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.

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.

ESGO/ESTRO/ESP Guidelines for the management of patients with cervical cancer - Update 2023.

In 2018, the European Society of Gynecological Oncology (ESGO) jointly with the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published evidence-based guidelines for the management of patients with cervical cancer. Given the large body of new evidence addressing the management of cervical cancer, the three sister societies jointly decided to update these evidence-based guidelines. The update includes new topics to provide comprehensive guidelines on all relevant issues of diagnosis and treatment in cervical cancer.To serve on the expert panel (27 experts across Europe) ESGO/ESTRO/ESP nominated practicing clinicians who are involved in managing patients with cervical cancer and have demonstrated leadership through their expertise in clinical care and research, national and international engagement, profile, and dedication to the topics addressed. To ensure the statements were evidence based, new data 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 international development group. Before publication, the guidelines were reviewed by 155 independent international practitioners in cancer care delivery and patient representatives.These updated guidelines are comprehensive and cover staging, management, follow-up, long-term survivorship, quality of life and palliative care. Management includes fertility sparing treatment, early and locally advanced cervical cancer, invasive cervical cancer diagnosed on a simple hysterectomy specimen, cervical cancer in pregnancy, rare tumors, recurrent and metastatic diseases. The management algorithms and the principles of radiotherapy and pathological evaluation are also defined.

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.

Coverage probability planning for simultaneously integrated boosts of inguinal lymph nodes in vulvar cancer.

BACKGROUND AND PURPOSE: Strategies for minimizing irradiation of organs at risk (OARs) from pathological inguinal lymph node (PILN) boosting are needed to minimize the risk of morbidity. Coverage probability (CovP) is a conformal planning strategy for simultaneously integrated boost (SIB). Our aim was to investigate if SIB of PILN using CovP can be delivered safely in vulvar cancer. MATERIALS AND METHODS: Ten consecutive patients treated with definitive radiotherapy (RT) including SIB of PILN and with daily cone beam CT (CBCT) were included. Dose prescription was 51.2/32 fx to the elective target and 64 Gy/32 fx to the gross disease at the vulva and to positive lymph nodes (LN). PILN were contoured on both planning CT and MRI (GTV-N) and combined to form ITV-N. Each PILN GTV-N was contoured on every third CBCT, in total 11 CBCT for each patient. OARs were subcutaneous tissue (SC), inguinal vessels, skin rim, bowel, and body contour. Three plans were created for every patient: A) Standard CT-based planning; PTV-N based on GTV-NCT with a 10 mm isotropic margin. B) CT and MRI-based planning with smaller margins: PTV-N based on ITV-N with a 5 mm isotropic margin. C) CovP. The total delivered dose to GTV-Ns was estimated by accumulating dose across all fractions based on GTV-Ns contoured on CBCT. RESULTS: Thirty-five PILNs were boosted. There was no significant difference in accumulated GTV-N D98% between the three plans. CovP delivered a higher mean dose to the GTV-N D50% and D2% (p < 0.001). The planned mean doses to the OARs were reduced when applying CovP. CONCLUSIONS: SIB of PILN in vulvar cancer based on CovP and a 5 mm PTV margin does not compromise target coverage during RT and reduces the dose to normal tissues in the groin.

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.

Dosimetric impact of edema on inguinal lymph node boost in locally advanced vulvar cancer.

We aimed to evaluate the extent of groin edema and its dosimetric effect in boosted inguinal lymph nodes (LN) for vulvar cancer patients. The level of edema was determined in 10 patients treated with radical radiotherapy. A dosimetric evaluation of six LNs in the patient with the maximum level of edema was performed. The accumulated dose across CBCT fractions was acceptable for all six LNs (>94% of prescribed dose) even with the development of up to 13 mm of edema. The major contributor to fractional dose degradation was geographical displacement of the nodes. We suggest evaluation of edema on daily CBCT.

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.

Early clinical outcome of coverage probability based treatment planning for simultaneous integrated boost of nodes in locally advanced cervical cancer.

INTRODUCTION: More than 50% of patients with locally advanced cervical cancer (LACC) have pathological nodes. Coverage probability (CovP) is a new planning technique allowing for relaxed dose at the boost periphery minimising collateral irradiation. The aim was to report the first early clinical outcome data for CovP based simultaneous integrated boost (SIB) in LACC. MATERIAL AND METHODS: Twenty-three consecutive node positive patients were analysed. FIGO stage IB2/IIB/IIIB/IVA/IVB was 1/14/3/1/4. Treatment was radio(chemo)therapy (RT) delivering 45 Gy/25 fx whole pelvis ± para-aortic region (PAN) using volumetric arc therapy (VMAT) followed by magnetic resonance imaging (MRI) guided brachytherapy. PAN RT (13 pts) was given if >2 nodes or if node(s) were present at the common iliac vessels or PAN. Nodal gross tumour volumes (GTV-N) were contoured on both PET-CT and MRI. Clinical target volume (CTV-N) was formed by fusion of GTV-NCT and GTV-NMRI. A 5-mm isotropic margin was used for planning target volume (PTV-N). Nodes in the small pelvis were boosted to 55.0 Gy/25 fx. Common iliac and para-aortic nodes received 57.5 Gy/25 fx. Planning aims for CovP were PTV-N D98 ≥ 90%, CTV-N D98 ≥ 100% and CTV-N D50 ≥ 101.5%. RESULTS: Seventy-four nodes were boosted. A consistent 5.0 ± 0.7 Gy dose reduction from CTV-N D98 to PTV-N D98 was obtained. In total, 73/74 nodes were in complete remission at 3 months PET-CT and MRI. Pelvic control was obtained in 21/23 patients. One patient (IB2, clear cell) had salvageable local disease, while another (IIB) failed in a boosted node. Two patients failed in un-irradiated PAN. One patient age 88 (IIIB) did not receive PAN RT, despite a common iliac node. The other (IIB) recurred above L1. Two further patients (IVB) failed systemically. CONCLUSION: Since complete remission at 3 months is predictive for favourable long-term nodal control, our study indicates that CovP for SIB is promising.

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.

A 30-year experience in using oral methotrexate as initial treatment for gestational trophoblastic neoplasia regardless of risk group.

BACKGROUND: Treatment of postmolar gestational trophoblastic neoplasia (GTN) is often stratified according to FIGO score using methotrexate (MTX) for low-risk patients and first-line multi-agent chemotherapy (e.g. EMA-CO) for high-risk patients. In contrast, oral MTX may be given as first-line therapy to all GTN patients regardless of risk group. The aim was to examine the efficacy of oral MTX and a response-adapted treatment policy, which has been used for three decades at Aarhus University Hospital (AUH). MATERIAL AND METHODS: Seventy-one consecutive postmolar GTN patients treated 1981-2011 were included. Data were obtained from medical records, using histopathology and human choriogonadotropin (hCG) to verify the diagnosis. All patients received oral MTX as first-line chemotherapy. Second- and third-line chemotherapy was given according to response. RESULTS: Sixty-four (90%) patients were retrospectively categorized as FIGO low-risk disease, whereas seven patients (10%) had high-risk disease. Complete response to first-line oral MTX chemotherapy was observed in 35/71 (49%) patients, while 62/71 (87%) had complete remission on MTX (first-line) and/or MTX plus dactinomycin (second-line), without the use of multi-agent therapy. Nine patients (13%) received third-line multi-agent chemotherapy, six low-risk (67%) and three high-risk (33%) patients. There were no recurrences and no patients died as a consequence of toxicity or disease. CONCLUSION: Fifty percent of all patients can be cured on oral MTX alone. By adding dactinomycin, about 90% are cured without use of multi-agent chemotherapy. The use of oral MTX as initial treatment can minimize the number of patients receiving multi-agent chemotherapy.

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.

Early and Late Outcomes of Surgery for Locally Recurrent Rectal Cancer: A Prospective 10-Year Study in the Total Mesorectal Excision Era.

AIM: The aim of this study was to assess the outcome of all locally recurrent rectal cancer (LRRC) patients who were referred to a tertiary care center. The study examined LRRC patients who underwent surgery after prior total mesorectal excision. METHOD: The data of 213 consecutive LRRC patients who were registered in a database between 2001 and 2010 were accessed. RESULTS: A total of 115 patients (54 %) with a median age of 63 (range 34-81) years underwent tumor resection. The 30-day mortality rate was 0.8 % (95 % CI 0.02-4 %), and the complication rate was 42 % (95 % CI 33-51 %). R0 resection was achieved in 70 patients (61 %), R1 resection in 38 patients (33 %), and R2 resection in 7 patients (6 %). The 3- and 5-year survival rates for R0 resections were 55 % (95 % CI 41-66) and 40 % (95 % CI 26-53), respectively; 42 % (95 % CI 26-58) and 16 % (95 % CI 5-31), respectively, for R1 resections; no patients who received an R2 resection survived to the 3-year mark. Patients with prior abdominoperineal excision (APE) had significantly poorer survival rates than patients with prior resection with anastomosis (p = 0.02). CONCLUSION: Acceptable long-term survival can be achieved for patients undergoing surgery for LRRC, but radical resection is mandatory. Prior APE was associated with poorer survival rates.

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.

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.

Correction of diffusion-weighted magnetic resonance imaging for brachytherapy of locally advanced cervical cancer.

BACKGROUND: Geometrical distortion is a major obstacle for the use of echo planar diffusion-weighted magnetic resonance imaging (DW-MRI) in planning of radiotherapy. This study compares geometrical distortion correction methods of DW-MRI at time of brachytherapy (BT) in locally advanced cervical cancer patients. MATERIAL AND METHODS: In total 21 examinations comprising DW-MRI, dual gradient echo (GRE) for B0 field map calculation and T2-weighted (T2W) fat-saturated MRI of eight patients with locally advanced cervical cancer were acquired during BT with a plastic tandem and ring applicator in situ. The ability of B0 field map correction (B0M) and deformable image registration (DIR) to correct DW-MRI geometric image distortion was compared to the non-corrected DW-MRI including evaluation of apparent diffusion coefficient (ADC) for the gross tumor volume (GTV). RESULTS: Geometrical distortion correction decreased tandem displacement from 3.3 ± 0.9 mm (non-corrected) to 2.9 ± 1.0 mm (B0M) and 1.9 ± 0.6 mm (DIR), increased mean normalized cross-correlation from 0.69 ± 0.1 (non- corrected) to 0.70 ± 0.10 (B0M) and 0.77 ± 0.1 (DIR), and increased the Jaccard similarity coefficient from 0.72 ± 0.1 (non-corrected) to 0.73 ± 0.06 (B0M) and 0.77 ± 0.1 (DIR). For all parameters only DIR corrections were significant (p < 0.05). ADC of the GTV did not change significantly with either correction method. CONCLUSION: DIR significantly improved geometrical accuracy of DW-MRI, with remaining residual uncertainties of less than 2 mm, while no significant improvement was seen using B0 field map correction.

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.

Voxelwise comparison of perfusion parameters estimated using dynamic contrast enhanced (DCE) computed tomography and DCE-magnetic resonance imaging in locally advanced cervical cancer.

PURPOSE: Dynamic contrast enhanced (DCE) imaging has gained interest as an imaging modality for assessment of tumor characteristics and response to cancer treatment. However, for DCE-magnetic resonance imaging (MRI) tissue contrast enhancement may vary depending on imaging sequence and temporal resolution. The aim of this study is to compare DCE-MRI to DCE-computed tomography (DCE-CT) as the gold standard. MATERIAL AND METHODS: Thirteen patients with advanced cervical cancer were scanned once prior to chemo-radiation and during chemo-radiation with DCE-CT and -MRI in immediate succession. A total of 22 paired DCE-CT and -MRI scans were acquired for comparison. Kinetic modeling using the extended Tofts model was applied to both image series. Furthermore the similarity of the spatial distribution was evaluated using a Γ analysis. The correlation between the two imaging techniques was evaluated using Pearson's correlation and the parameter means were compared using a Student's t-test (p < 0.05). RESULTS: A significant positive correlation between DCE-CT and -MRI was found for all kinetic parameters. The results showing the best correlation with the DCE-CT-derived parameters were obtained using a population-based input function for MRI. The median Pearson's correlations were: volume transfer constant K(trans) (r = 0.9), flux rate constant kep (r = 0.77), extracellular volume fraction ve (r = 0.58) and blood plasma volume fraction vp (r = 0.83). All quantitative parameters were found to be significantly different as estimated by DCE-CT and -MRI. The Γ analysis in normalized maps revealed that 45% of the voxels failed to find a voxel with the corresponding value allowing for an uncertainty of 3 mm in position and 3% in value (Γ3,3). By reducing the criteria, the Γ-failure rates were: Γ3,5 (37% failure), Γ3,10 (26% failure) and at Γ3,15 (19% failure). CONCLUSION: Good to excellent correlations but significant bias was found between DCE-CT and -MRI. Both the Pearson's correlation and the Γ analysis proved that the spatial information was similar when analyzing the two sets of DCE data using the extended Tofts model. Improvement of input function sampling is needed to improve kinetic quantification using DCE-MRI.