Thesis Protocol

Table of contents
TITLE OF THE
THESIS.............................................................................................................................. 3
Abstract for Institutional Review Board (IRB) ................................................................. 4
Introduction………………................................................................................................. 5
Rationale of the study........................................................................................................ ..7
Research Hypothesis............................................................................................................8
Objectives of the study........................................................................................................ 8
Materials and methods........................................................................................................ 8
Study Population .................................................................................................................8
Permission for the study ......................................................................................................8
Sample size..........................................................................................................................9
Selection of patients ..........................................................................................................10
Sampling Technique ......................................................................................................... 11
Research Instrument ......................................................................................................... 11
Study method......................................................................................................................11
Variables……………. ...................................................................................................... 11
Pretreatment evaluation .................................................................................................... 13
Registration…………….................................................................................................... 14
Analysis and Interpretation of Data ................................................................................. 14
Treatment Plan................................................................................................................. ..14
Ethical Considerations..................................................................................................... . 15
Case Collection ................................................................................................................ 16
Patient assessment ............................................................................................................ 16
Limitations of the study..................................................................................................... 17
Data Collection.................................................................................................................. 17
Operational definition ....................................................................................................... 18
References ........................................................................................................................ 20
Appendix.......................................................................................................................... 23
Title of the thesis:
Comparison of clinical response and toxicities between concurrent chemo-radiation with
Cisplatin versus Gemcitabine in locally advanced carcinoma cervix.

Name of the student: Dr Fatema Yasmin

MD resident Phase-B (Oncology)
Dhaka Medical College and hospital,
Dhaka.

Place of study: Dhaka medical college and hospital

Type of study: Quasi- experimental study

Name of the guide: Professor Dr Aliya Shahnaz

MBBS, FCPS (Radiotherapy)
Head Of Department Radiotherapy
Dhaka medical college and hospital

Signature of the student:

Signature of the guide:

Abstract for Institutional Review Board (IRB):
Title: Comparison of clinical response and toxicities between concurrent chemo-radiation
with Cisplatin versus Gemcitabine in locally advanced carcinoma cervix.
Summary:
Carcinoma cervix is recognized as fourth most common cause of cancer in women. It is the
second most prevalent cancer in women of Bangladesh. The main cause of this high incidence in
least developing countries like Bangladesh is the dearth of screening programs, vaccination, lack
of knowledge. So, at the time of diagnosis most of the patient present with locally advanced
stage (FIGO stage IIB-IVA). At these stage, concurrent chemo-radiation is the treatment of
choice worldwide. Concurrent chemo-radiation with weekly cisplatin is widely used. The
proposed study is to evaluate the effectiveness of concurrent chemo-radiation between weekly
Cisplatin versus weekly Gemcitabine in locally advanced cervical cancer as gemcitabine is also
considered as a potent radiosensitizer. The study will be carried on two concurrent chemo-
radiation arms: Arm A & Arm B who will receive injection of Cisplatin 40 mg/m2 I/V 1 hour
infusion before radiation, repeated weekly for 5 cycles, and Gemcitabine 125 mg/m2 I/V 1 hour
infusion before radiation, repeated weekly for 5 cycles, respectively. The planned dose of
external beam radiotherapy is 50Gy in 25 fractions (2Gy per fraction) in 5 weeks in both arms.
Patients in both arms will receive additional 3 fractions of weekly HDR brachytherapy each of
7Gy, after completion of external beam radiotherapy. A quasi-experimental study will be done on
90 patients using a purposive sampling technique. Patients with locally advanced carcinoma
cervix having no previous history of treatment, attending department of Radiotherapy in Dhaka
Medical College and Hospital, will be included in this study. After recruitment in the study, the
objective, nature, purpose and potential risks and benefits of all procedures of this study will be
explained in detail to the patients and their legal guardian and informed written consent will be
taken from the patient. Detailed history, clinical examination, performance status, pre and post
treatment local control, toxicity profile will be collected. The data will be analyzed using “t” test
for continuous variables & Chi-square test for categorical variables. The record of this study will
be kept, and no name of the participants will be used. The selected participants will be given the
option to read the Bangla version of the consent form; if they choose to participate willingly and
with full informed consent, they will be recruited.
INTRODUCTION
Each year globally about 90% of deaths in women are attributed to cervical cancer, which is
regarded as a serious global health issue. (World Health Organization. Cervical Cancer
Elimination Initiation, Accessed June ,5, 2022). It is considered as the second most common
malignancy in women (World health organization, 2020). Although incidence and death rates are
declined in developed countries over the past century due to screening and effective vaccination,
still it ranks as the fourth most common cause of cancer incidence and mortality worldwide
(Arbyn M, Weiderpass E, Bruni L, et al) with an anticipated 604127 (3.1%) cases and 341831
(3.4%) deaths in 2020. The Incidences are higher in least developed countries like Sub-Saharan
Africa and Southeast Asia.
In Bangladesh there is no recent nationwide registered data until this time, but
GLOBOCAN,2020 declares that there are about 8268 (5.3 %) new cases with 4971 deaths in
Bangladesh.
Numerous epidemiological studies have repeatedly shown that factors such as sexual activity
levels, the number of sexual partners, age at first sexual encounters, and the sexual conduct of a
woman's male partner have a significant impact on her chance of developing cervical cancer
(Schiffman et al 1996). Additionally, smoking, immunosuppression, and HIV infection are also
considered as co-factors (Walter Miller et al., 2019). Low access to immunization and screening
resources is a major issue in less developed nations like Bangladesh to diagnose at early stages.
It is estimated that more than 90% of cervical cancers are caused by the Human Papilloma Virus
(HPV) infection usually spread via sexual contact. (Bosch FX, Lorincz A, Munoz N, et al.). HPV
type 16 and 18 accounts for about 70% of cancer incidence.
There are numerous histological subtypes associated with cervical cancer. Epithelial tumors of
the cervix are divided into three categories: squamous, glandular (adenocarcinoma) and other
epithelial tumors including neuroendocrine tumors (carcinoid, atypical carcinoid and
neuroendocrine carcinomas) and undifferentiated carcinoma; however, squamous cell carcinoma
accounts for 90% of cases, making it the most frequent histology. Adenocarcinoma accounts for
approximate 7-10% of cases. (Chao et al., 2011).
The transformation zone of the endocervical canal known as the squamo-columner junction is
typically the site of squamous cell carcinoma of the cervix. Cellular transformation proceeds
step-by-step from a normal to a higher degree of dysplasia, and this higher degree of dysplasia
most likely leads to cancer, especially when co-factors like smoking or impaired immunity are
present. (Barron BA, et al., 1970).

Patients with cervical cancer should get care in close coordination with radiation oncologists,
radiologists, and gynecologic oncologists (Halperin et al. 2013). The initial course of treatment is
either surgery, radiation therapy (RT), or a combination of radiotherapy and chemotherapy. The
choice of treatment for locally advanced carcinoma cervix (FIGO-ⅡB to IVA) depends on the
histology of the tumor, probability of lymph node involvement, age and performance status of
the patient (Dobbs et al., 2009). Primary chemoradiation and Intracavitary irradiation has been
identified as an optimal modality for the treatment of locally advanced carcinoma cervix (Koh et
al., 2019). Radiotherapy techniques include two-dimensional (2D) therapy, three-dimensional
conformal radiotherapy (3DCRT), advanced conformal radiotherapy (intensity modulated
radiotherapy, IMRT). Chemotherapy alone is not used as a primary modality of treatment for
carcinoma cervix (Pazdur et al. 2010).

There are several controlled randomized studies which show efficacy of treatment can be
improved by the use of concurrent chemo-radiotherapy (Umayahara K et al., 2009, Walker JL et
al., 2009, Peters WA et al., 2000). Here the chemotherapy drug plays role as radiosensitizer
resulting in improved treatment response. The drugs that are used in concurrent chemo-radiation
are cisplatin, carboplatin, Gemcitabine, Paclitaxel, 5-flourouracil, capecitabine etc (Vincent T.
Devita et al., 2019).

Concurrent chemoradiation, using platinum-containing chemotherapy (cisplatin alone preferred),

is the treatment of choice for locally advanced cervical cancer patient based on the results of
randomized clinical trials. (Rose, P G et al 1999).

Another study shows weekly gemcitabine had similar disease control and tolerable toxicity
profile with cisplatin (arun k verma). A phase 3 trial conducted in india shows synchronous
chemo-radiotherapy using either gemcitabine or cisplatinum as radiation sensitizer is
feasible in locally advanced carcinoma cervix with similar overall response rate and acute
toxicity profile with a significantly higher complete response rate when gemcitabine is used
as a chemotherapeutic drug.(m.bhatt)
The aim of this study is to compare the clinical response of concurrent chemoradiation with
cisplatin and concurrent chemoradiation with gemcitabine and to investigate toxicity of
gemcitabine-based chemo-radiotherapy in locally advanced cervical cancer .
 Rationale of the study
Radiotherapy plays a vital role in curative intent for cervical cancer specially local control of
tumor, but associated with acute and chronic toxicities (Lin et al., 2018). Therefore, at present,
combination of concurrent chemo-radiation with External beam radiotherapy followed by
intracavitary brachytherapy is widely accepted in treatment of locally advanced carcinoma
cervix.
Cisplatin (platinum-based anticancer drug) is commonly used in concurrent chemoradiation
therapy for locally advanced carcinoma cervix. But some cisplatin induced toxicities have been
well recognized like nausea, vomiting, nephrotoxicity, neurotoxicity is common and specific
hydration policy must be maintained during cisplatin administration. Multivariate analyses have
shown that overall treatment time of <8 weeks are associated with improved pelvic tumor control
and survival in women with uterine cervix cancer. Treatment times beyond 8 weeks (56 days)
result in an up to 1% decline, per extended treatment day, in recurrence-free survival. But many
patients can not complete the treatment as scheduled due to toxicities of concurrent chemo-
radiation with weekly Cisplatin. These facts have stimulated interest in exploring other
alternative concurrent chemotherapeutic agents with potential clinical effects.

Gemcitabine, 2',2'-difluorodeoxycytidine, is a very potent and specific deoxycytidine analog that

has been evaluated in combination with concurrent radiation for treatment of various types of
cancer, demonstrating its safety within the range 100–1000 mg/m 2/wk when used concurrently
with radiation (88). It has shown significant cytotoxic activity against cervical cancer cells in
various trials with good clinical response, less toxicities (dose limiting toxicity is
myelosuppression) and no strict hydration policy. So, it may be also effective in terms of patient
with co morbidities like altered renal function, HTN, IHD. In my study, the effectivity of
Gemcitabine as alternative concurrent chemotherapeutic agent will be evaluated in terms of
response & toxicities.
 Hypothesis
Alternate Hypothesis (H1):
Concurrent chemoradiation with Gemcitabine is effective, less toxic and more convenient than
cisplatin in the treatment of Locally advanced carcinoma cervix.

Null hypothesis (H0):

There is no difference between concurrent chemoradiation with cisplatin and concurrent
chemoradiation in Gemcitabine in term of effectiveness, toxicity in the treatment of Locally
advanced carcinoma cervix.
 OBJECTIVES

 General Objectives:
To evaluate and compare the clinical response and toxicity of concurrent chemoradiation
with cisplatin versus gemcitabine in locally advanced carcinoma of cervix.

 Specific Objectives:

1. To evaluate and compare the treatment response in terms of relief of symptoms and reduction
of tumor size of concurrent chemoradiation with cisplatin versus gemcitabine in locally
advanced carcinoma of cervix.

2. To evaluate and compare the toxicity profile of concurrent chemoradiation with cisplatin
versus gemcitabine in locally advanced carcinoma of cervix.

3. To determine the socio-demographic characteristics of patients with locally advanced

carcinoma cervix.
 Materials and Methods
Study design:
Quasi-experimental study

Duration of study:
One year after IRB approval

Places of study:

This study will be conducted in –

1. Department of Radiotherapy, Dhaka Medical College and Hospital, Dhaka.

2. National Institute of Cancer Research & Hospital (NICRH), Dhaka.

Many cases of locally advanced carcinoma cervix are referred to these centers from all over Bangladesh.
Therefore, it will be easy to enroll adequate number of cases in this study.

Study population:
Carcinoma cervix patients FIGO stage IIB-stage IVA attending the Out-Patient Department of the above
mentioned centers will be enrolled in this study.

Permission for the study

1. Proper permission will be taken from the department concerned of the study.

2. Informed written consent will be taken from each patient before enrolling in the study.

Sampling technique
Non-probability, convenient and purposive sampling
Sample Size:
For determination of sample size following formula has been applied: -
n =𝑝1(1−𝑝1) + 𝑝2(1−𝑝2) (𝑝1−𝑝2)2 X (Zα+Zβ)2
p1 = Proportion of patients developing outcome in one arm (Arm A)
p2 = Proportion of patients developing outcome in another arm (Arm B)
Zα = 1.96, From Z table at 5% level of significance with 95% confidence interval. (Hoque M.
2021, p. 392) (Appendix-VII)
Zβ = 1.28, From Z table at 80% power (Hoque M. 2021, p. 394) (Appendix-VIII)
Concurrent CCRT with gemcitabine is expected to produce complete response in 89 % of locally
advanced carcinoma cervix patients (m bhatt) and CCRT with cisplatin expected to produce same
response of 72% (m.bhatt)
Here,
P1 = 89% (0.89)
P2 = 72% (0.72)
Zα = 1.96
Zβ = 1.28
n = Sample size
n = 0.89(1−0.89)+0.72(1−0.72)(0.89−0.73)2 X (1.96+1.28)2
n = 82
With 10% allowance for lost to follow up final sample size is 82 + 8.2=90.2
A total of ?90 patients with above mentioned criteria will be selected as sample 45 in each arm.
Sampling Technique
Non-probability type of purposive sampling
Selection of Patients:
Inclusion Criteria:
1. Biopsy proven squamous cell carcinoma and adenocarcinoma of cervix in locally advanced stage
(FIGO stage IIB to IVA)

2. Patients having ECOG performance status up to scale 2.

3. Patients having hemoglobin > 10 g/dL, leucocytes > 4,000/mm3, platelets > 150,000/mm3; serum
transaminase < 2.5 times the upper normal limit; serum creatinine < 1.5 mg/dL.

4. Those who has no metastasis and without urinary obstructive feature.

5. Age more than 20 years to 70 years.

Exclusion Criteria:
1. Pregnant or lactating woman.

2. Other epithelial tumors of cervix including neuroendocrine tumors (carcinoid, atypical carcinoid
and neuroendocrine carcinomas etc) and undifferentiated carcinoma.

3. Prior chemotherapy, pelvic radiotherapy (EBRT or ICRT) or surgery.

4. Serious concomitant medical illness including severe heart disease, uncontrolled diabetes mellitus
or uncontrolled hypertension.

5. Patient with uncontrolled infection. Example - pelvic inflammatory disease.

6. Patient dropped out, lost to follow up before completion of study.

Criteria for discontinuation from study:
• Patient’s refusal to continue study participation.
• Occurrence of unacceptable toxicity necessitating major modification of treatment.
Justification for Inclusion and Exclusion Criteria:
Patient’s age equal or more than 20 years will not be included due to cervical cancer usually
develop 10-20 years after the initial exposure to Human Papilloma Virus. A cut off age 70 years
is selected because at this age range, patients have co-morbidities as well as limited life
expectancy. Due to adverse effects of radiation on fetus like spontaneous abortion, congenital
malformation and mental retardation pregnant patients will be excluded from this study. Patient
with distant metastasis will also be excluded as their modalities of treatment is palliative instead
of curative. The presence of uncontrolled diabetes mellitus, uncontrolled hypertension, serious
pelvic infection and a history of prior surgery may complicate the adverse effects of
radiotherapy.
Prior radiation therapy may distort the normal anatomy of the pelvis by forming new scar tissue
and fibrosis, which may complicate the insertion of brachytherapy instruments.SO,these patients
will also be excluded from this study.
Research instrument
A structured data collection form, consists of sociodemographic information, relevant
history, clinical examination and investigations will be used as research instrument (Appendix-
II)
Study method:
Locally advanced carcinoma cervix patients who will fulfill the inclusion criteria
will be enrolled in this study after informed written consent. The patient will be counselled about
treatment expenditure, procedure, expected response and toxicities of the two arms. According to
patient choice and financial condition, they will be enrolled in both arms either arm-A or arm-B.
About 40 patients will be enrolled in each arm. Patients of arm-A will be treated by Combined
Chemoradiation (CCRT) with weekly cisplatin at a dose of 40 mg/m2. Patients of arm-B will be
treated by Combined Chemoradiation (CCRT) with weekly gemcitabine at a dose of 125 mg
/m2. Maximum of six courses of Cisplatin or Gemcitabine will be given to all patients with
sufficient kidney and bone marrow function during the EBRT. All patients will receive Whole
pelvic radiotherapy (WPRT) to the primary tumor and pelvic lymph nodes by conventional
radiotherapy to the total dose of 50 Gy in 25 fractions by 2-D CO-60 machine. After completing
pelvic radiation with EBRT, all the patients of both arms will be treated with ICRT. Total three
insertions (one insertion per week) of ICRT, 7Gy for each insertion will be given. Assessment of
patients of both arms will be conducted weekly during CCRT, starting from the onset of
radiotherapy. Response evaluation will be done during and after treatment. Acute and late
toxicities (both hematological and non-hematological), if present, will be recorded
using CTCAEv5.0 criteria (Appendix-IV) and ‘Toxicity criteria of the radiation therapy
oncology group (RTOG) /The European Organization for Research and Treatment of Cancer
(EORTC) 1995’ (Appendix-IV)
 Pre-treatment Evaluation

Following procedures will be followed to evaluate the patient’s condition before treatment –
General:
 Complete history, performance status and physical examination.

 Location and size of the tumor by per-vaginal examination will be recorded prior to
treatment.

Diagnostic procedure:
 Histopathology report that has been done by taking biopsy from primary tumor site.

 Per-vaginal examination

 Per-speculum examination

 Per-rectal examination

Laboratory studies:
 Complete blood count

 Renal function test.

 Liver function test.

 ECG

 Echocardiography

Radiological studies:
 X-ray chest P/A view.

 Ultra-sonogram of whole abdomen

 MRI of whole abdomen and pelvis with contrast

 Intravenous urography
Case Collection:

80 patients (40 patients in each arm) will be selected from different hospitals
mentioned above. After selection, a informed written consent will be taken from them
before their participation in the study. The researcher will counsel each patient and history
will be documented according to prescribed data-sheet. Clinical examination and necessary
investigations will also be done. Many cases of cervical cancer are referred to these centers
from all over Bangladesh. Therefore, it will be easy to enroll adequate number of cases in this
study.

Registration Procedures:
Patients are registered after pre-treatment evaluation completed and eligibile
criteria met. Following information were provided –
 Patient's name and registration
 Eligibility criteria information
 Treatment date

Data collection
Findings of observation will be recorded in a prescribed data collection form (attached
herewith, Appendix - II)

Confidentiality:
The utmost confidentiality of the patients will be maintained. All information and record will
be kept anonymous. A code number will be used on each data collection sheet which contains
patient’s personal information.
 Intervention
Patients will be divided equally into two arm, arm A and arm B by purposive sampling.
Selected patients in each Arm will be received treatment as mentioned below:
Arm A:
 Patients of arm-A will be treated by Concurrent Chemoradiation (CCRT) with weekly
cisplatin at a dose of 40 mg/m2.
Arm B:
 Patients of arm-B will be treated by Concurrent Chemoradiation (CCRT) with weekly
gemcitabine at a dose of 125mg/m2.
For both arms:
 For both the arms, all patients will receive Whole pelvic radiotherapy (WPRT) to the
primary tumour and pelvic lymph nodes by conventional radiotherapy to the total dose
of 50 Gy in 25 fractions by 2-D Co-60 machine.
 After pelvic irradiation with EBRT, all the patients of both arms will be treated with
ICRT. Three insertions (one insertion per week) of ICRT, 7Gy for each insertion will
be given.
 Patient assessment

Assessment during treatment:

Assessment of these patient for treatment response and side effects will be done every weekly.
Duration of treatment will be measured from the first day of treatment upto the end
day of intracavitary brachytherapy.

Assessment after Treatment:

• Careful evaluation of patient will be done with clinical examination and relevant investigations
at 2 weeks, 4 weeks, 12 weeks of completion of treatment (both CCRT and
brachytherapy)
• At 1st follow up (after 2week of treatment) and 2nd follow up (after 4 week of treatment)
clinical examination, and associated laboratory investigations will be done to assess the
relief of symptom, quality of life and toxicities due to radiotherapy.
• The final response will be documented at 3rd follow up (after 12 week of treatment)
after completion of all therapy by clinical examination, ultra-sonogram of whole
abdomen and CT scan of abdomen (when needed) and associated laboratory
investigations to assess disease response and late toxicity. Designation of complete
response, partial response, stable disease, or progressive disease will be based on
standard Response Criteria.
Response Criteria:
Response assessment will be done based on RECIST criteria which is attached in appendix VI.

Toxicity reporting
For toxicity assessment, the American National Cancer Institute’s ‘Common Terminology
Criteria for Adverse Events, v.5.0’ published on 27th November, 2017 and ‘Toxicity
criteria of the radiation therapy oncology group (RTOG) /The European Organization
for Research and Treatment of Cancer (EORTC) 1995’ will be used (Appendix-IV). If
any toxicity develops during treatment, it will be managed appropriately.

Variables

Independent variables:
Demographic variables:
• Age of the patient
• Socio-economic status
Patient variables:
• Age of marriage
• Parity
• Use of Oral Contraceptive Pill
• Cigarette smoking
• Nutritional status
• Personal hygiene
• Educational status
Clinical variables:
• History of post-coital bleeding
• History of intermenstrual bleeding
• History of postmenopausal bleeding
• Excessive prevaginal foul smelling serosanguinous or yellowish discharge
• Pain in the pelvis or hypogastrium
• Symptoms of bladder, rectal involvement
• FIGO stage of the disease at diagnosis
Laboratory variables:
• Histopathological grading

Dependent variable:
• Treatment outcome.
• Treatment related toxicities:
Non-Hematological toxicity:
▪ Nausea (Grade 0-III)
▪ Vomiting (Grade 0- IV)
▪ Diarrhea (Grade 0- IV)
▪ Rectal toxicities (Grade 0- III)
▪ Urinary bladder toxicity (Grade 0- III)
▪ Renal toxicity (Grade 0- IV)
▪ Neurotoxicity (Grade 0- IV)
▪ Ototoxicity (Grade 0- IV)
Hematological toxicity:
▪ Leucopenia (Grade 0- IV)
▪ Anemia (Grade 0- IV)
▪ Thrombocytopenia (Grade 0- IV)
 OPERATIONAL DEFINITION

Concurrent chemoradiotherapy:
Use of chemotherapy during radiotherapy is termed concurrent chemoradiotherapy.
Here chemotherapeutic agent acts as radio-sensitizer and prevent distant occult
metastasis. Many cytotoxic agents like Cisplatin, 5-flurouracil, Gemcitabine, Paclitaxel etc.
shows potential radio-sensitizing activity.

Radiotherapy
Basic principle of radiotherapy is to cure the patient with minimal functional and structural
impairment. Treatment planning involves accurate localization of the tumor and prescription of
daily fractions of radiation for a specific period of time. Biological effect of radiation depends on
the amount of energy absorbed per unit mass resulting in eradication of the tumor, a high quality
of life, and prolongation of survival at a reasonable cost. Radiotherapy for cervical cancer
consists of a combination of EBRT and ICRT.

External beam radiotherapy (EBRT)

All patients will receive EBRT 50 Gy in 25 daily fractions (2 Gy per fraction/day, five days per
week). All patients will be treated by parallel opposed fields (Anterior posterior fields)

Brachytherapy (ICRT)
Brachytherapy delivers a very high dose of radiotherapy to the tumor volume to obtain maximal
local control without exceeding the tolerance of surrounding normal tissues. In carcinoma cervix
we use the Manchester system for prescribing dose in reference points named Point A and Point
B.
After completion of EBRT, patients in both the arms will receive HDR brachytherapy of weekly
7Gy in 3 fractions (Total dose of 21 Gy). The first HDR brachytherapy application will be
inserted no later than 7 days after completion of pelvic radiation.
 About used chemotherapeutic drugs:

Cisplatin :

Mechanism of action:
It is a heavy metal alkylator of DNA. Covalently binds to proteins, RNA, and especially DNA,
forming DNA cross-linking and intra-strand N-7 adducts, causing DNA damage, inhibition of
DNA replication, failure to repair strand breaks, and cell death.

Toxicity:
Cisplatin causes myelosuppression with dose-limiting thrombo-cytopenia, and also can cause
ototoxicity and asthenia. Nausea and vomiting occur in almost all patients and is often severe.
Renal toxicity can be significant and may result in electrolyte abnormalities.Intravenous
hydration both before and after administering cisplatin is necessary to reduce the incidence of
renal toxicity.

Gemcitabine:

Mechanism of action:
It belongs to antimetabolite cytotoxic group (Fluorine-substituted deoxycytidine analog)
Intracelluler transformation to the cytotoxic gemcitabine triphosphate metabolite incorporate into
DNA, resulting in chain termination and inhibition of DNA synthesis and function. It also
incorporates into RNA, resulting in alterations in RNA processing and mRNA translation. Both
of the activity results in cell death.

Toxicity:
Myelosuppression is dose-limiting, with neutropenia more common. Nausea, vomiting, hepatic
dysfunction specially increase in serum transaminase, serum bilirubin.
Anemia
Anemia is usually defined as a decrease in the hemoglobin (< 10 g/dl) in the blood in
relation to age and sex. It can also be defined as a lowered ability of the blood to carry
oxygen or reduced total amount of red blood cells.

Neutropenia
Neutropenia is an abnormally low count of neutrophils per unit volume of blood
(<1,500/cmm). Neutropenia makes the patients susceptible to infection.

Thrombocytopenia
Thrombocytopenia is the deficiency of platelets (<150,000/cmm) in the blood.

Performance status
Performance status refers to the level of activity to which a patient is capable of (Khleif,
Rixe & Skeel 2016, p. 7). (Appendix-III)

Socio-economic condition:
According to the report of household income and expenditure survey, statistics and
informatics division, Bangladesh Bureau of Statistics, Ministry of planning, March 2011,
economic condition of study population can be divided into:
i) Group I (Poor): Monthly income TK. <12,260/-
ii) Group II (Middle class): Monthly income TK. 12,260 – 31,640/-
iii) Group III (Upper class): Monthly income TK. >31,640/-
 Analysis and Interpretation of Data
The data will be tabulated in separate tables for both Arm-A and Arm-B. It will be
checked, edited, coded manually and finally saved in computer. Data analysis will be done
according to the objectives of the study by using the SPSS (Statistical Package for Social
Science) software program for Windows, version 21.

Missing data imputation:

In the analysis of clinical trial results, dropouts need to be addressed during the trial. In
this trial, the Intention-to-treat analysis (ITT) method will be used. It is considered good
practice not to ignore dropouts. ITT analysis includes every subject who is randomized
according to randomized treatment assignment. It ignores noncompliance, protocol deviations,
withdrawal, and anything that happens after randomization (Gupta, 2011). US Food and Drug
Administration (FDA) guidelines for ‘The Format and Content of the Clinical and Statistical
Sections of Applications’ explains that the results of a clinical trial should be assessed not only
for the subset of patients who completed the study, but also for the entire patient
population randomized (FDA, 1988). ITT analysis reflects the practical clinical scenario
because it admits noncompliance and protocol deviations. ITT analysis maintains
prognostic balance generated from the original random treatment allocation. It gives
an unbiased estimate of treatment effect (Montori and Guyatt, 2001). ITT analysis preserves
the sample size because if noncompliant subjects and dropouts are excluded from the final
analysis, it might significantly reduce the sample size, leading to reduced statistical power
(Wertz, 1995). In addition, it minimizes type I error due to cautious approach and allows for
the greatest generalizability (Fergusson et al., 2002).
Ethical Consideration
Ethical issues related to this study will be maintained carefully. In this study the
following criteria will be ensured to maintain the ethical standard.
• All patients will be given an explanation of the study including the risks and benefits.
• All patients will be included in the study after taking their informed consent.
• Informed consent form will be supplied in Bengali & English versions.
• It will also be explained to them that they have the right to refuse or accept to participate
in the study.
• The patient will not gain any financial benefit from the study.
• All data obtained during the study period from the patient will remain confidential.
Permission will be taken by the institutional review board of Dhaka medical college and hospital

Limitations of the study

 Period of study is one and half year, which is insufficient to conduct a quality study.

 Due to lack of understanding and education some patient may not attend in follow up visits
according to the schedule.

 All relevant examination will not be possible to be done due to financial constrain of the
patient.

 If there are more limitations in the study, that will be discussed after completion of the study.
 Dummy tables

Table 1: Distribution of patients by age in arm A and arm B

Arm A Arm B p value

Age of the patients (n=40) (n=40)
(years)
n % n %

18-29

30-39

40-49

50-59

60-70

p value reached from Chi square test

Table 2: Acute Neutropenia in Arm A (n=40) and Arm B (n=40)

Response Arm A (n=30) Arm B (n=30) p value

n % n %

Grade 1

Grade 2

Grade 3
Grade 4

S = significant
p value reached from Chi square test
 References

Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018:
A worldwide analysis. Lancet Glob Health, 2020;8(2):e191–e203.
Global Cancer Observatory, ©2020. GLOBOCAN 2020. [Viewed 15 june 2022]. Available from:
https://gco.iarc.fr/today/home

Schiffman MH, Brinton LA. Devesa SS, Fraumeni JF Jr. Cervical cancer. In: Schottenfeld D, Fraumeni
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