Multicentric development and evaluation of 18F-FDG PET/CT and MRI radiomics models to predict para-aortic lymph node involvement in locally advanced cervical cancer.

PURPOSE: To develop machine learning models to predict para-aortic lymph node (PALN) involvement in patients with locally advanced cervical cancer (LACC) before chemoradiotherapy (CRT) using 18F-FDG PET/CT and MRI radiomics combined with clinical parameters. METHODS: We retrospectively collected 178 patients (60% for training and 40% for testing) in 2 centers and 61 patients corresponding to 2 further external testing cohorts with LACC between 2010 to 2022 and who had undergone pretreatment analog or digital 18F-FDG PET/CT, pelvic MRI and surgical PALN staging. Only primary tumor volumes were delineated. Radiomics features were extracted using the Radiomics toolbox®. The ComBat harmonization method was applied to reduce the batch effect between centers. Different prediction models were trained using a neural network approach with either clinical, radiomics or combined models. They were then evaluated on the testing and external validation sets and compared. RESULTS: In the training set (n = 102), the clinical model achieved a good prediction of the risk of PALN involvement with a C-statistic of 0.80 (95% CI 0.71, 0.87). However, it performed in the testing (n = 76) and external testing sets (n = 30 and n = 31) with C-statistics of only 0.57 to 0.67 (95% CI 0.36, 0.83). The ComBat-radiomic (GLDZM_HISDE_PET_FBN64 and Shape_maxDiameter2D3_PET_FBW0.25) and ComBat-combined (FIGO 2018 and same radiomics features) models achieved very high predictive ability in the training set and both models kept the same performance in the testing sets, with C-statistics from 0.88 to 0.96 (95% CI 0.76, 1.00) and 0.85 to 0.92 (95% CI 0.75, 0.99), respectively. CONCLUSIONS: Radiomic features extracted from pre-CRT analog and digital 18F-FDG PET/CT outperform clinical parameters in the decision to perform a para-aortic node staging or an extended field irradiation to PALN. Prospective validation of our models should now be carried out.

Outcome analysis of HDR compared to PDR IGABT in locally advanced cervical cancer: a single-center cohort analysis.

PURPOSE: This monocentric study aimed to assess the impact of technical advancement in brachytherapy (BT) on local control (LC) and cancer-specific survival (CSS) in locally advanced cervical cancer (LACC). METHODS: Since 2010, 211 patients with LACC have been treated with 45/50.4 Gy or 60 Gy radiochemotherapy (RTCT) followed by image-guided adaptive brachytherapy (IGABT) at the authors' institution. In 2013, combined intracavitary and interstitial brachytherapy (BT IC/IS) was implemented and in 2018, pulsed-dose-rate BT (PDR-BT) was replaced by high-dose-rate BT (HDR-BT). LC, CSS, and morbidity according to the RTOG/EORTC scoring system were analyzed. Dose-volume parameters for the high-risk clinical target volume (HRCTV) and organs at risk (OAR) were reported. RESULTS: While 27 (12.8%) patients died of LACC, complete local remission was achieved in 199 (94.3%). Local relapse decreases with a high D95 in the HRCTV (hazard ratio, HR = 0.85, p = 0.0024). D95 in the HRCTV is lower after 60 Gy even if interstitial BT is used. Mean D95 in the HRCTV is 78.2 Gy, 83.3 Gy, and 83.4 Gy with PDR-BT IC, PDR-BT IC/IS, and HDR-BT IC/IS, respectively, after 45/50.4 Gy. D2 cc of OARs is significantly reduced by using interstitial BT. The mean rectum and sigmoid D2 cc are about 61.5 Gy with PDR-BT IC/IS and significantly decreased with HDR-BT IC/IS. This translates into a low fistula incidence. A very low rate of severe gastrointestinal (3.4%) and genitourinary (2.3%) toxicity was observed with HDR-BT IC/IS. CONCLUSION: This large monocentric study provides further evidence that implementation of BT IC/IS has an impact on D95 in the HRCTV, LC, and CSS. There are no differences between HDR and PDR in terms of efficacy, D95 in the HRCTV, and toxicity grade ≥ 3.

[18F]FDG PET radiomics to predict disease-free survival in cervical cancer: a multi-scanner/center study with external validation.

PURPOSE: To test the performances of native and tumour to liver ratio (TLR) radiomic features extracted from pre-treatment 2-[18F] fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT and combined with machine learning (ML) for predicting cancer recurrence in patients with locally advanced cervical cancer (LACC). METHODS: One hundred fifty-eight patients with LACC from multiple centers were retrospectively included in the study. Tumours were segmented using the Fuzzy Local Adaptive Bayesian (FLAB) algorithm. Radiomic features were extracted from the tumours and from regions drawn over the normal liver. Cox proportional hazard model was used to test statistical significance of clinical and radiomic features. Fivefold cross validation was used to tune the number of features. Seven different feature selection methods and four classifiers were tested. The models with the selected features were trained using bootstrapping and tested in data from each scanner independently. Reproducibility of radiomics features, clinical data added value and effect of ComBat-based harmonisation were evaluated across scanners. RESULTS: After a median follow-up of 23 months, 29% of the patients recurred. No individual radiomic or clinical features were significantly associated with cancer recurrence. The best model was obtained using 10 TLR features combined with clinical information. The area under the curve (AUC), F1-score, precision and recall were respectively 0.78 (0.67-0.88), 0.49 (0.25-0.67), 0.42 (0.25-0.60) and 0.63 (0.20-0.80). ComBat did not improve the predictive performance of the best models. Both the TLR and the native models performance varied across scanners used in the test set. CONCLUSION: [18F]FDG PET radiomic features combined with ML add relevant information to the standard clinical parameters in terms of LACC patient's outcome but remain subject to variability across PET/CT devices.

Optimal treatment in locally advanced cervical cancer.

Introduction: Locally advanced cervical cancer (LACC) (International Federation of Gynecology and Obstetrics (FIGO) 2009/2018 - stages IB2-IVA/IB3-IVA, respectively) is treated using a multimodal approach that includes chemoradiotherapy followed by brachytherapy.Areas covered: This review provides an overview of the progress made over the past decade in the treatment of LACC. Prognostic factors, FIGO classification and the role of imaging staging will be discussed. Efficacy of external-beam radiotherapy, brachytherapy and chemotherapy will be detailed. Indications for para-aortic staging lymphadenectomy and adjuvant hysterectomy, as well as follow-up and special population, will be covered.Expert opinion: The initial workup is one of the most crucial steps in the optimal care of patients, which should be realized by a multidisciplinary expert team. With the implementation of modern conformal radiotherapy techniques, the local control rate has been optimized. Nevertheless, 40% of patients experience recurrence with distant metastasis and a dismal prognosis. Currently, a clear benefit of neo- and adjuvant chemotherapy has not been established. The future likely involves (1) improved selection of patients for whom treatment intensification is justified, (2) a combination of new drugs with chemoradiation that are currently being tested in trials, and (3) the development of tailored treatment based on molecular characteristics.

Tumor total lesion glycolysis and number of positive pelvic lymph nodes on pretreatment positron emission tomography/computed tomography (PET/CT) predict survival in patients with locally advanced cervical cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic value of metabolic parameters obtained at pretreatment [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in patients with locally advanced cervical cancer. We hypothesize that these metabolic parameters could optimize the treatment decision and thus favor the outcome of patients suffering locally advanced cervical cancer. METHODS: Patients with locally advanced cervical cancer underwent pretreatment PET/CT. Standard uptake values (maximum, mean, peak), metabolic tumor volume, and total lesion glycolysis were measured in the tumor and in the hypermetabolic pelvic lymph nodes. The relationship between clinical, pathological, and PET/CT metabolic parameters with recurrence-free survival and overall survival was assessed by Cox regression analysis. RESULTS: 115 patients with a median age of 52 years (range 23-77) presented with locally advanced cervical cancer. After a mean follow-up of 33.0 months after initiation of therapy, 26 patients (22.6%) recurred of which 17 patients had distant metastasis; 18 (15.7%) patients died. Recurrence-free survival at 2 and 5 years was 79.2% and 72.2%, respectively. The total lesion glycolysis of the tumor and the delay between diagnosis and treatment were significantly associated with recurrence-free survival in the multivariate analysis (HR 1.00, p=0.004, and HR 2.04, p=0.02, respectively). Only the total lesion glycolysis of the tumor ≥373.54 (HR 2.49, 95% CI 1.15 to 5.38; p=0.02) remained significant after log rank testing. Overall survival at 2 and 5 years was 91.7% and 68.8%, respectively. The number of PET-positive pelvic lymph nodes was the only independent prognostic factor for overall survival in the multivariate analysis (HR 1.43, 95% CI 1.13 to 1.81; p=0.003). CONCLUSION: Tumor total lesion glycolysis and the number of positive pelvic lymph nodes on pretreatment PET/CT appear to be independent prognostic factors for recurrence and survival in patients with locally advanced cervical cancer. This may help to select patients who may benefit from therapeutic optimization and closer surveillance.

Correlation between hematological parameters and outcome in patients with locally advanced cervical cancer treated by concomitant chemoradiotherapy.

BACKGROUND: Hemoglobin (Hb), white blood cell (WBC), and polymorphonuclear neutrophil (PMN) blood counts may be correlated with outcomes in patients with locally advanced cervical cancer. METHODS: Hb, WBC, and PMN counts were measured at diagnosis and during concomitant cisplatin-based chemoradiotherapy (CCRT) in a retrospective sample of 103 patients between 2010 and 2017. Red blood cell (RBC) transfusions were also recorded. The associations between hematological variables and patient overall survival (OS) and recurrence-free survival (RFS) were assessed by Cox regression models. RESULTS: The 3-year OS and RFS rates were 81.4% and 76.8%, respectively. In addition to tumor size and smoking, OS and RFS were found to be significantly associated with changes in WBC and PMN counts from the first to the last cisplatin cycle. Hb count throughout the treatment and RBC transfusions were not predictive of outcome. CONCLUSIONS: This study found no association between Hb count or RBC transfusions and outcome. The daily practice of maintaining the Hb count above 12 g/dL during CCRT should be weighed against the potential risks of transfusions. Drops in WBC and PMN counts during treatment positively impacted OS and RFS and could, therefore, serve as biomarkers during CCRT to adapt the follow-up and consider the need for adjuvant systemic treatments.

Clinical efficacy and toxicity of radio-chemotherapy and magnetic resonance imaging-guided brachytherapy for locally advanced cervical cancer patients: A mono-institutional experience.

BACKGROUND: To evaluate efficacy and toxicity of radio-chemotherapy (RCT) and MR-guided pulsed-dose-rate (PDR) adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC). MATERIAL AND METHODS: Between 2007 and 2014 85 patients with FIGO stage 1B1 N+ or ≥ 1B2 cervical cancer were treated with RCT+ IGABT. The treatment consisted of a pelvic± paraaortic external beam radiotherapy (EBRT) (45-50.4 Gy ± 10 Gy boost to primary tumor and/or to pathologic lymph nodes) with concurrent cisplatin followed by 25-35 Gy of PDR IGABT in 30-50 pulses. The ratio of 3D-CFRT/IMRT was 61/24 patients. Dose-volume parameters of high-risk clinical target volume (HR-CTV), intermediate-risk clinical target volume (IR-CTV) and D2cm(3) organs at risk (OARs) were reported. Local control (LC), cancer-specific survival (CCS) and overall survival (OS) were analyzed actuarially and morbidity crude rates were scored using CTCAEv4.0. RESULTS: Mean follow-up was 36 months (range 6-94). The mean D90 and D98 for HR-CTV was 84.4 ± 9 Gy and 77 ± 8.1 Gy, while for IR-CTV was 69.1 ± 4.3 Gy and 64.8 ± 4.3 Gy, respectively. The mean D2cm(3) for OARs was the following: bladder: 77.3 ± 10.5 Gy, rectum: 65 ± 6.8 Gy, sigmoid: 63 ± 7.9 Gy and intestine: 64.0 ± 9.1 Gy. Three year LC, CSS and OS were: 94%, 85% and 81%. The three-year regional- and distant control rates were 95% and 74%. Node negative patients had significantly higher three-year CSS (100 vs. 72%, p = 0.016) and OS (92 vs. 72%, p = 0.001) compared to node positive ones. Three-year actuarial late Grade ≥ 3 morbidity was the following: GI: 8%, GU: 5%, Vaginal: 8%. The frequency of Grade ≥ 3 hematological toxicities including anemia/leukopenia/neutropenia/thrombocytopenia were 8.6%/34.7%/24.3%/24.3%, respectively. CONCLUSION: This large mono-institutional experience builds up further evidences that IGABT in conjunction with RCT should be the standard of care for patients suffering LACC.

Which α/ß ratio and half-time of repair are useful for predicting outcomes in prostate cancer?

PURPOSE: To calculate the α/ß of prostate adenocarcinoma. MATERIALS AND METHODS: From January 1997 to December 2005, 328 patients were treated consecutively with external beam radiotherapy and brachytherapy boost. The patients with at least one of the following adverse prognostic factors were included: PSA>10 ng/ml, Gleason score ≥7, T≥2B. A total EQD2 of 80 Gy was delivered uniformly within the same timeframe. Prior to August 2002, the patients were treated to low-dose-rate brachytherapy using (192)Ir (n=201), and those treated thereafter received a high-dose-rate brachytherapy boost (n=127). The equivalency of dose was established using the incomplete repair model, with generally accepted α/ß ratio of 3 Gy, and half-time for repair of sublethal damage (HTR) of 1.5h. RESULTS: In a Cox proportional hazards model, the two groups displayed no difference (HR: 0.99, 95% CI: 0.87-1.1, p=0.98) in biochemical control. Analyzing using the linear quadratic model, the data fit well an α/ß ratio of 3.41 Gy (95% CI: 2.56-4.26) and the recently published HTR of 1.9 h (95% CI: 1.4-2.4), but also an α/ß of 5.87 Gy (95% CI: 4.67-7.07) and the more widely established HTR of 1.5 h. CONCLUSIONS: Unlike the previously published data, calculation of the α/ß ratio from consecutive patients and using a uniform treatment duration points to higher values than 2.5 Gy.

Dosimetric comparison of high-dose-rate brachytherapy and intensity-modulated radiation therapy as a boost to the prostate.

PURPOSE: We compared the dose conformity of two radiation modalities: high-dose-rate brachytherapy (HDR BT) and intensity-modulated radiation therapy (IMRT) to deliver a boost to the prostate after external beam radiotherapy (EBRT). METHODS AND MATERIALS: Ten successive patients with prostate adenocarcinoma treated with a single 10-Gy HDR BT boost after EBRT were investigated. Four theoretical IMRT plans were computed: (a) 32.85 Gy IMRT and (b) 26 Gy IMRT with CTV-PTV expansions, doses corresponding to the equivalent dose in 2-Gy fractions (EQD2) of one 10-Gy fraction calculated with a prostate alpha/beta ratio of respectively 1.5 and 3 Gy; and (c) 32.85 Gy IMRT and (d) 26 Gy IMRT without CTV-PTV expansions. The dose-volume histogram values converted in EQD2 with an alpha/beta ratio of 3 Gy for the organs at risk were compared. RESULTS: The HDR BT plan delivered higher mean doses to the PTV compared with IMRT plans. In all, 33% of the rectal volume received a mean dose of 5.32 +/- 0.65 Gy and 20% of bladder volume received 4.61 +/- 1.24 Gy with HDR BT. In comparison, doses delivered with IMRT were respectively 13.4 +/- 1.49 Gy and 10.81 +/- 4 Gy, even if only 26 Gy was prescribed to the PTV with no CTV-PTV expansion (p < 0.0001). The hot spots inside the urethra were greater with HDR BT but acceptable. CONCLUSIONS: Use of HDR BT produced a more conformal plan for the boost to the prostate than IMRT even without CTV-PTV expansions.

A dosimetric selectivity intercomparison of HDR brachytherapy, IMRT and helical tomotherapy in prostate cancer radiotherapy.

BACKGROUND AND PURPOSE: Dose escalation in order to improve the biochemical control in prostate cancer requires the application of irradiation techniques with high conformality. The dosimetric selectivity of three radiation modalities is compared: high-dose-rate brachytherapy (HDR-BT), intensity-modulated radiation radiotherapy (IMRT), and helical tomotherapy (HT). PATIENTS AND METHODS: Ten patients with prostate adenocarcinoma treated by a 10-Gy HDR-BT boost after external-beam radiotherapy were investigated. For each patient, HDR-BT, IMRT and HT theoretical treatment plans were realized using common contour sets. A 10-Gy dose was prescribed to the planning target volume (PTV). The PTVs and critical organs' dose-volume histograms obtained were compared using Student's t-test. RESULTS: HDR-BT delivers spontaneously higher mean doses to the PTV with smaller cold spots compared to IMRT and HT. 33% of the rectal volume received a mean HDR-BT dose of 3.86 + or - 0.3 Gy in comparison with a mean IMRT dose of 6.57 + or - 0.68 Gy and a mean HT dose of 5.58 + or - 0.71 Gy (p < 0.0001). HDR-BT also enables to better spare the bladder. The hot spots inside the urethra are greater with HDR-BT. The volume of healthy tissue receiving 10% of the prescribed dose is reduced at least by a factor of 8 with HDR-BT (p < 0.0001). CONCLUSION: HDR-BT offers better conformality in comparison with HT and IMRT and reduces the volume of healthy tissue receiving a low dose.

Can intensity-modulated radiation therapy of the paraaortic region overcome the problems of critical organ tolerance?

BACKGROUND AND PURPOSE: The recent RTOG guidelines for future clinical developments in gynecologic malignancies included the investigation of dose escalation in the paraaortic (PO) region which is, however, very difficult to target due to the presence of critical organs such as kidneys, liver, spinal cord, and digestive structures. The aim of this study was to investigate intensity-modulated radiotherapy's (IMRT) possibilites of either increasing, in a safe way, the dose to 50-60 Gy in case of macroscopic disease or decreasing the dose to organs at risk (OR) when treatment is given in an adjuvant setting. MATERIAL AND METHODS: The dosimetric charts of 14 patients irradiated to the PO region at the Department of Radiation Oncology, University Hospital of Liege, Belgium, in 2000 were analyzed in order to compare six-field conformal external-beam radiotherapy (CEBR) and five-beam IMRT approaches. Both CEBR and IMRT investigations were planned to theoretically deliver 60 Gy to the PO region in the safest way possible. Dose-volume histograms (DVHs) were calculated for clinical target volume (CTV), planning target volume (PTV), and OR. Student's t-test was used to compare the paired DVH data issued from CEBR and IMRT planning. RESULTS: The IMRT approach allowed to cover the PTV at a higher level as compared to CEBR. Using IMRT, the maximal dose to the spinal cord was reduced from 42.5 Gy to 26.2 Gy in comparison with CEBR (p < 0.00001). Doses to the kidneys were significantly reduced, with < 20% receiving >or= 20 Gy in the IMRT approach (p < 0.00001). Irradiation of digestive structures was not different, with < 25% receiving 35 Gy. Doses to the liver remained low regardless of the method used. CONCLUSION: At 60 Gy, IMRT is largely sparing the spinal cord and kidneys as compared to CEBR and represents an interesting approach not only for dose escalation up to 50-60 Gy (probably facilitating the radiochemotherapy approaches) but also in an adjuvant setting at lower doses. The dosimetric data of this study are in the same range as those published recently with a dynamic arc conformal approach.