumours with a T-score ≥10. HPV 16/18 was not associated with improved DFS in neither in univariate nor in multivariate analysis. CONCLUSION: 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.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology Guidelines for the Management of Patients With Cervical Cancer.

BACKGROUND: Despite significant advances in the screening, detection, and treatment of preinvasive cervical lesions, invasive cervical cancer is the fifth most common cancer in European women. There are large disparities in Europe and worldwide in the incidence, management, and mortality of cervical cancer. OBJECTIVE: The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly develop clinically relevant and evidence-based guidelines in order to improve the quality of care for women with cervical cancer across Europe and worldwide. METHODS: The ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of cervical cancer (23 experts across Europe). To ensure that the guidelines are evidence based, the current literature identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 159 international reviewers, selected through ESGO/ESTRO/ESP and including patient representatives. RESULTS: The guidelines cover comprehensively staging, management, and follow-up for patients with cervical cancer. Management includes fertility sparing treatment; stage T1a, T1b1/T2a1, clinically occult cervical cancer diagnosed after simple hysterectomy; early and locally advanced cervical cancer; primary distant metastatic disease; cervical cancer in pregnancy; and recurrent disease. Principles of radiotherapy and pathological evaluation are defined.

Impact of bowel gas and body outline variations on total accumulated dose with intensity-modulated proton therapy in locally advanced cervical cancer patients.

INTRODUCTION: Density changes occurring during fractionated radiotherapy in the pelvic region may degrade proton dose distributions. The aim of the study was to quantify the dosimetric impact of gas cavities and body outline variations. MATERIAL AND METHODS: Seven patients with locally advanced cervical cancer (LACC) were analyzed through a total of 175 daily cone beam computed tomography (CBCT) scans. Four-beams intensity-modulated proton therapy (IMPT) dose plans were generated targeting the internal target volume (ITV) composed of: primary tumor, elective and pathological nodes. The planned dose was 45 Gy [Relative-Biological-Effectiveness-weighted (RBE)] in 25 fractions and simultaneously integrated boosts of pathologic lymph nodes were 55-57.5 Gy (RBE). In total, 475 modified CTs were generated to evaluate the effect of: 1/gas cavities, 2/outline variations and 3/the two combined. The anatomy of each fraction was simulated by propagating gas cavities contours and body outlines from each daily CBCT to the pCT. Hounsfield units corresponding to gas and fat were assigned to the propagated contours. D98 (least dose received by the hottest 98% of the volume) and D99.9 for targets and V43Gy(RBE) (volume receiving ≥43 Gy(RBE)) for organs at risk (OARs) were recalculated on each modified CT, and total dose was evaluated through dose volume histogram (DVH) addition across all fractions. RESULTS: Weight changes during radiotherapy were between -3.1% and 1.2%. Gas cavities and outline variations induced a median [range] dose degradation for ITV45 of 1.0% [0.5-3.5%] for D98 and 2.1% [0.8-6.4%] for D99.9. Outline variations had larger dosimetric impact than gas cavities. Worst nodal dose degradation was 2.0% for D98 and 2.3% for D99.9. The impact on bladder, bowel and rectum was limited with V43Gy(RBE) variations ≤3.5 cm3. CONCLUSION: Bowel gas cavities and outline variations had minor impact on accumulated dose in targets and OAR of four-field IMPT in a LACC population of moderate weight changes.

Clinical outcome of interstitial pulsed dose rate brachytherapy in multimodality treatment of locally advanced primary or recurrent rectal and sigmoid cancer with high risk of incomplete microscopic resection.

OBJECTIVE: To evaluate the role of interstitial pulsed dose rate brachytherapy (PDR-BT) in multimodality treatment of locally advanced primary or recurrent rectal and sigmoid cancer with high risk of microscopic incomplete resection (R1). METHODS AND MATERIAL: A total of 73 consecutive patients (recurrent/primary: 40/33) were treated with PDR-BT between 2001 and 2010. Patients received preoperative external beam radiotherapy (EBRT) and concomitant chemotherapy. Following resection of the tumor and the involved pelvic organs, a median of four (3-8) catheters were sutured to the tumor bed with a distance of approximately 1 cm between the catheters. A target respecting the catheters with a margin of 5 mm was contoured on computed tomography (CT) and three-dimensional (3D) dose planning with a planning aim for BT of D90 > 30 Gy, (0.6 Gy/pulse, 1 pulse/h) was performed. Previously irradiated patients (27%) underwent surgery that was directly followed by PDR-BT. Postoperative EBRT was then applied to the tumor bed 3-5 weeks after PDR-BT. RESULTS: A total of 23 patients (31%) received a radical resection (R0) and 45 patients (62%) received an R1 resection. Five patients (7%) received a macroscopic incomplete resection (R2). The five-year overall survival was 33%. Local control at five years was 67% for patients who received a R0 resection and 32% for patients who received an R1 resection. The five-year actuarial risk of a grade 3-4 BT-related complication was 5%. CONCLUSIONS: Meaningful disease control and survival can be obtained at an acceptable rate of late morbidity in selected patients with locally advanced primary and recurrent rectal or sigmoid cancer using (chemo) RT, extensive surgery and PDR-BT when a high risk of an R1 resection is expected.

Impact of radiation dose and standardized uptake value of (18)FDG PET on nodal control in locally advanced cervical cancer.

BACKGROUND: Despite local control now exceeding 90% with image-guided adaptive brachytherapy (IGABT), regional and distant metastases continue to curb survival in locally advanced cervical cancer. As regional lymph nodes often represent first site of metastatic spread, improved nodal control could improve survival. The aim of this study was to examine optimal volume and dose of external beam radiotherapy (EBRT) to maximize regional control including dose contribution from IGABT. MATERIAL AND METHODS: In total 139 patients from the EMBRACE study were analyzed. Individual nodal dose was determined by dose-maps from EBRT and IGABT. All PET/CT scans were re-evaluated and nodal maximal standard uptake value (SUVmax) was determined. Nodal failures were registered to planning scans and related to boosted nodes and treated volume. Relation between SUVmax and nodal control as well as the pattern of regional nodal failure were analyzed. RESULTS: Eighty-four patients were node positive. Nine patients had all metastatic nodes surgically removed. Seventy-five patients had 209 nodes boosted with EBRT. Median nodal boost dose was 62 Gy EQD2 (53-69 Gy EQD2). Median SUVmax was 6 (2-22). No patients had persistent nodal disease, but six patients recurred in a boosted node. SUVmax was significantly higher in nodes that recurred (p = 0.02). However, there was no correlation to nodal dose or volume. Twenty-one patients had a nodal failure including para-aortic nodal (PAN) metastases above the irradiated volume. Nine patients had a PAN-only failure. Patients receiving ≤ 4 cycles of weekly cisplatin had higher risk of nodal failure (p < 0.01). CONCLUSION: Current RT practice provides a high level of control in both boosted nodes and the elective irradiated regional target. However, a high nodal SUVmax is a negative prognostic predictor for nodal control. Attention should be raised to administration of a complete schedule of concurrent chemotherapy as well as treatment of para-aortic nodes.

Diffusion-weighted magnetic resonance imaging during radiotherapy of locally advanced cervical cancer--treatment response assessment using different segmentation methods.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) and the derived apparent diffusion coefficient (ADC) value has potential for monitoring tumor response to radiotherapy (RT). Method used for segmentation of volumes with reduced diffusion will influence both volume size and observed distribution of ADC values. This study evaluates: 1) different segmentation methods; and 2) how they affect assessment of tumor ADC value during RT. MATERIAL AND METHODS: Eleven patients with locally advanced cervical cancer underwent MRI three times during their RT: prior to start of RT (PRERT), two weeks into external beam RT (WK2RT) and one week prior to brachytherapy (PREBT). Volumes on DW-MRI were segmented using three semi-automatic segmentation methods: "cluster analysis", "relative signal intensity (SD4)" and "region growing". Segmented volumes were compared to the gross tumor volume (GTV) identified on T2-weighted MR images using the Jaccard similarity index (JSI). ADC values from segmented volumes were compared and changes of ADC values during therapy were evaluated. RESULTS: Significant difference between the four volumes (GTV, DWIcluster, DWISD4 and DWIregion) was found (p < 0.01), and the volumes changed significantly during treatment (p < 0.01). There was a significant difference in JSI among segmentation methods at time of PRERT (p < 0.016) with region growing having the lowest JSIGTV (mean± sd: 0.35 ± 0.1), followed by the SD4 method (mean± sd: 0.50 ± 0.1) and clustering (mean± sd: 0.52 ± 0.3). There was no significant difference in mean ADC value compared at same treatment time. Mean tumor ADC value increased significantly (p < 0.01) for all methods across treatment time. CONCLUSION: Among the three semi-automatic segmentations of hyper-intense intensities on DW-MR images implemented, cluster analysis and relative signal thresholding had the greatest similarity to the clinical tumor volume. Evaluation of mean ADC value did not depend on segmentation method.

Tracer kinetic model selection for dynamic contrast-enhanced magnetic resonance imaging of locally advanced cervical cancer.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a unique capability to probe tumour microvasculature. Different analysis of the acquired data will possibly lead to different conclusions. Therefore, the objective of this study was to investigate under which conditions the Tofts (TM), extended Tofts (ETM), compartmental tissue uptake model (C-TU) and 2-compartment exchange model (2CXM) were the optimal tracer kinetic models (TKMs) for the analysis of DCE-MRI in patients with cervical cancer. MATERIAL AND METHODS: Ten patients with locally advanced cervical cancer (FIGO: IIA/IIB/IIIB/IVA - 1/5/3/1) underwent DCE-MRI prior to radiotherapy. From the two-parameter TM it was possible to extract the forward volume transfer constant (K(trans)) and the extracellular-extravascular volume fraction (ve). From the three-parameter ETM, additionally the plasma volume fraction (vp) could be extracted. From the three-parameter C-TU it was possible to extract information about the blood flow (Fp), permeability-surface area product (PS) and vp. Finally, the four-parameter 2CXM extended the C-TU to include ve. For each voxel, corrected Akaike information criterion (AICc) values were calculated, taking into account both the goodness-of-fit and the number of model parameters. The optimal model was defined as the model with the lowest AICc. RESULTS: All four TKMs were the optimal model in different contiguous regions of the cervical tumours. For the 24 999 analysed voxels, the TM was optimal in 17.0%, the ETM was optimal in 2.2%, the C-TU in 23.4% and the 2CXM was optimal in 57.3%. Throughout the tumour, a high correlation was found between K(trans)(TM) and Fp(2CXM), ρ = 0.91. CONCLUSION: The 2CXM was most often optimal in describing the contrast agent enhancement of pre-treatment cervical cancers, although this model broke down in a subset of the tumour voxels where overfitting resulted in non-physiological parameter estimates. Due to the possible overfitting of the 2CXM, the C-TU was found more robust and when 2CXM was excluded from comparison the C-TU was the preferred model.

MRI-guided adaptive radiotherapy in locally advanced cervical cancer from a Nordic perspective.

BACKGROUND: The first Nordic protocol for three-dimensional (3D) planned radiotherapy in locally advanced cervical cancer was the prospective NOCECA study (1994-2000). NOCECA consisted of computed tomography (CT)-based 3D conformal external beam radiotherapy (EBRT) with a simultaneous integrated boost (SIB) to the primary tumour combined with brachytherapy (BT) based on x-ray imaging. In NOCECA the planning aim was to achieve 80 Gy at point A from EBRT and BT combined. However, the balance of dose between EBRT and BT was determined by tumour size at diagnosis with more EBRT dose given to point A and less by BT in more advanced stages. In 2005 image-guided adaptive brachytherapy (IGABT) based on magnetic resonance imaging (MRI) and optimisation of the BT dose distribution to the remaining tumour and cervix at time of BT (HR CTV) was introduced in Aarhus. EBRT remained like in NOCECA until 2008 when the SIB to the primary tumour was abandoned and IMRT was introduced as routine technique. In this study, we report outcome of our first five-year experience with IGABT using our NOCECA cohort as reference. MATERIAL AND METHODS: The NOCECA cohort comprising 99 patients was compared with 140 consecutive patients treated by IGABT. Patients with para-aortic nodes were excluded in NOCECA but were present in 9% of the patients treated with IGABT. No patient in NOCECA received chemotherapy whereas concomitant cisplatin was given to 79% of the IGABT patients. RESULTS: With IGABT actuarial local control was 91% at three years. When comparing NOCECA with IGABT overall survival was significantly improved from 63% to 79% (p = 0.005). In parallel, both moderate and severe late morbidity were reduced by about 50% (p = 0.02). CONCLUSION: Introduction of IGABT reduced morbidity and generated a very high rate of local control, which likely has improved survival by at least as much as concomitant chemotherapy.

Circulating cell-free HPV DNA is a strong marker for disease severity in cervical cancer.

For cervical cancer (CC), circulating cell-free HPV DNA (ccfHPV) may establish disease severity. Furthermore, HPV integration has been correlated to viral load and survival. In this study, pre-treatment plasma from 139 CC cases (50 primary surgery patients, 22 primary surgery + adjuvant oncological therapy patients, and 67 primary oncological therapy patients) was collected (2018-2020). Furthermore, plasma from 25 cervical intraepithelial neoplasia grade 3 patients and 15 healthy women (negative controls) were collected. Two next-generation sequencing (NGS) panels were used to establish ccfHPV presence and human papillomavirus type 16 (HPV16) integration status. ccfHPV was detected in four primary surgery (8.0%), eight primary surgery + adjuvant oncology (36.4%), and 54 primary oncology (80.6%) patients. For primary oncology patients with HPV16-related cancer (n = 37), more ccfHPVneg than ccfHPVpos patients had HPV16 integration (P = 0.04), and in patients with HPV16 integration (n = 13), ccfHPVpos patients had higher disease stages than ccfHPVneg patients (P = 0.05). In summary, ccfHPV presence is related to disease severity and may add to the debated Sedlis criteria used for identifying patients for adjuvant oncological therapy. However, ccfHPV detection is influenced by HPV integration status and disease stage, and these factors need to be considered in ccfHPVneg patients.

Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

Anal cancer brachytherapy: From radon seeds to interstitial Papillon technique in a century. What does the future hold?

Evidence from studies which combined 2D-3D external beam radiotherapy (EBRT) ± chemotherapy with 2D brachytherapy (BT) for anal cancer suggest favorable outcomes when compared with chemo-EBRT alone. Further improvement of results can be expected in the era of intensity modulated EBRT and MRI-guided adaptive BT. Despite this, BT is not discussed as a therapeutic option in the prominent international guidelines and its use remains limited to selected institutions. Special skills, complexity, equipment, cost and reimbursement policies have been highlighted as barriers for its wider implementation. However, these factors are relevant for modern radiotherapy in general. Therefore, it can be argued that the role of BT as a component of chemoradiation should be redefined. We describe the historical evolution and current role of BT boost for anal cancer and outline its potential in the context of combined intensity modulated EBRT, chemotherapy and MRI-guided adaptive BT.

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.

PURPOSE: 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. METHODS AND MATERIALS: 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 (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions. RESULTS: Median TSD and TSBT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment. CONCLUSIONS: 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.

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

PURPOSE: 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). METHODS AND MATERIALS: 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 EQD210)) were evaluated. RESULTS: Median(range) tumor width at diagnosis was 5.5(3.6; 7.5)cm; CTVHR volume was 45(23; 136)cm3 with maximum distance from tandem to CTVHR border of 3.4(2.5; 4.8)cm. T-stage distribution was IIB/III/IVA in 6(30%)/9(45%)/5(25%) of patients. At BT, 13(65%) patients had distal parametrial/pelvic wall infiltration. Median(range) number of needles per patient was 11(8-18). Average distribution of intrauterine, vaginal and interstitial dwell times were 31%, 25% and 44%, respectively. Median(range) dwell-time per dwell position was 11(2-127)% of average point-A based standard loading. Median V85Gy/V150%/V200%/V300% were 85(38; 171)/41(21; 93)/22(12; 41)/7(4; 19) cm3; CTVHR D90% was 93(83; 97)Gy EQD210; bladder/rectum/sigmoid/bowel D2cm3 were 78(64; 104)/65(52; 76)/59(53; 69)/61(47; 76)Gy EQD23. CONCLUSIONS: 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.

Dosimetric Impact of Intrafraction Motion in Online-Adaptive Intensity Modulated Proton Therapy for Cervical Cancer.

PURPOSE: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT. METHODS AND MATERIALS: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm. RESULTS: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 GyRBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 GyRBE1.1. When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 GyRBE1.1. In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders. CONCLUSIONS: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion.

Nomogram Predicting Overall Survival in Patients With Locally Advanced Cervical Cancer Treated With Radiochemotherapy Including Image-Guided Brachytherapy: A Retro-EMBRACE Study.

PURPOSE: To present a nomogram for prediction of overall survival (OS) in patients with locally advanced cervical cancer (LACC) undergoing definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). METHODS AND MATERIALS: Seven hundred twenty patients with LACC treated with radiochemotherapy including IGABT in 12 institutions (median follow-up 56 months) were analyzed; 248 deaths occurred. Thirteen candidate predictors for OS were a priori chosen on the basis of the literature and expert knowledge. Missing data (7.2%) were imputed using multiple imputation and predictive mean matching. Univariate analysis with a multivariable Cox regression model for OS stratified by center was performed. Stepwise selection of predictive factors with the Akaike Information Criterion was used to obtain a predictive model and construct a nomogram for OS predictions 60 months from diagnosis; this was internally validated by concordance probability as a measure of discrimination and a calibration plot. RESULTS: Thirteen potential predictive factors were evaluated; 10 factors reached statistical significance in univariate analysis (age, Hemoglobin, FIGO Stage2009, tumor width, corpus involvement, lymph node involvement, concurrent chemotherapy, dose to 90% of the high-risk clinical target volume, volume of CTV at the first brachytherapy [CTVHRVolumeBT], overall treatment time [OTT]). Four factors were confirmed significant within the multivariable Cox regression model (FIGO Stage2009, lymph node involvement, concurrent chemotherapy, CTVHRVolumeBT). The predictive model and corresponding nomogram were based on 7 Akaike Information Criterion-selected factors (age, corpus involvement, FIGO Stage2009, lymph node involvement, concurrent chemotherapy, CTVHRVolumeBT, OTT) and showed promising calibration and discrimination (cross-validated concordance probability c = 0.73). CONCLUSIONS: This is the first nomogram to predict OS in patients with LACC treated with IGABT. In addition to previously reported factors (age, FIGO2009 stage, corpus involvement, chemotherapy delivery, OTT, lymph node involvement), status of primary tumor at the time of brachytherapy seems to be an essential outcome predictor. These results can facilitate individualized tailoring of treatment and patient counseling during the treatment.

A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin.

OBJECTIVE: Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting. METHODS: Patients who had received prior platinum and paclitaxel with a TFI 0-12 months received PLD 25 mg/m(2)day 1 plus gemcitabine 800 mg/m(2)day 1, 8 every 21 days. Gemcitabine was dose escalated to 1000 mg/m(2)day 1, 8 from course 2 in the absence of grade 3/4 toxicity. The primary endpoint was progression-free survival (PFS). Patients were stratified according to response to primary chemotherapy. RESULTS: Seventy-nine patients (n=26 with CR on prior chemotherapy and TFI 6-12 months; n=20 with CR and TFI 0-6 months; n=33 with PR/SD and TFI 0-12 months) were enrolled. The median age was 59 years (range 31-77 years), and 33 patients had received ≥ 2 prior treatments. A median of five courses was delivered per patient (total 389 courses). Gemcitabine was dose escalated in 124 courses and reduced in 105 courses. No PLD dose reductions occurred. Grade 3/4 toxicities were febrile neutropenia (n=4), PPE (n=2), and mucositis (n=2). One toxic death occurred (pneumonitis/alveolitis). Responses were complete in 5.1%, partial in 27.9%, and stable disease in 55.7%. Median OS and PFS were 12.5 and 6.4 months, respectively. CONCLUSIONS: The PLD-gemcitabine combination is an effective and well-tolerated salvage treatment for relapsed epithelial ovarian cancer and is a valid candidate for evaluation in a phase III trial.