Journal of Cancer and Clinical Oncology JCCO

Vol. 3(2), pp. 024-029, June, 2019. © www.premierpublishers.org. ISSN:5907-4449

Research Article

Role of Oral Gefitinib In Recurrent Carcinoma Cervix in

Relation to EGFR Status
Debabrata Barmon1, *Bipul Prasad Deka2, A.C. Kataki3, Dimpy Begum4, Megha Nandwani5
1Professor and HOD Department of Gynae-oncology Dr. B. Borooah Cancer Institute, Guwahati, Assam
2,5Fellow, Department of Gynae-oncology Dr. B. Borooah Cancer Institute, Guwahati, Assam
3Director, Dr. B. Borooah Cancer Institute, Guwahati, Assam
4Senior Resident, Department of Gynae-oncology Dr. B. Borooah Cancer Institute, Guwahati, Assam

Cervical cancer is among the most commonly diagnosed cancers in women worldwide. it may
persist or recur months or years after completion of the primary treatment. Management of the
residual /recurrent disease depends on mode of primary treatment and the extent of recurrence.
The treatment options for these include chemotherapy, radiotherapy or surgery. The role of
chemotherapy in cervical cancer recurrence is palliative only. This was a prospective study
conducted in Dr.B.Borooah Cancer Institute, Guwahati, Assam, A grant in aid institute of
Department of Atomic Energy, Govt.of India from October 2017 to March 2019. In our study we
evaluated the clinical outcome of oral Gefitinib in recurrent carcinoma cervix cases. The main
objective was to investigate the correlation of baseline EGFR expression with tumor response
and disease control with Gefitinib. 30 patients with recurrent carcinoma cervix were treated with
Gefitinib. Out of these 10 patients had progression of disease during the study period. Median
PFS was 10 months. Overall progression free survival and median overall survival was 42.6% and
93.3% respectively at the end of study period of 18 months. Gefitinib is a good option as oral
chemotherapy having a good PFS with minimal side effects for recurrent carcinoma of cervix in
palliative setting.

Keywords: cervical cancer, chemotherapy, radiotherapy, EGFR (epidermal growth factor receptor), Gefitinib, PFS
(progression free survival).

INTRODUCTION

Cervical cancer is among the most commonly diagnosed
cancers in women worldwide. In 2018, according to the
GLOBOCAN estimates, there were 5,69,847 new cases of
cervical cancer worldwide and in India cervical cancer is
the third most common cancer with 96922 new cases
(Bray et a l2018,Ferlay j et al 2018).cervical cancer may
have high mortality(Turkiye klinikleri 2018) .It ranked 4th as
far as mortality is concerned with 60078 death (Bray et al
2018,Ferlay j et al 2018).
Cervical cancer may persist or recur months or years after
the completion of initial cancer directed treatment, which
may have included surgery, radiation and/or
chemotherapy. The recurrence may be local/pelvic, distant
metastases, or a combination of both. The recurrence rate
is lower for those with early stage disease (Delgado et
al1990). A 10-20% recurrence rate has been reported
following primary surgery or radiotherapy in patient with
stage 1b-2a cervical cancers without lymph node
involvement. The rate increases upto70% in patients with
nodal metastasis and/or locally advanced disease
(Burgghardt et al1992, Perez et al1995,Stehman FB et al
1991,Ziano r j et al1992).
*Corresponding Author: Bipul Prasad Deka, U Fellow,
Department of Gynae-oncology Dr. B. Borooah Cancer
Institute, Guwahati, Assam. E-mail:
bipuldeka012@gmail.com, Tel: 7002692997.
Co-Author Email: 1drdbarmon@gmail.com;
3
dramalchkataki@yahoo.com; 4drdimpyb@gmail.com;
5
megha.nandwani@gmail.com

Role of Oral Gefitinib In Recurrent Carcinoma Cervix in Relation to EGFR Status

Barmon et al. 025
The management of recurrent or residual disease depends
on the mode of primary treatment and on the site and
extent of recurrence (Thigpen T et al 1981). If the disease
recurs in the pelvis after primary radiation therapy, surgical
resection/pelvic exenteration may be performed in some
patients. Radiation therapy is the treatment of choice if
pelvic recurrence occurs after primary surgery (Hogg R et
al 2003,Long HJ 2007). Chemotherapy is often
recommended for patients with recurrent or residual
disease who are not candidates for radiotherapy or
exenterative surgery.
The role of chemotherapy in cervical cancer recurrence is
palliation (Taba et al 2018). The primary objective is to
relieve the symptoms and improve the quality of life. The
secondary objective is to prolong the survival ((Hogg R et
al 2003,Long HJ 2007). The chemotherapy options include
platinum alone or in combination with paclitaxel,
irinotecan, topotecan, gemcitabine (Burnett A F et
al2000,Lhomme C et al1999, Lhomme C et al 2000,Morris
M et al 2004,Muggia F M et al 2004,Mundt A J et al 2004,
Rose P G et al1999,Taba et al 2018, Tiersten A D et al
2004).With current chemotherapy regimens, the Overall
and Progression free survival is poor and so alternative
treatment options are required.
Epidermal growth factor receptor (EGFR) is a glycoprotein
that dimerizes to activate a tyrosine kinase domain which
modulates functions such as cell growth, differentiation,
development, gene expression etc (Pao W Miller et
al2004). EGFR inhibitors have demonstrated efficacy in
clinical trials involving patients with colon, lung, head and
neck cancers (Rossi S 2004, Sordella R et al 2004).
Evidence suggests that EGFR is expressed at moderate
to high levels in cervical stroma. EGFR is known to be
overexpressed in greater than 75% of squamous cell
carcinoma of cervix, although the impact of EGFR
overexpression on the prognosis of patients with cervical
cancer is controversial (Bellones et al 2007, Kim J W et
al1966,Scambia G et al 1998).
Gefitinib is the first selective inhibitor of EGFRs tyrosine
kinase domain. Gefitinib inhibits EGFR tyrosine kinase by
binding to ATP binding site of the enzyme. Thus, the
function of tyrosine kinase in activating the anti-apoptotic
RAS signal transduction cascade is inhibited, and
malignant cells are inhibited (Lynch TJ et al2004,Motte
Rouge 2006).
AIMS AND OBJECTIVES
To determine the tumour response and disease control
with Gefitinib and relation to EGFR status if any.
To determine the progression free survival, overall survival
and toxicity following use of Gefitinib.
Role of Oral Gefitinib In Recurrent Carcinoma Cervix in Relation to EGFR Status
MATERIALS AND METHOD
It is a Prospective phase 1 study carried out in the
Department of Gynaecologic Oncology, Dr. B. Borooah
Cancer Institute, Guwahati, Assam.
DURATION OF STUDY: One and half year (October 2017
to March 2019)
STUDY DESIGN
The study was carried out in the department of
Gynaecology-oncology in Dr. B. Borooah Cancer Institute,
Guwahati (Assam) India. Histopathological examination
was performed for confirmation of recurrence. Tissue from
the recurrent growth was sent for EGFR study.
Ultrasonography or CT scan was performed for evaluation
of extent of disease. A specially designed proforma was
used to collect the information of the patients. The purpose
of the study with beneficial effects as well as side effects
of the drug was explained to each eligible patient and the
informed written consent was taken. 30 patients were
included in the study. They were prescribed Gefitinib 250
mg orally daily until disease progression, development of
intolerable side effects or withdrawal of consent. The
primary end point of the study was progression free
survival and secondary end points was stable disease,
overall survival and toxicity.
During the course of treatment, all patients were
followed up every 4 weekly to monitor the general
condition and treatment related toxicities. Follow up
included clinical examination, CBC, RFT and LFT.
Imaging investigations like USG, CT, MRI etc were
advised if and when required, to determine the
local/systemic control/spread. After 3 months of starting
the therapy repeat imaging was done to see the
response. Patients were followed upto March 2019 to
assess the progression-free interval and WHO
performance status.
Statistical method used – Kaplan Meier method for
survival analysis
INCLUSION CRITERIA
1. Patients who developed loco regional recurrence (LRR)
OR Distal metastasis (DM) from cervical cancer after
primary treatment were enrolled in the study. Diagnosis
of LLR or DM will be established either by
Histopathological examination or cytology
2. Age below 60 years.
3. Histological proof of malignancy at diagnosis.
4. WHO performance score 0 to2.
5. Haematologic parameters
HB% 9 gm/dl. WBC>3000/cubic mm, Absolute
granulocyte count >1500/cubic mm, Platelet count
>100000/microlt.
 J. Cancer Clin. Oncol. 026

RESULTS AND OBSERVATION

Out of the thirty patients with recurrent cervical cancer,

twenty-six patients were of squamous cell carcinoma
variety and four patients with adenocarcinoma were
enrolled in the study between October 2017 and march
2019. They were treated with Gefitinib 250 mg orally. The
median duration of treatment was 8 months (range2
months to 18 months). All patients received prior
radiotherapy and chemotherapy except one who received
only radiotherapy.

Table 1.Patient demographic characteristics

Age distribution Nos.
40-45 years 7
50-59 years 17
60-69 years 6
MEAN AGE 57.2 years.
WHO performance status Nos.
0 5
1 21 Overall Survival 93.3% at the end of study period.
2 4
Histology Nos.(percentage)
Squamous cell carcinoma 26(86.66%)
Adenocarcinoma 4(13.33%)
EGFR status Nos.(percentage)
Positivity in squamous cell 23 (88.41%)
carcinoma
Positivity in adenocarcinoma 3 (75%)
Initial staging at the time of Nos.(percentage)
diagnosis
Stge IIB 18 (60%)
Stage IIIB 11 (36.66%)
Stage IVA 1 (3.33%)
Site of recurrence
Pelvis 27(90%)
Distant 3(10%)
Prior treatment received
Concurrent CT-RT 29(96.66%)
Only RT 1(3.33%)

Out of 30 patients, 2 patients expired about 2 and 3 months

after starting of treatment. One patient expired due to
uraemia following obstructive uropathy. Second patient
expired following anaemic heart failure due to severe
anaemia. During the treatment, 10 patients had
progressive disease which was diagnosed by imaging
study(ultrasonography or CT scan). Twenty patients had
stable disease, at the end of the study. Regarding EGFR
status most of the cases expressed EGFR positivity in both
squamous and adenocarcinoma variety.

Role of Oral Gefitinib In Recurrent Carcinoma Cervix in Relation to EGFR Status

Barmon et al. 027

Table 2: Progression free survival

Means and Medians for Survival Time
Meana Median
95% Confidence Interval 95% Confidence Interval
Estimate Std. Error Lower Bound Upper Bound Estimate Std. Error Lower Bound Upper Bound
10.260 .642 9.002 11.518 10.000 1.065 7.913 12.087
a. Estimation is limited to the largest survival time if it is censored.
The median progression free survival is 10 months.
Overall Progression free survival = 42.6%

Table 3:Status at the end of study: palliative. Targeted therapeutics represents a promising
Status area which needs further research( Motte Rouge
2006).There are limited data or publications regarding the
Valid Cumulative efficacy of Gefitinib in recurrent cervical cancer cases.
Frequency Percent Percent Percent
80% of lung cancer patients who are carriers of EGFR tk
Valid Alive 28 93.3 93.3 93.3 domain mutations experience partial response or marked
Dead 2 6.7 6.7 100.0 clinical improvement with Gefitinib or Elrotinib. Patients
without such mutations are refractory to these agents(
Total 30 100.0 100.0 Lynch TJ 2004)
Out of 30 patients 28 patients were alive at the end of the
study. In our study majority cases were found to be squamous
cell carcinoma .EGFR expressed in about 88% cases of
Table 4:Response to treatment at 18 months squamous cell carcinoma and about 75% cases of
Total patients for study 30 adenocarcinoma. A median progression free survival of 10
Alive 28 months was observed.Overall progression free survival
Complete remission Nil and median overall survival was 42.6% and 93.3%
Partial remission Nil respectively at the end of study period. Disease response
Progressive disease 10 in relation to EGFR status could not be evaluated as EGFR
Stable disease 20 negative sample is too low (only 4 cases were EGFR
negative).These findings can be compared with following
Expired 02
studies.
Patient leaving study duo to toxicity Nil
Progression free survival 10 months
A Goncalves et al(2008) in their study evaluated 28
Median overall survival 93.3% patients for efficacy of Gefitinib in recurrent ca cervix. In
WHO status their study no objective response was found.6 patients had
0 stable disease lasting 77 -118 days(median 111.5
1 5 days).22 patients had progressive disease. Median time to
2 11 progression was 37 days. Median overall survival was 107
3 12 days. At closure of trial 10% patients were alive. In their
study 86.7% of the cases expressed EGFR positivity .No
Adverse effects correlation was found between EGFR expression and
disease control.
In our study 12 patients had anaemia of varying degree.
Out of these 7 patients had on and off bleeding per vagina, In our study 81% patients showed EGFR positivity.
so anaemia may not be related to the drug. 10 patients had Sharma, Dayanand et al(2013) evaluated 20 recurrent ca
symptom of anorexia. Acne like rash appeared in 2 cervix cases with Gefitinib. The median PFS was 4
patients which was treated with soothing agent. 3 patients months. Median OS was 5 months. Toxicity of Gefitinib
gave history of excessive discharge per vagina. 1 patient was within acceptable limit.
had diarrhoea after starting the drug, treated with iv fluids.
Russell j et al(2009) in their phase 2 trial of Elrotinib in
recurrent squamous cell carcinoma cervix evaluated 25
DISCUSSION patients. In their study no objective response was
found.16% patients had stable disease.1 patient had PFS
Current treatment for advanced stage/recurrent cervical of > 6months.
carcinoma has only limited efficacy and is most often

Role of Oral Gefitinib In Recurrent Carcinoma Cervix in Relation to EGFR Status


CONCLUSION
Cervical cancer despite being potentially preventable,
remains an important cause of morbidity and mortality
throughout the world. The role of radiotherapy is limited in
recurrent carcinoma cervix so also the systemic
chemotherapy due to poor performance status. So oral
chemotherapy is becoming an important treatment
modality in recurrent carcinoma cervix. Study of Gefitinib
in recurrent carcinoma cervix is still in preliminary stage
though its role in lung cancer is well established. In our
study we found that Gefitinib is a good option as oral
chemotherapy having a good PFS with minimal tolerable
side effects. Further studies are needed to evaluate the
effectiveness of Oral Gefitinib in recurrent carcinoma
cervix cases.
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CONFLICT OF INTEREST
There is no conflict of interest amongst the authors.
Accepted 10 June 2019
Citation: Barmon D, Deka BP, Kataki AC, Begum D,
Nandwani M (2019). Role of Oral Gefitinib In Recurrent
Carcinoma Cervix in Relation to EGFR Status. Journal of
Cancer and Clinical Oncology 3(2): 024-029.
Copyright: © 2019: Barmon et al. This is an open-access
article distributed under the terms of the Creative
Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium,
provided the original author and source are cited.

Role of Oral Gefitinib In Recurrent Carcinoma Cervix in Relation to EGFR Status