Concurrent chemoradiation and brachytherapy alone or in combination with nelfinavir in locally advanced cervical cancer (NELCER): study protocol for a phase III trial.

INTRODUCTION: In locally advanced cervical cancer, nodal, local and distant relapse continue to be significant patterns of relapse. Therefore, strategies to improve the efficacy of chemoradiation are desirable such as biological pathway modifiers and immunomodulating agents. This trial will investigate the impact of nelfinavir, a protease inhibitor that targets the protein kinase B (AKT) pathway on disease-free survival (DFS). METHODS AND ANALYSIS: Radiosensitising effect of nelfinavir in locally advanced carcinoma of cervix is a single-centre, open-label, parallel-group, 1:1 randomised phase-III study. Patients aged over 18 years with a diagnosis of carcinoma cervix stage III are eligible for the study. After consenting, patients will undergo randomisation to chemoradiation and brachytherapy arm or nelfinavir with chemoradiation and brachytherapy arm. The primary aim of the study is to compare the difference in 3-year DFS between the two arms. Secondary aims are locoregional control, overall survival, toxicity and quality of life between the two arms. Pharmacokinetics of nelfinavir and its impact on tumour AKT, programmed cell death ligand 1, cluster of differentiation 4, cluster of differentiation 8 and natural killer 1.1 expression will be investigated. The overall sample size of 348 with 1 planned interim analysis achieves 80% power at a 0.05 significance level to detect a HR of 0.66 when the proportion surviving in the control arm is 0.65. The planned study duration is 8 years. ETHICS AND DISSEMINATION: The trial is approved by the Institutional Ethics Committee-I of Tata Memorial Hospital, Mumbai (reference number: IEC/0317/1543/001) and will be monitored by the data safety monitoring committee. The study results will be disseminated via peer-reviewed scientific journals, and conference presentations. Study participants will be accrued after obtaining written informed consent from them. The confidentiality and privacy of study participants will be maintained. TRIAL REGISTRATION NUMBER: The trial is registered with Clinical Trials Registry-India (CTRI/2017/08/009265) and ClinicalTrials.gov (NCT03256916).

Cancer Stem Cells, CD44, and Outcomes Following Chemoradiation in Locally Advanced Cervical Cancer: Results From a Prospective Study.

PURPOSE: Although cancer stem cells (CSCs) have been reported across solid tumors, there is a dearth of data regarding CSC and its impact on outcomes of cervical cancer. METHODS AND MATERIALS: From October 2013 to December 2015, patients with squamous cancer of the cervix (stage IB2-IVA) were included. Pretreatment and posttreatment biopsy was obtained and immunohistochemistry was performed for SOX-2, OCT-4, Nanog, CD44, and Podoplanin. All patients received concurrent radiation and brachytherapy to an equivalent dose of 80 to 84 Gy to point A with concurrent weekly cisplatin. Correlation of CSC expression was performed with known prognostic factors. The effect of stem cell expression on disease outcomes was tested within multivariate analysis. RESULTS: One hundred fifty patients were included. The median dose to point A was 83 Gy (46-89 Gy) and a median of 4 cycles (range, 0-6 cycles) of chemotherapy was administered. At baseline, moderate to strong immunohistochemical expression of SOX-2, OCT-4, Nanog, CD44, and Podoplanin was observed in 12.8%, 4.8%, 24.4%, 15.5%, and 1.3% of patients, respectively. At median follow-up of 30 months (range, 3-51 months), locoregional and distant relapse was observed in 12.2% and 23.1% of patients, of whom 4.7% had both local and distant relapse. The 3-year disease-free survival rate was 87%. On multivariate analysis, moderate to high CSC expression and CD44 low status (hazard ratio [HR] = 8.8; 95% confidence interval [CI], 1.0-77.2; P < .04) independently predicted for locoregional relapse-free survival. International Federation of Gynecology and Obstetrics stage (HR = 2.6; 95% CI, 1.3-5.4; P = .004) and presence of residual tumor after external radiation (HR = 3.5; 95% CI, 1.8-6.5; P = .0001) predicted for a detriment in disease-free survival. CONCLUSIONS: The presence of stem cell proteins and loss of CD44 independently predicts for reduced locoregional control in locally advanced cervical cancer. Further investigation into the interaction of stem cell and CD44 biology is warranted.

Standard Chemoradiation and Conventional Brachytherapy for Locally Advanced Cervical Cancer: Is It Still Applicable in the Era of Magnetic Resonance-Based Brachytherapy?

Purpose Recent guidelines recommend magnetic resonance imaging-based brachytherapy (MRBT) for locally advanced cervical cancer. However, its implementation is challenging within the developing world. This article reports the outcomes of patients with locally advanced cervical cancer treated with chemoradiation and point A-based brachytherapy (BT) using x-ray- or computed tomography-based planning. Methods Patients treated between January 2014 and December 2015 were included. Patients underwent x-ray- or computed tomography-based BT planning with an aim to deliver equivalent doses in 2 Gy (EQD2) > 84 Gy10 to point A while minimizing maximum dose received by rectum or bladder to a point or 2 cc volume to < 75 Gy EQD2 and < 90 Gy EQD2, respectively. The impact of known prognostic factors was evaluated. Results A total of 339 patients were evaluated. Median age was 52 (32 to 81) years; 52% of patients had stage IB2 to IIB and 48% had stage III to IVA disease. There was 85% compliance with chemoradiation, and 87% of patients received four or more cycles. Median point A dose was 84 (64.8 to 89.7) Gy. The median rectal and bladder doses were 73.5 (69.6 to 78.4) Gy3 and 83 (73.2 to 90.0) Gy3, respectively. At a median follow-up of 28 (4 to 45) months, the 3-year local, disease-free, and overall survival for stage IB to IIB disease was 94.1%, 83.3%, and 82.7%, respectively. The corresponding rates for stage III to IVA were 85.1%, 60.7%, and 69.6%. Grade III to IV proctitis and cystitis were observed in 4.7% and 0% of patients, respectively. Conclusion This audit demonstrates good 3-year outcomes that are comparable to published MRBT series. Conventional BT with selective use of interstitial needles and MRBT should continue as standard procedures until level-I evidence for MRBT becomes available.

Impact of timing of radiation therapy on outcomes in atypical meningioma: A clinical audit.

BACKGROUND: The role of early adjuvant radiation therapy (RT) in patients with atypical meningioma remains controversial. The goal of this work was to report the impact of timing of RT on outcomes in atypical meningioma. METHODS AND MATERIALS: Patients of atypical meningioma were identified through electronic search of institutional database. Following surgery, RT was delivered either in upfront adjuvant setting (early adjuvant RT) or after recurrence/progression (salvage RT). RESULTS: There were 51 patients in the early adjuvant RT group and 30 patients in the salvage RT group. Six of 51 (12%) patients in the early adjuvant RT group recurred/progressed compared with 34 of 35 (97%) patients kept on observation after initial surgery. Thirty of these 34 patients received salvage RT, mostly after reexcision. Twelve of 30 (40%) patients recurred/progressed after salvage RT, compared with 6 of 51 (12%) patients after early adjuvant RT (P = .003). Post-RT 5-year progression-free survival was significantly better for early adjuvant RT compared to salvage RT (69% vs 28%, log-rank P < .001). CONCLUSIONS: Within the limitations of any retrospective analysis, upfront early adjuvant RT can significantly reduce the risk of local recurrence/progression in atypical meningiomas compared with initial observation. A sizeable proportion of patients who are observed initially recur/progress over time necessitating salvage therapy; however, reexcision followed by salvage RT may not be as effective as early adjuvant RT.

A study on the necessity of kV-CBCT imaging compared to kV-orthogonal portal imaging based on setup errors: considering other socioeconomical factors.

PURPOSE: Evaluation of setup accuracy in kV-orthogonal portal imaging (OPI)-based and kV-CBCT-based radiotherapy treatment and to find out the necessity of cone-beam computed tomography (CBCT) compared to OPI. MATERIALS AND METHODS: A retrospective study was carried out on 30 patients, who received radiotherapy to the Brain, Head and Neck, and Pelvis. In the OPI technique, anterior-posterior and right-lateral portal images were taken by the On Board Imaging (OBI) system and were superimposed on the reference images. Similarly, in the kV-CBCT technique, CBCT was performed by the OBI system and CBCT images were superimposed on the reference CT images. A total of 150 comparison sets of kV-OPI and kV-CBCT images were analyzed and evaluated. Shifts in the Lateral, Longitudinal, and Vertical directions were noted in both techniques. The iso displacement vector (IDV) was calculated for all imaging. RESULTS: The mean IDV (in cm) are found to be 0.3395 (SD: 0.1477) and 0.3088 (SD: 0.1593) in cases of the brain, 0.4266 (SD: 0.1511) and 0.3666 (SD: 0.1533) in cases of the head and neck, and 1.0339 (SD: 0.5893) and 0.9498 (SD: 0.6047) in cases of the pelvis for the CBCT and OPI techniques, respectively. The P values were 0.3201, 0.0515, and 0.4829 for the brain, head and neck, and pelvic cases, respectively. CONCLUSIONS: There is statistically no significant difference between both the imaging techniques. As the dose delivered by the CBCT technique is higher than that by the OPI technique, from the socioeconomical and radiation safety point of view, the OPI technique is possibly better than the CBCT technique. Hence, it can be concluded that CBCT is not a mandatory technique compared to the OPI technique in routine brain, head and neck, and pelvic cases, except in those cases where better information about interfraction movements of soft tissue is necessarily required for positioning of the target, as is the case in prostate carcinoma.

Association of polymorphism in cytochrome P450 2C9 with susceptibility to head and neck cancer and treatment outcome.

The present case-control study involving 750 cases and equal number of healthy controls investigates the association of polymorphism in cytochrome P450 2C9 (CYP2C9) with head and neck squamous cell carcinoma (HNSCC) and response in patients receiving chemotherapy or combination of radio-chemotherapy. The frequency of heterozygous or homozygous genotypes of CYP2C9*2 & CYP2C9*3, which leads to the poor metabolizer (PM) genotype was significantly higher in HNSCC cases when compared to the healthy controls resulting in significantly increased risk in the cases. Tobacco use in the form of tobacco smoking or tobacco chewing was found to increase the risk several fold in cases when compared to the non-tobacco users. Likewise, alcohol intake in cases with variant genotypes of CYP2C9*2 or CYP2C9*3 also significantly increased the HNSCC risk in cases when compared to non-alcohol users. Further, majority of the cases carrying variant alleles of both CYP2C9*2 or CYP2C9*3 were found to respond poorly to the chemotherapy or combination of radio-chemotherapy. The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome.