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.

Quantitative and qualitative application of clinical drawings for image-guided brachytherapy in cervical cancer patients.

PURPOSE: Clinical drawings are integral part of image-guided adaptive brachytherapy (IGABT) of cervical cancer. It was used in EMBRACE study protocol as a useful tool. In our study clinical drawings from EMBRACE study were modified to include scales in all the dimensions for more accurate representation of various tumor related volumes. The aim of the present study was to understand patterns of tumor regression and relationship between gross tumor at diagnosis (GTVD) and high-risk clinical target volume (CTV-THR)/intermediate-risk clinical target volume (CTV-TIR) in brachytherapy (BRT), using modified clinical drawings. MATERIAL AND METHODS: 42 cervical cancer patients, staged as FIGO IIB-IIIB according to EMBRACE study, were enrolled. Advanced schematic 3D mapping diagram (3D-MD) in axial, coronal, and sagittal orientations, with a measurement scale (grid with 10 mm distance) for precise assessment and documentation was applied (through MRI at diagnosis and during brachytherapy). Dimensions, including height, width, and thickness as well as volumes (GTVD, CTV-THR and CTV-TIR) were compared both qualitatively and quantitatively. RESULTS AND CONCLUSIONS: We found qualitative and quantitative correlation of the dimensions of final CTV-THR with initial GTVD. Meticulous mapping of tumor volumes can provide useful insights to CTV-THR volume during brachytherapy.

Single Application Multifractionated Image Guided Adaptive High-Dose-Rate Brachytherapy for Cervical Cancer: Dosimetric and Clinical Outcomes.

PURPOSE: A prospective phase 2 study was conducted to evaluate the feasibility and safety of single-application multifractionated (SA-MF), high-dose-rate (HDR), image guided adaptive brachytherapy (IGABT) for cervical cancer. METHODS AND MATERIALS: Patients (N = 41) with International Federation of Gynaecology and Obstetrics 2009 stage IIB-IVA disease recruited between 2017 and 2019 underwent SA-MF. After completion of external beam radiation therapy of 50 Gy in 25 fractions, patients received magnetic resonance IGABT. The IGABT protocol consisted of a single brachytherapy (BT) application and treatment with 3 fractions of HDR (9 Gy on day 1; 2 fractions of 7 Gy with a minimum 6-hour gap on day 2) after achieving planning aims of the high-risk clinical target volume (HRCTV) receiving >84 Gy EQD2 and 2 cm3 of the bladder and rectum/sigmoid receiving ≤85 Gy and <71 Gy, respectively. Interfraction variation was addressed by performing computed tomography planning and coregistration using a mutual information-based coordinate system on day 2 before the second fraction. Organ at risk contouring was done on computed tomography, and doses were re-evaluated and reoptimized if required. RESULTS: Thirty-eight patients were treated as per the protocol. All patients underwent Intracavitary + Interstitial BT with needles (median, 4; range, 3-11). The mean ± standard deviation HRCTV volume was 41 ± 21 cm3 and HRCTV D90 dose was 87.2 ± 3.6Gy. The 0.1 cm3 and 2 cm3 to bladder, rectum, and sigmoid were -103.2 ± 10.6 Gy and -84.6 ± 6.8 Gy, 82.2 ± 9.5 Gy and -68.3 ± 5.7 Gy, and 83.5 ± 9.8 Gy and -69.5 ± 5.9 Gy, respectively. Six patients required reoptimization before the second fraction to meet planning aims. Mean overall treatment time was 47 ± 6 days. With a median follow up of 22 months (range, 2-37), 2-year local control and disease-free and overall survival were 90.1%, 85%, and 94.5%, respectively. So far 1 patient with grade II and 2 patients with grade III rectal toxicities have been reported. CONCLUSION: Magnetic resonance IGABT with SA-MF BT was feasible in 95% of patients. The dosimetric parameters and clinical results achieved so far look promising.

Ten years and counting: Survival in stage IV metastatic squamous cell carcinoma of anal canal following radical treatment.

A 60-year-old male ptient presented with a 2-month history of altered bowel habits and occasional bleeding per rectum. On evaluation, he was diagnosed with squamous cell carcinoma of the anal canal (SCCAC) with an isolated hepatic lesion in segment II estimated as 4.3 cm × 3.5 cm on ultrasound. Subsequent needle biopsy confirmed metastatic squamous cell carcinoma deposits. The final diagnosis was SCCAC, cT4N1M1 (Stage IV). The patient was offered radical intent treatment. As per institutional protocol, the patient received two cycles of induction cisplatin + 5fluorouracil (FU) followed by chemo-radiation. 5FU and mitomycin C was given concurrently with irradiation. The primary and metastatic sites were irradiated using 6 MV photons on helical tomotherapy using conventional fractionation. Fluorodeoxyglucose positron emission tomograph-computed tomography performed 4 months after treatment completion showed a complete metabolic and morphological response. As of the date of writing, the patient is alive and disease free, 10 years after treatment with no long term sequelae.

Cisplatin Chemoradiotherapy vs Radiotherapy in FIGO Stage IIIB Squamous Cell Carcinoma of the Uterine Cervix: A Randomized Clinical Trial.

IMPORTANCE: The evidence for concurrent chemoradiotherapy (CT-RT) in International Federation of Gynecology and Obstetrics (FIGO) stage IIIB squamous cell carcinoma of the uterine cervix is not robust. This study reports the final results of a randomized clinical trial of concurrent cisplatin-based CT-RT and radiotherapy alone (RT) in women with FIGO stage IIIB squamous cell carcinoma of the uterine cervix. OBJECTIVE: To investigate the benefit of concurrent CT-RT in FIGO stage IIIB squamous cell carcinoma of the uterine cervix. DESIGN, SETTING, AND PARTICIPANTS: This phase 3 open-label randomized clinical trial accrued 850 women in Mumbai, India, between July 7, 2003, and September 22, 2011. Of 2121 screened, 850 women with FIGO stage IIIB squamous cell carcinoma of the uterine cervix suitable for concurrent cisplatin chemotherapy were randomly assigned to CT-RT and RT using block randomization (1:1). The data were updated for a minimum follow-up period of 5 years until December 2016. The final analyses were performed in February and March 2017. This single-institution study was conducted at a tertiary cancer center setting. INTERVENTIONS: Randomization to receive RT (RT arm), comprising a combination of external beam RT (50 Gy in 25 fractions over 5 weeks) and brachytherapy, or to receive in addition to the same RT concurrent weekly cisplatin chemotherapy (40 mg/m2 per week) (CT-RT arm). MAIN OUTCOMES AND MEASURES: The primary end point was 5-year disease-free survival (DFS), defined as the time between the date of randomization and the date of any recurrence or death (whichever occurred first) in the intent-to-treat population. RESULTS: This trial included 424 women assigned to CT-RT (mean [SD] age, 49.4 [7.9] years) and 426 women assigned to RT (mean [SD] age, 49.3 [7.9] years). At a median follow-up of 88 months (interquartile range, 61.3-113.1 months), there were 222 recurrences and 213 deaths in the CT-RT arm and 252 recurrences and 243 deaths in the RT arm. The 5-year DFS was significantly higher in the CT-RT arm (52.3%; 95% CI, 52.2%-52.4%) compared with the RT arm (43.8%; 95% CI, 43.7%-43.9%), with a hazard ratio for relapse or death of 0.81 (95% CI, 0.68-0.98) (P = .03). Similarly, the 5-year overall survival (OS) was significantly higher in the CT-RT arm (54.0%; 95% CI, 53.9%-54.1%) compared with the RT arm (46.0%; 95% CI, 45.9%-46.1%), with a hazard ratio for death of 0.82 (95% CI, 0.68-0.98; P = .04). After adjusting for prognostic factors, CT-RT continued to be significantly superior to RT for DFS and OS. There was a higher incidence of acute hematological adverse effects in the CT-RT arm. CONCLUSIONS AND RELEVANCE: Chemoradiotherapy using weekly cisplatin results in significantly better DFS and OS compared with RT in women with stage IIIB squamous cell carcinoma of the uterine cervix. This study provides level 1 evidence in the largest clinical trial reported so far in favor of concurrent weekly cisplatin chemotherapy in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00193791.

Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study.

OBJECTIVE: With an aim to investigate the impact of Human Papilloma Virus (HPV) 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy, we undertook this prospective study. METHODS: Between May 2010 and April 2012, 150 histologically proven cervical cancer patients treated with radio (chemo) therapy were accrued. Cervical biopsies/brushings were collected at pre-treatment, end of treatment and at 3 monthly intervals up to 24months. Quantitative estimation of HPV 16/18 was done using real-time polymerase chain reaction (RT-PCR) and correlated with various clinical end-points. RESULTS: Out of 150 patients accrued, 135 patients were considered for final analysis. Pre-treatment HPV16/18 DNA was detected in 126 (93%) patients, with HPV-16 present in 91%. The mean log (±SD) HPV-16 and HPV-18 viral load at pre-treatment was 4.76 (±2.5) and 0.14 (±2.1) copies/10ng of DNA, respectively. Though significant decline in viral load was observed on follow-ups (p<0.0001); by 9-month follow-up, 89 (66%) patients had persistence of HPV infection. Patients with persistent HPV 16/18 infection had a significantly higher overall and loco-regional relapses [44/89 (49%) and 29/89 (32%)] as compared to HPV clearance by 9months [12/43 (28%) and 5/43 (11%)] with p=0.024 and p=0.02, respectively. Also, persistent HPV infection by 24-month showed a significant impact on loco-regional control (LRC) and recurrence-free survival (RFS). CONCLUSION: In locally advanced cervical cancers treated with radical radio (chemo) therapy, persistent HPV 16/18 infection is significantly high in immediate post-treatment period and correlated with higher loco-regional, overall relapses and was also associated with early relapses.

Magnetic Resonance Image Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: An Experience From a Tertiary Cancer Center in a Low and Middle Income Countries Setting.

PURPOSE: To determine the clinical impact of magnetic resonance image guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer (LACC) (stages II and III) in a tertiary care cancer hospital in a low and middle income countries setting. METHODS AND MATERIALS: Ninety-four LACC patients enrolled in a prospective EMBRACE (An International Study on MRI-Guided Brachytherapy in Locally Advanced Cervical Cancer) protocol treated with external radiation therapy (45 Gy in 25 fractions) with or without weekly cisplatin, followed by magnetic resonance IGABT (4 fractions of 7 Gy), were analyzed in detail for dosimetric and clinical outcomes including late toxicities. RESULTS: The mean (± standard deviation) high-risk clinical target volume (HR-CTV) at the first session of brachytherapy and at the second session of brachytherapy for the current study cohort was 46.94 ± 24.6 cm3 and 42.7 ± 22.5 cm3, respectively, with mean minimum dose received by 90% volume (D90) of 88.3 ± 4.4 equivalent 2-Gy fractionation (GyEQD2). At median follow-up (39 months), the local control rate (LCR) and overall progression-free survival rate were 90.1% ± 3.4% and 72.1% ± 4.8%, respectively, with grade 3 bladder toxicity in 3% of patients and rectum toxicity in 9%. The LCR at 39 months was significantly better in patients with stage IIB and IVA disease versus stage IIIB disease (100% vs 85%, P=.013). Local failures were limited to stage IIIB only and were associated with significantly larger HR-CTVs at brachytherapy (70 ± 25.7 cm3 vs 44.3 ± 21.9 cm3, P=.01) but not with HR-CTV D90 doses (which were similar for patients who had local failures vs those who did not: 86.3 ± 3.9 α/ß equal to 10 Gy (Gy10) vs 88.5 ± 5 α/ß equal to 10 Gy, P=.987). CONCLUSIONS: IGABT leads to a significant improvement in LCR and overall progression-free survival in LACC and should be considered for wider implementation in developing countries to improve outcomes.

Income generated by women treated with magnetic resonance imaging-based brachytherapy: A simulation study evaluating the macroeconomic benefits of implementing a high-end technology in a public sector healthcare setting.

PURPOSE: To estimate the difference in income generated if all women presenting in our institute over a 5-year period were treated with MRI-based image-guided brachytherapy (MR-IGBT) instead of conventional radiograph-based brachytherapy (CR-BT). METHODS AND MATERIALS: Outcome data from 463 patients (94 treated with MR-IGBT) treated in our institute was used to simulate cumulative women-days of work and cumulative income over 5 years for 5526 patients expected to be treated in this period. The average daily income for a woman was derived from the National Sample Survey Organization (NSSO) survey data. Outcomes from both unmatched and propensity score-matched data sets were simulated. RESULTS: The cumulative income in 5 years ranged between Rs 101-168 million if all patients presenting at our institute underwent MR-IGBT. The simulated excess income ranged from Rs 4-45 million after 5 years, which represented 6-66% of the expenditure incurred for acquiring the required equipment and manpower for practicing exclusive MR-IGBT. CONCLUSIONS: Using outcome data from a prospective cohort of patients treated with MR-IGBT in our institute, we demonstrated that significant economic gains may be realized if MR-IGBT was used instead of CR-BT.

Cardiac metastasis in cervical cancer.

Metastasis of cervical carcinoma to the heart is uncommon. Most cases are found during autopsy. These type of metastasis occur mostly in epicardium and myocardium. We present a case report of a patient with carcinoma cervix stage IIIB who presented to the hospital with pitting edema of right lower limb, post 1 year of completion of treatment. PET-CT scan showed FDG avid inguinal, iliac and retroperitoneal lymph nodes, which were bulky on right side causing pedal edema. There was FDG avid uptake seen in right atrial wall and in the atrioventricular groove indicative of metastasis to the heart. Patient refused biopsy or further treatment and hence received best supportive care only. She had a disease free survival of 12 months, and survived for 11 months after being diagnosed with recurrence. Overall survival was 23 months.