TYPE OF STUDY:

A Prospective randomized controlled study

INCLUSION CRITERIA:

1. Biopsy proven carcinoma cervix

2. Age group – 20 to 65 years

3. Stage of IIB to IV A carcinoma of cervix (Staging will be done according to International Federation of Gynecology and Obstetrics)

4. ECOG Performance score 0,1.

5. Patients who signed informed consent.

6. EBRT treatment under 3DCRT

EXCLUSION CRITERIA:

1. Stages of IA, IA2, IB1, IB2, IB3, IIA1, IIA2, IVB

2. Neuroendocrine histology carcinoma of cervix

3. ECOG performance status >2

4. Patient with prior EBRT or Brachytherapy to pelvis.

5. Pregnant or Lactating women

6. Metastatic or recurrent carcinoma of cervix.

7. Patients with GFR <45ml/min

SELECTION OF PATIENT:

The study will be conducted on patients with carcinoma cervix satisfying the inclusion criteria, in those presenting to Radiotherapy OPD at SVIMS, Tirupati.

DIAGNOSTIC WORKUP

1. Complete history

2. Physical examination and gynaecological examination.

3. Biopsy from tumour.

4. Complete blood count

5. Liver function test

6. Renal function tests.

7. CT scan Abdomen and Pelvis - Plain and Contrast or MRI abdomen and pelvis – for diagnosis and also for response assessment.

8. Cardiology evaluation- ECG ,2D ECHO

9. Chest X ray, US Abdomen – for metastatic workup

SIMULATION AND RADIOTHERAPY TECHNIQUE:

1.Patients are kept in supine position with arms over the chest and immobilisation will be done with Vaclok/ with head rest and knee rest.

2. Simulation is will be done on Siemens AS 20 CT Simulator. (Seimens Inc., Berlin, Munich-Germany)

3. CT scan will be done with 3mm slices from Diaphragm to Mid-thigh along with full bladder by following bladder protocol i.e., patient was asked to empty the bladder first, then drink 500 ml of water and asked to wait for 30 mins, then patient was set up on couch with Vaclok/ with head rest and knee rest and marker was kept to mark the lower extent of growth in vagina and plain CT will be taken followed by contrast scan with intravenous non-ionic contrast 1-2 ml/kg body weight.

4. The treatment consists of a combination of EBRT with concurrent chemotherapy which will be given as appropriate along with brachytherapy ICRT/ISBT

5. EBRT will be planned with 3DCRT technique on Oncentra/Eclipse treatment planning system

6. A total of 46 - 50 Gy in 23 - 25# (1.8 - 2Gy/#), 5- 6 days a week, one fraction a day will be delivered.

7. Brachytherapy will be given by ICRT/ISBT method, 7Gy in 4# dose prescribed to Point A/HRCTV as appropriate.

STUDY TECHNIQUE

1. Patients will be divided into two groups (Arm A and Arm B) before the start of study by opaque sealed envelope technique.

2. All the patients in both arms will receive EBRT with concurrent chemotherapy and brachytherapy accordingly.

3. During chemotherapy Arm A receives weekly cisplatin of 40mg/m2, Arm B receives weekly cisplatin 40mg/m2 and paclitaxel 40mg/m2.

CHEMOTHERAPY ADMINISTRATION

Before chemotherapy administration patient will be evaluated by the parameters

1. Physical examination of height and weight

2. ECOG Score ≤ 1

3. Total count of ANC >2,500/mm3

4. Platelet count >1,50,000/mm3

5. Bilirubin <1.25 X ULN

6. ALT <10 X ULN

GFR will be calculated by Cock-croft Gault formula 

Body surface area will be calculated by using Mosteller formula 

For the administration of cisplatin, GFR >60 ml/min will be given full dose, if GFR is 45-59ml/min 75% of dose will be given.

During chemotherapy

1.Patients in Arm A will receive Inj. Cisplatin 40mg/m2 weekly during EBRT for a total of 4 cycles

2. Patients in Arm B will receive Inj. Paclitaxel 40mg/m2 on Day1 inj. Cisplatin 40mg/m2 on Day 2, weekly during EBRT for a total of 4 cycles

Drug Administration Protocols

1. As paclitaxel has a major side-effect of hypersensitivity, the patient will be pre-medicated with Inj. Dexamethasone 8 mg, 12 hrs, 6 hrs prior to chemotherapy.

2. On the day 1 of chemotherapy patient will be premedicated with Inj. Ondansetron 16mg along with Inj. Dexamethasone 12 mg in 100 ml Normal saline over 30 mins, followed by Inj. Pheniramine maleate 25 mg, Inj. Promethazine 25mg, Inj. Hydrocortisone 100mg 30min before the administration of paclitaxel.

3. This will be followed by an infusion Inj. Paclitaxel 40mg/m2 in 500 ml of Ecoflac normal saline over a period of 2-3 hours with non-PVC I.V set followed by normal saline 100 ml over 30 mins

4. On day 2 As cisplatin is highly emetic Cap. Aprepitant will be given 1hr before administering cisplatin.

5. Before administration of cisplatin, patient will be premedicated with Inj. Ranitidine 100mg, Inj. Dexamethasone 12 mg, Inj. Ondansetron 16 mg in 100 ml Normal Saline over 30 mins

6. Inj Potassium chloride 40mmol with Inj. Magnesium sulphate 1gm in 500ml Normal saline I.V over one hour.

7. Inj. Cisplatin 40mg/m2 dose in 500 ml of normal saline solution over 1 hour with 20% mannitol will be given.

8. Post chemotherapy of cisplatin Inj. Potassium chloride 40mmol with Inj. Magnesium sulphate 1gm in 500ml Normal saline I.V over one hour further hydration with 1 litre of normal saline will be given over 4 hours.

9. EBRT will be delivered 1 hour after the chemotherapy. This will be given weekly for 4 cycles.

10. Post chemotherapy medications cap. Aprepitant 80mg for 2 days, Tab Ondansetron 8mg TDS, Tab Pantop 40 mg OD, Tab Dexamethasone4mg BD will be given for 3 days. (APPENDIX 4)

Arm A will be receiving Inj. cisplatin 40mg/m2 per week for 4 cycles with the same protocol as mentioned above (APPENDIX 5)

FOLLOW UP AND EVALUATION OF PATIENTS

1. Conventionally acute RT induced toxicities are those defined as toxicities that develop within 90 days from start of radiotherapy such as anaemia, neutropenia, thrombocytopenia, and gastroenteritis.

2.Toxicities will be graded according to CTCAE criteria version 5.0 [34](APPENDIX 2)

3. Response assessment will be done based on RECIST 1.1 criteria. [35](APPENDIX 3)

4. Patients will be examined once in a month for first 3 months and at 3 months patient will be assessed for tumour response clinically.

5. All patients will undergo thorough clinical examination and necessary investigations will be done as per indications.

STATISTICAL ANALYSIS

Data will be collected from proforma and will be entered in Microsoft Excel(Windows 11, version 2021) and analysed using the Statistical Package for Social Science (SPSS) standard version 16(SPSS Inc. Released 2007. SPSS for Windows, Version 16.0. Chicago, SPSS Inc.). Descriptive statistical analysis will be carried out to explore the distribution of several categorical/qualitative and continuous/quantitative variables. All continuous variables (Eg: Age, height) will be summarised using Mean (SD) or Median (IQR). Categorical variables (Eg: gender, stage of disease) will be summarised using proportions. All the results will be presented in tabular form and will be shown graphically. The difference in the two groups will be tested for statistical significance using unpaired t-test and categorical variables will be tested by chi-square test. P-value of <0.05 will be considered statistically significant.