Clinical outcomes of adaptive intracavitary and interstitial brachytherapy technique in locally advanced cervical cancer: A real-world data.

PURPOSE: To evaluate clinical outcomes of CT-based adaptive intracavitary and interstitial brachytherapy (IC followed by IC-ISBT) in locally advanced cervical cancer (LACC) in resource-constrained settings. METHODS AND MATERIALS: LACC patients treated with adaptive brachytherapy techniques were analyzed to evaluate treatment characteristics and clinical outcomes. The Kaplan-Meier method was used for survival analysis, and the log-rank test for univariate analysis. RESULTS: Out of 141 eligible patients with LACC, 87 (61.7%) patients received external beam radiotherapy (EBRT) in referral hospitals, while 54 (38.3%) were treated at our center. We divided our cohort into two groups: poor EBRT responder group (n = 70 [49.6%]) where IC-ISBT was adapted to achieve optimum tumor doses and OAR optimization group 71 (50.4%) where IC-ISBT was performed to reduce OAR doses. Median HRCTV-D90 dose was 88 Gy (range 70-109 Gy) with median HRCTV volume 33cc (range 15-96). Median D2cc doses to OARs were 90 Gy (range 70-107), 71 Gy (range 55-105) and 70 Gy (range 47-90) to bladder, rectum and sigmoid, respectively. At median follow-up of 32 months, 3-year local control (LC), locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) were 83%, 75%, 64% and 72%, respectively. Subgroup analysis revealed significantly better outcomes for OAR optimization compared to poor EBRT responders, with 3-year LC (95% vs. 70.1%, p < 0.001), LRC (87.3% vs. 62.7%, p < 0.001), DFS (79.2% vs. 49.4%, p < 0.001), and OS (86.2% vs. 57.4%, p < 0.001) CONCLUSION: In resource-constrained settings, implementation of Adaptive IC-ISBT is a viable alternative for optimizing OAR doses in LACC. However proactive approach employing IC-ISBT for tumor dose-escalation from first fraction of BT is warranted for improving LC in poor EBRT responders.

Clinical Implementation of "Plan of the Day" Strategy in Definitive Radiation Therapy of Cervical Cancer: Online Adaptation to Address the Challenge of Organ Filling Reproducibility.

PURPOSE: Definitive pelvic intensity modulated radiation therapy (IMRT) in cervical cancer is susceptible to geographic miss due to daily positional and volumetric variations in target and organs at risk. Hence, despite evidence of reduced acute and late treatment-related toxicities, implementation of image-guided IMRT (IG-IMRT) with a reasonable safety margin to encompass organ motion is challenging. METHODS AND MATERIALS: In this prospective, nonrandomized phase 2 study, patients with cervical cancer International Federation of Gynecology and Obstetrics (2009) stage IB2-IIIB between the ages of 18 and 65 years were treated with definitive pelvic chemoradiotherapy with a prespecified organ (bladder and rectum) filling protocol. Reproducibility of organ filling was assessed along with the implementation of daily comprehensive adaptive image-guided radiotherapy (IGRT), with a library of 3 IMRT (volumetric modulated arc therapy) plans with incremental expansions of clinical target volume (CTV) to planning target volume (PTV) (primary) margins (small, 0.7 cm; adequate, 1 cm; and large, 1.5 cm) and a backup motion robust 3-dimensional conformal radiotherapy plan; the appropriate plan is chosen based on pretreatment cone beam computed tomography (CBCT) ("plan of the day" approach). RESULTS: Fifty patients with a median age of 49 years (IQR, 45-56 years) received definitive radiation therapy (45-46 Gy in 23-25 fractions to pelvis, with simultaneous integrated boost to gross nodes in 15 patients) with the aforementioned IGRT protocol. In the analysis of 1171 CBCT images (in 1184 treatment sessions), the mean planning computed tomography (CT) and CBCT bladder volumes were 417 and 373 cc, respectively. Significant interfractional variation in bladder volume was noted with a mean absolute dispersion of 29.5% with respect to planning CT; significant influential random factors were postchemotherapy sessions (P ≤ .001), pre-CBCT protocol duration (P = .001), and grades of chemotherapy induced nausea vomiting (P = .001). Significantly higher variation in bladder filling was noted in patients with older age (P = .014) and larger planning CT bladder volume (P ≤ .001). Time trend analysis of fraction-wise bladder volume revealed an absolute systemic reduction of 16.3% in bladder volume means from the first to the fifth week. Variation in rectal diameter was much less pronounced, with 19.2% mean dispersion and without any significant factors affecting it. Although in 19% and 2% of sessions large IMRT PTV and 3-dimensional conformal radiotherapy were necessary to cover the primary target, respectively, reduction in treated volume was possible in 43% of sessions with small PTV selection instead of standard adequate PTV (36% sessions). Plan of the day selection had a moderate to strong correlation with nonabsolute dispersion of bladder filling (Spearman ρ =0.4; P = .001) and a weak (but significant) correlation with grades of acute toxicities. The planned protocol was well tolerated with no radiation-induced local grade 3 toxicity. CONCLUSIONS: Interfractional variation in organ filling (especially bladder) is inevitable despite fixed pretreatment protocol in definitive settings (intact cervix). Despite the logistical challenges, adaptive IGRT in the form of plan of the day based on incremental CTV-to-PTV margins is a relatively simple and feasible strategy to minimize geometric uncertainties in radical IG-IMRT of cervical cancer.

Set-Up Errors, Organ Motion, Tumour Regression and its Implications on Internal Target Volume-Planning Target Volume During Cervical Cancer Radiotherapy: Results From a Prospective Study.

AIMS: Uterocervical motions and organ filling during cervical cancer conformal radiotherapy is complex. This prospective, observational study investigated set-up margins (clinical target vo, ume [CTV] to planning target volume [PTV]) for pelvic nodal CTV and internal margin (CTV to internal target volume [ITV]) expansions for uterocervical movements during cervical cancer radiotherapy. MATERIALS AND METHODS: During cervical cancer radiotherapy, a daily kilovoltage, cone-beam computed tomography (CBCT) scan was acquired. Bony anatomy-based rigid co-registration and matching to vessels/pelvic nodal region was carried out to document shifts, errors (systematic and random) and to calculate CTV to PTV margins. Subsequently, soft-tissue matching was carried out at the mid-cervical region and uterine fundus to record shifts, errors and to calculate CTV to ITV margins. RESULTS: In 67 patients, 1380 CBCT scans were analysed. The mean (±standard deviation) couch shifts for CTV pelvic nodal region in all directions were within 4.5-5.3 mm, systematic and random errors 3.0-3.6 mm and set-up margins of within 10 mm (except anterior margin 10.3 mm). For the mid-cervical region, mean shifts were 4.5-5.5 mm, systematic and random errors 2-4 mm amounting to <10 mm internal margins (CTV-ITV for cervix) and for uterine fundus mean (±standard deviation) shifts were larger in the superior direction (12.1 mm) but 4.0-7.5 mm in other directions, systematic and random errors 2-7 mm amounting to anisotropic margins in various directions (10 mm in anterior-posterior and lateral directions, 12-20 mm in superior-inferior directions) (CTV-ITV for uterine fundus). CONCLUSION: Our study suggests anisotropic CTV to ITV and CTV to PTV margins for cervical cancer radiotherapy.

Validation and applicability of para-aortic lymph nodal contouring atlas in cervical cancer.

BACKGROUND AND PURPOSE: CTV delineation guidelines for the para-aortic nodal region for patients with cervical cancer have been proposed (Keenan et al., 2018). The purpose of this study was to validate these guidelines with the use of CT datasets of cervical cancer patients with macroscopic PALN treated with definitive (chemo)radiation (CTRT) at our center. MATERIALS AND METHODS: Planning CT datasets of 71 cervical cancer patients with gross PA nodal disease treated with EFRT were used. Two hundred and two PALN were identified based on size and morphology on diagnostic CECT, PET CT, or histologically proven PALN. LN regions were divided into upper, middle, and lower and based on their relation to the aorta and IVC. Macroscopic PALN were contoured, and the CTV for PALN irradiation was generated based on the proposed guidelines on ECLIPSE (Version 13.5). The centre of mass (COMN) was calculated for each gross PALN. The evaluation was done to review the presence of COMN in relation to the CTV PALN. RESULTS: The most common location of PALN was Left para-aortic (105 LN-52%), Aortocaval (55 LN-27.2%), and Precaval (14 LN-6.9%). Lower PALN were the commonest (104 LN-51.5%). Ninety-three were middle PALN (46%), and 5 were upper PALN (2.5%). After excluding upper PALN, COMN for 11 PALN (5.5%) were outside the CTV while 20 were junctional. CONCLUSION: Our study shows that more than 95% of PALN in this patient cohort were covered using these guidelines with the addition of an extra 5 mm margin laterally on the left.

Early toxicity and treatment outcomes of extended field-intensity modulated radiotherapy for cervical cancer patients with para-aortic nodal metastasis.

OBJECTIVE: Extended-field radiotherapy (EFRT) with concurrent chemotherapy represents standard treatment in cervical cancer patients with para-aortic lymph nodal (PALN) metastasis. While EFRT with Intensity Modulated RT (IMRT) has been demonstrated to reduce toxicities, the dose thresholds for minimizing acute toxicity is not clear. The present study was undertaken to report the early toxicity with extended-field intensity-modulated radiotherapy (EF-IMRT) for carcinoma of the cervix in our cohort of patients and determine dose-volume parameters that predict ≥grade II haematological toxicity and diarrhoea. METHODOLOGY: This was a retrospective study of consecutive cervical cancer patients with PALN metastasis treated with EF-IMRT. Patients received rotational IMRT +/- neoadjuvant chemotherapy (NACT) and/or concurrent chemotherapy (45-50 Gy/25#/5 weeks) followed by high-dose rate brachytherapy. Acute haematological and gastrointestinal toxicity (diarrhoea and vomiting) was correlated with doses received by bowel and marrow. Receiver operator characteristics curves were used for deriving thresholds that predict for increased toxicity and tested on univariate and multivariate analysis. Finally, disease free and overall survival (DFS and OS) was calculated. RESULTS: A total of 43 patients were included. One-fourth of the patients (11/43) received NACT and 88% received concurrent chemotherapy. Within the upfront EF-IMRT cohort, 22.6% and 9.7% patients developed grade ≥III haematological (HT) and gastrointestinal (GI) toxicity respectively, with an increase in HT (≥ grade III HT =67%) in patients receiving NACT (p = 0.007). In the entire cohort bone marrow Volume receiving 10 Gy (V10>) 90% correlated with an increase in ≥ grade III HT (p = 0.05). No dose volume thresholds could be validated for GI toxicity. The OS and DFS at 2 years was 56% and 54%, respectively. CONCLUSION: EF-IMRT is a feasible option for cervical cancer patients with PALN involvement and is associated with acceptable grade III toxicity. Future studies need to focus on minimizing HT toxicity.