PROTOCOL Me
PROTOCOL Me
PROTOCOL Me
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.
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).
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.
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.
Duration of study:
One year after IRB approval
Places of study:
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.
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)
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.
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.
4. Serious concomitant medical illness including severe heart disease, uncontrolled diabetes mellitus
or uncontrolled hypertension.
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
ECG
Echocardiography
Radiological studies:
X-ray chest P/A view.
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
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.
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.
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
18-29
30-39
40-49
50-59
60-70
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
JF Jr, eds. (1996) ‘Cancer epidemiology and prevention’. New York: Oxford University Press; 1996.
p.1090-116.
Au‐Yeung, G., Mileshkin, L., Bernshaw, D.M., Kondalsamy‐Chennakesavan, S., Rischin, D. and
Narayan, K., 2013. Radiation with cisplatin or carboplatin for locally advanced cervix cancer: the
experience of a tertiary cancer centre. Journal of Medical Imaging and Radiation Oncology, 57(1),
pp.97-104.
Barrett, A., Morris, S., Dobbs, J. and Roques, T., 2009. Practical radiotherapy planning. CRC Press.
Cetina, L., Garcia-Arias, A., de Jesus Uribe, M., Candelaria, M., Rivera, L., Oñate-Ocaña, L.O.O.,
Coronel, J. and Dueñas-Gonzalez, A.D.G., 2008. Concurrent chemoradiation with carboplatin for
elderly, diabetic and hypertensive patients with locally advanced cervical cancer. European journal
of gynaecological oncology, 29(6), pp.608-612.
DeVita, V.T., Lawrence, T.S. and Rosenberg, S.A. eds., 2008. DeVita, Hellman, and Rosenberg's
cancer: principles & practice of oncology (Vol. 2). Lippincott Williams & Wilkins.
Donnelly, E.D., Refaat, T., Gentile, M., Herskovic, A., Boyle, J., Helenowski, I., Rademaker, A.,
Lurain, J., Schink, J., Singh, D. and Strauss, J.B., 2015. Evaluation of outcomes in patients with
carcinoma of the cervix treated with concurrent radiation and cisplatin versus cisplatin/5-FU
compared with radiation alone. American journal of clinical oncology, 38(5), pp.437-441.
Dueñas-González, A., Cetina-Perez, L., Lopez-Graniel, C., Gonzalez-Enciso, A., Gómez-Gonzalez,
E., Rivera-Rubi, L., Montalvo-Esquivel, G., Muñoz-Gonzalez, D., Robles-Flores, J., Vazquez-
Govea, E. and de La Garza, J., 2005. Pathologic response and toxicity assessment of
chemoradiotherapy with cisplatin versus cisplatin plus gemcitabine in cervical cancer: a randomized
phase II study. International Journal of Radiation Oncology* Biology* Physics, 61(3), pp.817-823.
Fu, Z.Z., Li, K., Peng, Y., Zheng, Y., Cao, L.Y., Zhang, Y.J. and Sun, Y.M., 2017. Efficacy and
toxicity of different concurrent chemoradiotherapy regimens in the treatment of advanced cervical
cancer: A network meta-analysis. Medicine, 96(2).
Global Cancer Observatory, ©2020. GLOBOCAN 2020. [Viewed 15 june 2022]. Available from:
https://gco.iarc.fr/today/home
Halperin, E.C., Wazer, D.E., Brady, L.W. & Perez, C.A. 2013, ‘Perez and Brady's principles and
practice of radiation oncology’, 6th edition, Lippincott Williams & Wilkins, London.
Haque, M.M., 2009. ABC of research methodology and biostatistics. 4th edition. Dhaka. September
2021
Hasan, M.R., Bari, M.A., Alam, S. and Sah, G.S., 2018. Concurrent weekly versus three weekly
cisplatin with radiotherapy in locally advanced uterine cervical carcinoma. JNMA: Journal of the
Nepal Medical Association, 56(213), p.842