Investigator:- Dr Rita Singh Guide:- Dr Ramesh.S. Bilimaga THESIS TITLE:- Comparison of Neoadjuvant Chemotherapy followed by Concurrent Chemoradiation and Concurrent Chemoradiation alone in locally advanced cervical cancer ( IIB-IVA) Investigator:- Dr Rita Singh Guide:- Dr Ramesh.S. Bilimaga   Co-guide:- Dr. Vijay Agarwal Department:- Radiation Oncology Healthcare Global Enterprises Ltd

Abbreviations NACT - Neoadjuvant chemotherapy CCRT - Concurrent chemoradiation ECOG - Eastern Cooperative Oncology Group RTOG - Radiation Therapy Oncology Group FIGO - Federation of Gynecology and Obstetrics NCI CTCAE - National cancer institute Common Terminology Criteria For Adverse Events EBRT - External beam radiotherapy 3D-CRT - Three- dimensional conformal radiotherapy IMRT - Intensity-modulated radiation therapy ICBT - Intracavitary brachytherapy ISBT - Interstitial brachytherapy Healthcare Global Enterprises Ltd

Introduction Cervical cancer is the 4th most frequent cancer among women worldwide. It is the 2nd most common cancer in less developed countries and In developing countries cervical cancer is the leading cause of cancer-related death. Despite the fall in incidence of cervical cancer, a large proportion of those diagnosed with invasive cancer have locally advanced disease at presentation. Healthcare Global Enterprises Ltd

Concurrent chemoradiotherapy has been the standard protocol of management for cervical cancer patient. 1An individual patient data meta-analysis based on 18 trials from 11 countries confirmed the benefit of CCRT, the estimated improvement in a 5-year overall survival (OS) was only 66%, with a disease free survival rate of 58%. About 30-40% of patient with locally advanced cervical cancer fail to achieve complete response to CCRT and locoregional recurrence is the main cause of failure; So alternative approaches are needed to improve the outcome for such patients. Healthcare Global Enterprises Ltd

We therefore postulated that NACT prior to concurrent chemoradiation have potential therapeutic advantages to control micrometastasic disease, preventing significant proportion of relapses, increasing radiosensitivity and decreasing the hypoxic cell fraction and response to NACT can be considered as prognostic factor. The disadvantage of these strategy include the delay in the onset of curative treatment, the possibility of accelerated repopulation of tumor cells and the risk of developing radioresistant cell clones. Healthcare Global Enterprises Ltd

The role of neoadjuvant chemotherapy has been examined in a number of trials. Although a meta-analysis of 21 randomized trials showed no improvement in OS with NACT, there was an association between outcome and short cycle length , the trials which used shorter cycle length showed 7% absolute improvement in 5-year survival. Result for overall and loco-regional disease-free survival and metastases-free survival similarly suggested a benefit of short cycle chemotherapy. The gap between the completion of chemotherapy and the initiation of radiotherapy also played an important role with early initiation of radiotherapy resulting in improvement in survival rates.5-7 Healthcare Global Enterprises Ltd

AIM To compare the response to treatment with Neoadjuvant chemotherapy followed by concurrent chemoradiation and concurrent chemoradiation alone in locally advanced cervical cancer. Healthcare Global Enterprises Ltd

Objectives Primary objectives :- To compare overall response, local control to Neoadjuvant chemotherapy followed by concurrent chemoradiation and concurrent chemoradiation alone in locally advanced cervical cancer. Secondary objectives:- To compare toxicity profile following administration of neoadjuvant chemotherapy followed by concurrent chemoradiation and concurrent chemoradiation alone in locally advanced cervical cancer. Healthcare Global Enterprises Ltd

  REVIEW OF LITERATURE Five randomized clinical trials performed by the Gynecologic Oncology Group, the Radiation Therapy Oncology Group and the Southwest Oncology Group have demonstrated a significant advantage both in progression-free and overall survival when chemotherapy was administered during radiation for advanced stages of cervical cancer. Based on the results of these trials, the US National Cancer Institute released a Clinical Announcement supporting the concurrent use of chemotherapy with radiation therapy for high-risk early stage and locally advanced stage cervical cancer.9 There are few phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer and Neoadjuvant chemotherapy for cervical cancer metaanalysis collaboration (NACCCMA Collaboration ).2,4 Healthcare Global Enterprises Ltd

Zhilan Chen et al at Wuhan general hospital of Guangzhou Military Command, Wuhan, China in july 2017.3 They designed a study to identify the prognostic value of early response to neoadjuvant chemotherapy for long- term survival of cervical cancer patients. 825 patients were included in their meta-analysis. They pooled the hazard ratios (HR) according to random-effects models. The HR between early response and 1-year overall survival (OS) was 3.60 ( 95% CI 1.93-6.72; I2=0). Similar result were found in the analysis of 3-year OS (HR 3.34; 95% CI 2.28-4.90; I2=0) and 5-year OS (HR 3.44; 95% CI 2.40-4.94; I2=0).Their findings indicate that early response is associated with long- term survival, and responders achieved a higher survival rate than non-responder. Healthcare Global Enterprises Ltd

M McCormack, L Kadayil et al at University College London Hospital, London, UK in 2013.1 Investigated the feasibility of dose-dense neoadjuvant chemotherapy with paclitaxel and carboplatin before concurrent chemoradiation on 46 patients with locally advanced cervical cancer. Patients received dose-dense carboplatin and paclitaxel weekly for 6 cycles followed by concurrent chemoradiation ( cisplatin weekly, 50.4 Gy,28 Fraction plus brachytherapy) and the response rate was assessed at 3month post CCRT which showed good response rate achieved by dose-dense weekly NACT with carboplatin and paclitaxel followed by concurrent chemoradiation Healthcare Global Enterprises Ltd

Type of study Study design:- Observational single institute study Study area:- Health Care Global Enterprises Limited, K R Road, Bengaluru Study duration:- August 2017 to January 2019 Healthcare Global Enterprises Ltd

Study sample This is a prospective, nonrandomized, double arm, comparative study in locally advanced cervical cancer to compare the neoadjuvant chemotherapy followed by definitive chemo-radiation to definitive chemo-radiation alone. 40 patients will be included in these studies with 20 patients in each arm . Arm A consisted of patients who will have concurrent chemoradiation alone. Arm B consisted of patients who will have neoadjuvant chemotherapy followed by concurrent chemo-radiation. Healthcare Global Enterprises Ltd

Eligibility criteria Exclusion Criteria: Inclusion Criteria: Aged 18 and over ECOG performance status 0 - 2 Histologically confirmed squamous, adeno or adenosquamous carcinoma of the cervix. FIGO stage IIB-IVA.   Exclusion Criteria: Distant metastasis. Multiple comorbidities. Post operative carcinoma cervix. Healthcare Global Enterprises Ltd

Treatment schedule 20 patient will be assigned to arm A who will have concurrent chemoradiation alone. And other 20 patient will be assigned to arm B who will have Neoadjuvant chemotherapy followed by concurrent chemoradiation . At baseline, all patients had an X-ray and ultrasound or CECT of the abdomen and pelvis. Biochemistry assessments were carried out weekly during treatment. Full blood counts were performed weekly during NACT and during CCRT then 6 weeks post-treatment and then 3-monthly for 2 years Healthcare Global Enterprises Ltd

In NACT we will give injection paclitaxel (175mg/m2) and carboplatin (AUC-5) weekly for a total of 2 cycles. After 3-6 weeks we will start concurrent chemoradiation with injection paclitaxel (50mg/m2) and injection carboplatin (AUC-2) weekly for 5 weeks. Radiotherapy :- EBRT(3D-CRT/IMRT) will be administered by using linear accelerator to a total dose of 45- 50.4Gy in 25-28 fraction over 5 -51/2weeks followed by HDR brachytherapy (ICBT/ISBT) under anaesthesia. Healthcare Global Enterprises Ltd

Severity of adverse events will categorized by using NCI CTCAE version 4.0 and Specific radiotherapy toxicities will be classified according to RTOG criteria.8 Clinical pelvic examination will be performed at the end of 6th week after complete treatment to assess clinical response. Local control will be determined by using ultrasound/CECT at 3 months of completion of treatment. Further radiological assessments will be conducted as clinically indicated.

Severity of adverse events will categorized by using NCI CTCAE version 4.0 and Specific radiotherapy toxicities will be classified according to RTOG criteria.8 Clinical pelvic examination will be performed at the end of 6th week after complete treatment to assess clinical response. Local control will be determined by using ultrasound/CECT at 3 months of completion of treatment. Further radiological assessments will be conducted as clinically indicated.

Statistical method and analysis In Descriptive statistics, continuous measurements will be presented on Mean ± SD / Median, Inter-quartile range and results on Categorical measurements will be presented in number (%). In Inferential statistics, chi-square/Fisher´s exact test will be used to find the significance on categorical variables. Independent sample `t` test / Mann- whitney `u` test will be used to find the significance between two groups on continuous variables. All Statistical Analysis will be tested at 95% confidence interval and P- value of <0.05 will be considered as statistically significant. Healthcare Global Enterprises Ltd

References McCormack M, Kadalayil L, Hackshaw A, et al. A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer. British J of Cancer. 2013;108:2464–9.  Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer Metaanalysis Collaboration. Neoadjuvant chemotherapy for locally advanced cervical cancer: a systematic review and meta-analysis of individual patient data from 21 randomised trials. Eur J Cancer. 2003;39:2470–86. Zhilan Chen, Yachen Shi, Shixuan Wang and Qiping Lu. Meta- analysis showing that early response to neoaadjuvant chemotherapy predicts better survival among cervical cancer patients. Impact journals.2017. Healthcare Global Enterprises Ltd

Tierney J. Neoadjuvant chemotherapy for cervical cancer meta-analysis collaboration (NACCCMA) collaboration. ‘Neoadjuvant chemotherapy for locally advanced cervix cancer’. Cochrane Database Syst Rev. 2004:14651858. Sardi JE, Giaroli A, Sananes C, et al. Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results. Gynecol Oncol. 1997;67:61–9. Leborgne F, Leborgne JH, Doldán R, Zubizarreta E, Ortega B, Maisonneuve J, et al. Induction chemotherapy and radiotherapy of advanced cancer of the cervix: A pilot study and phase III randomized trial. Int J Radiat Oncol Biol Phys 1997;37:343-50. Healthcare Global Enterprises Ltd

References Green JA, Kirwan JM, Tierney JF, Symonds P, Fresco L, Collingwood M, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: A systematic review and meta-analysis. Lancet 2001;358:781-6. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) Int J Radiat Oncol Biol Phys. 1995;31:1341–1346. [PubMed] 9. Nermina Kantardzic. Concurrent chemoradiation for cervical cancer: Results of Five randomized Trials.MED ARH 2010;64(6). PROFESSIONAL PAPER Healthcare Global Enterprises Ltd