Cervix Cancer

CONSENSUS DOCUMENT FOR THE
MANAGEMENT OF
CANCER CERVIX
Prepared as an outcome of ICMR Subcommittee on
Cancer Cervix
Indian Council of Medical Research,

Ansari Nagar, New Delhi 110029
2016
Disclaimer
This consensus document represents the current thinking of experts on the topic based on available
evidence. This has been developed by national experts in the field and does not in any way bind
a clinician to follow this guideline. One can use an alternate mode of therapy based on discussions
with the patient and institution, national or international guidelines. The mention of pharmaceutical
drugs for therapy does not constitute endorsement or recommendation for use but will act only as a
guidance for clinicians in complex decision making.
Dr. Soumya Swaminathan

Secretary,
Department of Health Research
and Director General, ICMR
Dr. V. K. Srivastava : Head (Publication & Information)
Compiled & Edited by : Dr Tanvir Kaur, Dr. S Shrisvastava
Published in 2016
Production Controller : JN Mathur
Published by the Division of Publication and Information on behalf of the Secretary DHR & DG, ICMR,
New Delhi.
Designed & Printed at M/s Aravali Printers & Publishers (P) Ltd., W-30, Okhla Industrial Area, Phase-II, New Delhi-110020
Phone: 47173300, 26388830-32
Foreword
I am glad to write this foreword for consensus document for management of
cancer cervix. The ICMR had constituted sub-committees to prepare consensus
document for management of various cancer sites. This document is the result
of the hard work of various experts across the country working in the area of
oncology.
This consensus document on management of cervix cancer summarizes
the modalities of treatment including the site-specific anti-cancer therapies,
supportive and palliative care and molecular markers and research questions. It
also interweaves clinical, biochemical and epidemiological studies.
The various subcommittees constituted under Task Force project on Review of Cancer Management
Guidelines worked tirelessly in formulating site-specific guidelines. Each member of the subcommittees
contribution towards drafting of these guidelines deserves appreciation and acknowledgement for their
dedicated research, experience and effort for successful completion. We hope that this document would
provide guidance to practicing doctors and researchers for the management of patients suffering from
cervix cancer and also focusing their research efforts in Indian context.
It is understood that this document represents the current thinking of national experts on subject
based on available evidence. Mention of drugs and clinical tests for therapy do not imply endorsement or
recommendation for their use, these are examples to guide clinicians in complex decision making. We are
confident that this first edition of Consensus Document on Management of Cancer Cervix would serve
the desired purpose.
(Dr.Soumya Swaminathan)
Secretary, Department of Health Research
and Director-General, ICMR
Message
I take this opportunity to thank Indian Council of Medical Research and all
the expert members of the subcommittees for having faith and considering me
as chairperson of ICMR Task Force project on guidelines for management of
cancer.
The Task Force on management of cancers has been constituted to plan
various research projects. Two sub-committees were constituted initially to review
the literature on management practices. Subsequently, it was expanded to include
more sub-committees to review the literature related to guidelines for management
of various sites of cancer. The selected cancer sites are lung, breast, oesophagus,
cervix, uterus, stomach, gall bladder, soft tissue sarcoma and osteo-sarcoma, tongue, acute myeloid
leukemia, acute lymphoblastic leukaemia, CLL, Non Hodgkins Lymphoma-high grade, Non Hodgkins
Lymphoma-low grade, Hodgkins Disease, Multiple Myeloma, Myelodysplastic Syndrome and Pediatric
Lymphoma. All aspects related to management were considered including, specific anti-cancer treatment,
supportive care, palliative care, molecular markers, epidemiological and clinical aspects. The published
literature till December 2016 was reviewed while formulating consensus document and accordingly
recommendations are made.
Now, that I have spent over a quarter of a century devoting my career to the fight against cancer,
I have witnessed how this disease drastically alters the lives of patients and their families. The theme
behind designing of the consensus document for managementof cancers associated with various sites
of body is to encourage all the eminent scientists and clinicians to actively participate in the diagnosis
and treatment of cancers and provide educational information and support services to the patients
and researchers. The assessment of the public-health importance of the disease has been hampered
by the lack of common methods to investigate the overall; worldwide burden. ICMRs National Cancer
Registry Programme (NCRP) routinely collects data on cancer incidence, mortality and morbidity in India
through its co-ordinating activities across the country since 1982 by Population Based and Hospital
Based Cancer Registries and witnessed the rise in cancer cases. Based upon NCRPs three year report
of PBCR (2012-2014) and time trends on Cancer Incidence rates report, the burden of cancer in the
country has increased many fold.
In summary, the Consensus Document for management of various cancer sites integrates diagnostic
and prognostic criteria with supportive and palliative care that serve our three part mission of clinical
service, education and research. Widespread use of the consensus documents will further help us to
improve the document in future and thus overall optimizing the outcome of patients. I thank all the
eminent faculties and scientists for the excellent work and urge all the practicing oncologists to use the
document and give us valuable inputs.
(Dr. G.K. Rath)

Chairperson
ICMR Task Force Project
Preface
The cancer of uterine cervix is the commonest cancer among the women in
India. However, the incidence is gradually reducing especially in urban areas as
observed in the population based registries. The treatment of early stage cancer
cervix is either radical surgery or radical radiotherapy with similar results, whereas,
for advanced stages the treatment remains as chemo-radiation. There has been
several advances and refinement in the treatment modalities for treatment of
cancer cervix in past few years.
The management of carcinoma cervix should be well defined and accomplished.
It has been noticed that there are variations in the treatment pattern across the
country. It is an admirable initiative of the ICMR for setting-up task force to bring out the consensus
document for the management of cancer cervix. These guidelines will be useful to the practicing
clinicians and students to optimize the treatment of their patients. This will also bring the uniformity in
the management across the country and establish collaborative studies. This will also help in bringing out
Indian data related to outcome and toxicity of the treatment and further refinement of management and
research in this area.
I am grateful to all members of the task group, who have been expert in their field, for devoting
their valuable time from their busy schedule and remained committed to their assigned task. I would
like to thank Dr GK Rath for his untiring support, inspiration and guidance and Dr Tanvir Kaur for her
continuous efforts and support in all meetings.
The ICMR deserves special thanks for these consensus documents. The consensus on the management
of cancers is a dynamic process in view of emerging evidence, and these will also be updated regularly
as the evidence evolves with newer knowledge. We would be happy to receive constructive feedback to
further improve this document for the benefit of our patients.
Shyam Kishore Shrivastava

Chairman
Sub-Committee for Carcinoma Cervix
Preface
Cancer is a leading cause of death worldwide. Globally Cancer of various types
effect millions of population and leads to loss of lives. According to the available data
through our comprehensive nationwide registries on cancer incidence, prevalence
and mortality in India among males cancers of lung, mouth, oesophagus and
stomach are leading sites of cancer and among females cancer of breast, cervix are
leading sites. Literature on management and treatment of various cancers in west
is widely available but data in Indian context is sparse. Cancer of gallbladder and
oesophagus followed by cancer of breast marks as leading site in North-Eastern
states. Therefore, cancer research and management practices become one of the
crucial tasks of importance for effective management and clinical care for patient in
any country. Hence, the need to develop a nationwide consensus for clinical management and treatment
for various cancers was felt.
The consensus document is based on review of available evidence about effective management and
treatment of cancers in Indian setting by an expert multidisciplinary team of oncologists whose endless
efforts, comments, reviews and discussions helped in shaping this document to its current form. This
document also represents as first leading step towards development of guidelines for various other cancer
specific sites in future ahead. Development of these guidelines will ensure significant contribution in
successful management and treatment of cancer and best care made available to patients.
I hope this document would help practicing doctors, clinicians, researchers and patients in complex
decision making process in management of the disease. However, constant revision of the document
forms another crucial task in future. With this, I would like to acknowledge the valuable contributions of all
members of the Expert Committee in formulating, drafting and finalizing these national comprehensive
guidelines which would bring uniformity in management and treatment of disease across the length and
breadth of our country.
(Dr. R.S. Dhaliwal)

Head, NCD Division
Acknowledgement
The Consensus Document on Management of Cervix Cancer is a concerted
outcome of effort made by experts of varied disciplines of oncology across the nation.
The Indian Council of Medical Research has constituted various sub committees to
formulate the document for management of different cancer sites. The Task Force
on Management of Cancers has been constituted to formulate the guidelines for
management of cancer sites. The sub-committees were constituted to review the
literature related to management and treatment practices being adopted nationally
and internationally of different cancer sites. The selected cancer sites are that of
lung, breast, oesophagus, cervix, uterus, stomach, gall bladder, soft tissue sarcoma
and osteo-sarcoma, tongue, acute myeloid leukaemia, ALL, CLL, NHL-high grade, NHL-low grade, HD,
MM, MDS, and paediatric lymphoma. All aspects related to treatment were considered including, specific
anti-cancer treatment, supportive care, palliative care, molecular markers, epidemiological and clinical
aspects.
This document represents a joint effort of large number of individuals and it is my pleasure to
acknowledge the dedication and determination of each member who worked tirelessly in completion of
the document.
I would like to take this opportunity to thank Dr. GK Rath, chairperson, ICMR Task Force on
Guidelines for Management of Cancer for his constant guidance and review in drafting the consensus
document. The chairperson of subcommittee is specially acknowledged in getting the members together,
organizing the meetings and drafting the document.
I would like to express gratitude to Dr. Soumya Swaminathan, Secretary, Department of Health
Research and Director General, Indian Council of Medical Research, for taking her special interest and
understanding the need of formulating the guidelines which are expected to benefit the cancer patients.
I would like to thank Dr. RS Dhaliwal for his support and coordination in finalizing this document.
I would like to acknowledge the assistance provided by administrative staff. This document is the result
of the deliberations by subcommittees constituted for this purpose. The guidelines were further ratified
by circulation to extended group of researchers and practitioners drawn from all over the country. It is
hoped that these guidelines will help the practicing doctors to treat cancer patients effectively and thus
help them to lead a normal and healthy life.
The ICMR appreciatively acknowledges the valuable contribution of the members for extending
their support in formulating these guidelines. The data inputs provided by National Cancer Registry
Programme are gratefully acknowledged..
(Dr.Tanvir Kaur)
Program Officer & Coordinator
Members of the Sub-Committee
Chairman
Dr S. K. Shrivastava
Prof. & Head, Department of Radiation Oncology,
Tata Memorial Hospital, Dr. E Borges Road,
Parel, Mumbai
Members
Dr G.K. Rath Dr Hemant Tongaonkar,

Chief, IRCH Consultant in Surgical Oncology,
All India Institute of Medical Sciences Tata Memorial Hospital, Dr. E Borges Road,
Ansari Nagar, New Delhi Parel, Mumbai
Dr Partha Basu, Dr BC Das,

Department of Gynaecological Oncology, Dr. BR Ambedkar Centre for
Chittaranjan National Cancer Institute, Kolkata Biomedical Research, University of Delhi
(North Campus), New Delhi
Dr Uma Devi, Dr Sudeep Gupta,

Professor, Gynecology Oncology Professor, Department of Medical Oncology,
Kidwai Memorial Institute of Oncology Tata Memorial Hospital, Dr. E Borges Road,
Bengaluru Parel, Mumbai
Dr Lalit Kumar, Dr Sunesh Kumar Jain,

Professor, Department of Medical Oncology, Professor, Department of Obstetrics &
IRCH, AIIMS, New Delhi. Gynaecology, AIIMS, New Delhi
Dr A. Selva Lakshmi, Dr Umesh Mahantshetty

Prof & Head, Radiotherapy Department, Additional Professor,
Adyar Cancer Institute, Chennai Department of radiation Oncology,
Tata Memorial Hospital, Mumbai
Dr Amita Maheshwari Dr Firuza Patel,

Professor, Dept. of Gynecology Oncology, Professor, Department of Radiotherapy,
Tata Memorial Hospital, Mumbai PGIMER, Chandigarh
Dr S. Radhika, Dr T.Subramanyshwar Rao,

Professor, Department of Cytology & Malakpet Cancer Hospital,
Gynaec Pathology, PGIMER, Chandigarh Himayet Nagar, Hyderabad
table of Contents
Page No.
Foreword 3
Message from Chairperson 4
Preface (Chairperson of Subcommittee) 5
Preface 6
Acknowledgement 7
Executive Summary 8
1 Introduction 10
2 Pre-treatment evaluation 12
3 Histopathological Types 13
4 Staging 15
5 Treatment 17
Stage I 17
Stage II + III
Stage IV
Stage V
6 Special Situations 26
7 Follow-up Strategies 30
8 Research Issues 31
9 Appendix 32
A - Biomarkers and cervical cancer 32
B - Pathology Reporting 36
C - Principles of Surgery 40
D - Principles of Radiotherapy 42
E - Principles of Chemotherapy 48
10 Bibliography 53
11 Abbreviations 59
1
CHAPTER
Introduction
C
ervical cancer remains a significant cause of morbidity and mortality among women globally,
even though it is the cancer with the greatest potential for secondary prevention. In some regions
of the world the incidence is alarmingly high, which includes India1, 2, however in some regions
in India there is decline in AARs over past few years3. This disease is highly preventable and curable. A
number of guideline documents are available for the management of common cancers in the published
literature. Large academic institutions typically produce their own local guidelines and use them on a daily
basis. In this document, all the recommended interventions are based on scientific evidence with the level
of evidence and/or grade of recommendation indicated.
1.1 EPIDEMIOLOGY
Cervical cancer is most common cancer in Indian women though breast is the leading cancer site globally.
In India, cervical cancer had increased from 0.11 million in 2000 to 0.16 million in 20104. The proportion
ranged from 15% to 55% of female cancers from different parts of the country. Over 80% of the cervical
cancer present at a fairly advanced stage and annually around 80,000 deaths are reported in India5.
According to global cancer statistics, cervical cancer is now the third most commonly diagnosed cancer
and the fourth leading cause of cancer death in females worldwide, accounting for 9% (529,800) of the
total new cancer cases and 8% (275,100) of the total cancer deaths among females in 2008. More than
85% of these cases occur in developing countries. India, the second most populous country in the world,
accounts for 27% (77,100) of the total cervical cancer deaths6. The disproportionately high burden of
cervical cancer in developing countries and elsewhere in medically underserved populations is largely due
to a lack of screening that allows detection of precancerous and early stage cervical cancer6,7.
It is now well recognized that cervical carcinogenesis occur in a stepwise fashion. This transition of
normal epithelium to pre-neoplastic lesions and invasive carcinoma occur sequentially and progress
through well recognized stages and takes approximately 1020 years to develop an overt malignancy.
The natural history of the disease suggests that screening should initially target those women who have
higher prevalence of high grade precancerous lesions (CIN2/CIN3) women mostly in their 30s and
40s. In India, the incidence of cervical cancer significantly rises around the age of 45 years and peaks
at 55 years of age. Persistent infection of Human Papilloma Virus (HPV), a sexually transmitted double-
stranded DNA virus is considered the most significant and necessary casual agent for the development
of cancer of uterine cervix. To date, more than 140 human and animal papilloma virus genotypes have
been characterized and sequenced. Approximately 30 HPVs that infect the anogenital tract, of these
15 HPV types classified as high-risk types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58,
59, 68, 73 and 82) are associated with high grade cervical cancer precursor lesions and invasive cervical
cancers. Molecular and clinico-epidemiological studies have demonstrated that HPV types 16 and 18 are
10 Consensus Document for the Management of Cancer Cervix

the two most common oncogenic HPV types found in invasive cervical cancer and high-grade cervical
intraepithelial neoplastic (CIN) lesions. On the other hand, 11 different HPV types classified as low-risk
types (HPV types 6, 11, 40, 42, 43, 44, 54, 61, 70, 81 and CP6108) are mainly associated with genital
warts and benign cervical lesions. Among these, HPV6 and HPV11 cause approximately 90% of genital
warts. In addition to HPV infection, co-factors such as parity, early age of marriage, genital hygiene,
promiscuity, use of oral contraceptives, smoking, immune suppression (eg HIV), infection with other
sexually transmitted agents and poor nutrition have been associated with the development of cervical
cancer8,9.
In India, the prevalence of HPV in cervical intraepithelial lesion and cancer is > 80% and the high risk
HPV 16/ 18 compiles in about > 90% of the cervical cancer cases. A population-based, cross-sectional
survey in married women aged 1659 years was conducted in rural Dindigul district, Tamil Nadu10.
Recently, it has been shown that a single round of HPV screening can cause a significant reduction in the
severity and mortality of the disease11. In India, approximately 90% of invasive cervical cancer cases are
squamous cell carcinoma, while 1012% is adenocarcinomas. In a national HPV mapping study in India,
prevalence of HPV16 was found to be highest in Chennai (88%), and lowest in Jammu and Kashmir
(14.2%)12,13.
The most effective secondary preventive strategy for cervical cancer is systematic screening of women
through an organized program along with treatment and follow-up of the screen detected precursor
lesions. Cervical screening should be advocated for all ever sexually active women within a certain age
group irrespective of whether they have any complaints, because there are often no signs and symptoms
of cervical precancers. The national guideline for cervical cancer screening in India advocates screening
of women between 30 years to 59 years of age. The focus on detection and prevention of cervical cancer
must be emphasized in a highly populated country like India.

2
CHAPTER
Pre-Treatment Evaluation for Cervical Cancer
2. Pretreatment Evaluation
Complete physical and gynecological examination (Examination Under Anesthesia if required to
confirm the stage)
Complete Blood Count and Biochemistry
Cervical biopsy: punch biopsy / wedge biopsy/ conization with electrosurgical loops or knife-
histopathological confirmation of malignancy is mandatory before starting the treatment
Chest radiograph
Optional investigations: The findings to be used to tailor the treatment rather than change the
staging
Ultrasonography abdomen and pelvis
CT Scan
MRI
PET-CT Scan
Cystoscopy / Procto-Sigmoidoscopy / Barium enema / Intra Venous Urogram - if clinical
suspicion of bladder, ureter or rectal involvement.

3
CHAPTER
HISTOPATHOLOGIC TYPES
Modified World Health Organization histological Classification of Invasive carcinoma of the uterine
cervix
Squamous Cell Carcinoma
Microinvasive (early invasive) squamous cell carcinoma
Invasive squamous cell carcinoma
Keratinizing
Nonkeratinizing
Basaloid
Verrucous
Warty
Papillary
Squamo-transitional
Lymphoepithelioma-like carcinoma
Adenocarcinoma
Usual type adenocarcinoma
Mucinous adenocarcinoma
Endocervical type
Intestinal type
Signet-ring type
Minimal Deviation
Villoglandular
Endometrioid adenocarcinoma
Clear cell adenocarcinoma
Serous adenocarcinoma
Mesonephric adenocarcinoma

Other Epithelial tumors
Adenosquamous carcinoma
Glassy cell variant
Adenoid Cystic carcinoma
Adenoid basal carcinoma
Neuroendocrine tumors
Carcinoid
Atypical carcinoid
Small cell carcinoma
Large cell Neuroendocrine carcinoma
Undifferentiated carcinoma

4
CHAPTER
STAGING
FIGO Staging 2009

(The new staging is effective from January 2009)
Stage Definition
Stage I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded)
IA Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion 5 mm
and largest extension 7 mm
IA1 Measured stromal invasion of 3.0 mm in depth and extension of 7.0 mm
IA2 Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm
IB Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IA
IB1 Clinically visible lesion 4.0 cm in greatest dimension
IB2 Clinically visible lesion >4.0 cm in greatest dimension
Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of
the vagina
IIA Without parametrial invasion
IIA1 Clinically visible lesion 4.0 cm in greatest dimension
IIA2 Clinically visible lesion >4 cm in greatest dimension
IIB With obvious parametrial invasion
Stage III The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes
hydronephrosis or non-functioning kidney*
IIIA Tumor involves lower third of the vagina, with no extension to the pelvic-wall
IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney
Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa
of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to
Stage IV
IVA Spread of the growth to adjacent organs
IVB Spread to distant organs
*On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis
or non-functioning kidney are included, unless they are known to be due to another cause.
Salient features of FIGO 2009 Staging

Approved changes to cervical cancer staging
Deletion of Stage 0: FIGO has decided to delete Stage 0 from the staging of all tumors, since it is a
pre-invasive lesion.
Stage IIA has been subdivided into IIA1 and IIA2 based on tumor size.

The Expert Committee has also taken into consideration further clinical and investigational
recommendations:
Cervical cancer remains a clinically staged disease; nevertheless, research in the field of surgical
staging is encouraged.
When available, all surgical-pathological findings (such as lympho-vascular space involvement (LVSI))
should be reported to the FIGO Annual Report Editorial Office or in other scientific publications,
although not included in the staging system.
The use of diagnostic imaging techniques to assess the size of the primary tumor is encouraged but
is not mandatory.
Others:
- For those institutions with access to MRI/CT scanning, radiological tumor volume and parametrial
invasion should be recorded and sent to the FIGO Annual Report Editorial Office for data entry
and inclusion in the Annual Report.
- Other investigations (i.e. examination under anesthesia, cystoscopy, sigmoidoscopy, intravenous
pyelography) are optional and no longer mandatory.
- Vaginal carcinoma may occur within 5 years after treatment. A malignancy purely confined to
vagina with a sustained complete response in cervical carcinoma is regarded as primary vaginal
cancer.

5
CHAPTER
TREATMENT
Stage IA1:
If stage IA1 cervical cancer is detected on punch/wedge biopsy it is mandatory to perform a cone
biopsy to rule out more invasive disease. Cone biopsy can be obtained with knife, Large Loop or Laser.
Following conization the further management options are:
Extrafascial Hysterectomy only (abdominal/laparoscopic/robotic/vaginal) if LVSI negative in cone
biopsy specimen, since the frequency of lymph node involvement is very low and hence lymph node
dissection is not required. Ovaries can be preserved in young women and if the histologic type is not
adenocarcinoma14. Grade B Recommendation.
Modified Radical hysterectomy or Trachelectomy (if fertility preservation is required) + pelvic
lymphadenectomy if LVSI positive in cone biopsy specimen
Stage I A1
Type I Extrafascial
hysterectomy
Close observation
(If fertility desired

and cone margins negative)
Stage IA 1
(diagnosed on cone
biopsy)
Modified Radical
hysterectomy or
Trachelectomy + pelvic
lymphadenectomy if LVSI
Brachytherapy alone
(No fit for surgery)

Repeat conization if the cone margins are positive and fertility preservation is required
Regular follow up if fertility preservation is required and LVSI negative in cone biopsy specimen and
the cone margins are free of disease. Grade B Recommendation.
Radical Brachytherapy with low dose rate / high dose rate. Total doses: 65- 70 Gy to point A (LDR
equivalent) One or 2 intracavitary insertions may be considered up to a dose of 100-125 Gy vaginal
surface dose or with HDR (LDR equivalent) in women who are not fit for surgery 15.
Stage I A2
Modified Radical Hysterectomy

+ Pelvic lymphadenectomy
Stage IA2 Radical Trachelectomy or Radical cone

(diagnosed on + Pelvic lymphadenectomy
cone biopsy)
Brachytherapy External beam

Radiotherapy
Stage IA2: The treatment options are

Modified Radical Hysterectomy + Pelvic lymphadenectomy
Removal of entire uterus, upper third vagina, bilateral parametria, medical half, uterosacral half, utero-
vesical ligaments. Bilateral salpingo-oophrectomy is discretionary depending on the patients age and
histological type of the tumour. The common iliac, external iliac, internal iliac and obturator groups of
lymph nodes should be removed from either side.
Radical Trachelectomy or Radical cone + Pelvic lymphadenectomy
In young women with cervical cancer, who are desirous of child bearing, in a select group of patients with
tumour size 2 cm, and negative pelvic lymph nodes no LUSI, marginsneg radical trachelectomy may be
done. Pelvic lymphadenectomy should always precede radical trachelectomy.

Radiation Therapy: Radical intracavitary radiotherapy or intracavitary with external pelvic irradiation
may be considered in women who are not fit for surgery.
Stages IB and IIA
Stages IB1 and IIA1
Radical hysterectomy
+ pelvic
lymphadenectomy
If fertility desired
Stage IB1 & IIA1 Radical trachelectomy +
pelvic
lymphadenectomy
Radical Radiotherapy
Brachytherapy +
External Radiotherapy
Stage IB1and IIA1:

Similar cure rates are obtained with radical surgery or radiotherapy for stages IB1 and IIA1 carcinoma
of the cervix. However, the long term complications profiles are different for radiation therapy and
surgery alone. Grade A Recommendation.
The choice of treatment depends upon the age of the patient, desire to preserve ovarian function,
co-morbid conditions, associated gynaecological conditions requiring surgery, facilities and expertise
available and the patients wish
The treatment options are:
Radical hysterectomy (type III) with pelvic node dissection
Para-aortic lymph node assessment during surgery
Radical trachelectomy + pelvic lymphadenectomy If fertility desired
Only for stage IB1, less than 2cm tumor with negative lymph nodes
Radical Radiation Therapy
Consist of external beam radiotherapy and brachytherapy. External-beam pelvic irradiation (40-
50 Gy in 4-5 weeks) combined with intracavitary applications, which together delivers the dose
of equivalent to 80Gy to point A. Concomitant cisplatin chemotherapy may be added to radical
radiotherapy for stage IIA1.

Stages IB2 and IIA2
Radical Chemo-
Radiotherapy (External
Radiotherapy +
Brachytherapy)
Stages IB2 &

IIA2
Radical hysterectomy
+
pelvic lymphadenectomy
Stage IB2 and IIA2:

The treatment options include concomitant chemo-radiation (Radiation therapy + Weekly Cisplatin) or
radical hysterectomy and lymphadenectomy.
Radical Radiation Therapy consists of external radiotherapy and brachytherapy. External-beam
pelvic irradiation (40-50 Gy in 4-5 weeks) combined with intracavitary applications, which
together delivers the dose of equivalent to 80Gy to point A.
Inj. Cisplatin 40 mg/M2 with appropriate hydration weekly during external radiotherapy.
Radical hysterectomy (Type III) and bilateral pelvic lymphadenectomy.
Removal of entire uterus, upper third vagina, bilateral parametria, uterosacral, utero-vesical
ligaments and bilateral pelvic lymph nodes. Bilateral salpino-oophrectomy is discretionary.
Para-aortic lymph node assessment during surgery

Adjuvant treatment after Radical surgery
Adjuvant therapy after Radical Surgery
High risk (any one)

Adjuvant RT
Node +ve with concomitant
Parametrium +ve chemotherapy
Cut margin +ve
Intermediate risk (any two)

Risk
Assessment on T> 4cm Adjuvant pelvic
detailed HPR Deep stromal invasion RT
LVSI + ve
Low risk
(none of the above observation
mentioned risk factors)
High Risk:
Patients with positive nodes, positive parametria, or positive surgical margins are at increased risk of
recurrence. Adjuvant chemo-radiation with external pelvic radiation therapy (45- 50 Gy @ 1.8 2 Gy per
fraction + / - vaginal brachytherapy boost) and concurrent weekly cisplatin chemotherapy is recommended
if any one of the above factors is present in the final histopathology16. Grade A Recommendations.
Intermediate Risk:
Lymphovascular Space involvement (LVSI), deep cervical stromal invasion or tumor size more than 4 cm
have increased risk of recurrence. Adjuvant pelvic radiation therapy is recommended if at least any two of
the above factors are seen on final histopathology. Adjuvant whole pelvic irradiation (45- 50 Gy @ 1.82
Gy per fraction +/- vaginal brachytherapy boost) reduces the local failure rate and improves progression-
free survival compared with patients treated with surgery alone17. Grade A Recommendations.
Low risk:
No adjuvant therapy recommended if none of the factors mentioned in high and intermediate risk groups
are present in final histopathology after adequate surgery.
For patients undergoing inadvertent hysterectomy/simple hysterectomy for invasive cervical cancer,
completion surgery may be considered. However, immediate second surgery is not practical, so these
patients should be considered as high risk and treated with adjuvant chemo-radiation. If compliance
to concomitant chemo-radiation is compromised because of medical and social reasons, radiotherapy
alone is an acceptable alternative.

Stage IIB and III
Radical Radiotherapy (External +

Para-aortic LN-ve Brachytherapy) + Concurrent
on Imaging weekly cisplatin
Stage IIB-IIIB
Para-aortic LN+ve Extended field RT* + Concurrent

on Imaging weekly cisplatin
Stage IIB and III: The options are

Radiotherapy remains the mainstay of treatment. Addition of concurrent chemotherapy reduces the
metastasis and improves the survival. Grade A recommendations
Radical radiotherapy is usually a combination of external beam pelvic radiation and intracavitary
brachytherapy (Low dose rate/ High Dose rate / Pulse dose rate)
External beam radiation therapy could be conventional 2dimensional or 3dimensional conformal
techniques.
In all patients treated with radical intent, brachytherapy should be an essential component.
Adequate and optimal total (external + Brachytherapy) doses to Point A (8090 Gy) depending on
the stage, response and doses to limiting normal structures should be achieved.
Planned radical radiation / concomitant chemo-radiation should be completed within 8 weeks without
significant treatment breaks, because prolonged overall treatment time result in poor outcome. Grade
C recommendations
Concurrent chemotherapy with Cisplatin 40 mg/m2 weekly during the course of external radiation
is recommended provided adequate renal functions / creatinine clearance is present.
Patients with positive common iliac or para-aortic nodes (up to 3 cm in maximum dimensions)
may be treated by extended field radiation with or without concurrent chemotherapy. Grade C
Recommendations

Stage IV
Palliative RT/CT
Stage IV A Pelvic Exenteration**
Individualized Rx Concurrent CT + RT**

Stage IV
Palliative Chemotherapy
Stage IV B Palliative Radiotherapy
Symptomatic and supportive care
**Select cases
Stage IVA:
Majority of stage IVA patients has poor general condition and extensive local disease in our setting
and are best treated with palliative radiation therapy / chemotherapy.
Major symptoms which can be palliated are vaginal bleeding, profuse discharge, low backache due
to local disease etc.
Hypo-fractionated palliative external beam radiation therapy regime of 30 Gy in 10 fractions over
two weeks or 30 Gy / 3# / 60 days (10 Gy / every month x 3#) is generally used and in few patients
who respond very well, this is followed by brachytherapy (LDR / HDR).
Palliative chemotherapy has been detailed in the management of FIGO stage IVB section.
Stage IVB:
Patients with metastatic disease are not curable and the intent of treatment is symptom control and
prolongation of survival.
Radiation therapy can be used for palliation of symptoms due to central disease or symptomatic
distant metastasis including skeletal metastases, enlarged para-aortic or supra-clavicular nodes, and
brain metastases.
Palliative radiotherapy should be given via larger fractions over shorter periods of time than
conventional radical courses of treatment.
Patients with poor performance status are not candidates for palliative chemotherapy, in general.

Palliative chemotherapy is generally used for extra-pelvic disease / recurrences or for pelvic recurrences
without previous irradiation. There is some evidence that it may palliate symptoms and/or prolong
survival in this setting. Grade B recommendation
Choice of chemotherapy:
Combination regimens have generally been shown to improve response rates (RR) and
progression-free survival (PFS) but not overall survival (OS) compared to single agent cisplatin17.
Most commonly used regimen is paclitaxel and either cisplatin or carboplatin18. Although there
is no randomized phase III evidence for carboplatin, there are several retrospective analyses
and prospective non-randomized studies that indicate equivalent efficacy19,20. Therefore it is
preferred over cisplatin (for which there is a randomized phase III trial18 because of ease of
administration and better tolerability with respect to emesis, renal toxicity, ototoxicity, etc. Grade
B recommendation
Another regimen that has been tested in a randomized phase III trial is topotecan plus cisplatin
that was shown to be superior to single agent cisplatin with respect to RR, PFS and OS21.
However it is not the preferred standard because of its unfavorable toxicity profile, including
myelosuppression and gastrointestinal toxicity. A recent phase III trial compared 4 platinum
doublets (cisplatin + either of the following: paclitaxel, topotecan, gemcitabine and vinorelbine
). There were no statistically significant differences in OS but there was a trend to superiority of
cisplatin-paclitaxel in RR, PFS and OS22. Grade B recommendation
Other agents uncommonly used as second line palliative chemotherapy include vinorelbine,
bevacizumab, irinotecan, ifosfamide and 5-FU.
To summarize the choice of palliative chemotherapy regimens: Paclitaxel plus carboplatin or
single agent cisplatin.
In patients in whom peripheral neuropathy is a concern, gemcitabine-platinum is an acceptable
alternative. Carboplatin is substituted for cisplatin in many regimens by most clinicians. Generally
4-6 cycles of chemotherapy are used.
Response evaluation: Patients on palliative chemotherapy should be evaluated for disease response
clinically (including symptomatic benefit) and radiologically as appropriate after every few cycles of
chemotherapy.
Patients not suitable for palliative radiotherapy or chemotherapy, symptomatic and supportive care
should be offered. Patients should also be referred to a palliative care team, if accessible, early
in the course of metastatic disease. Counseling and symptom control are some of the important
components of palliative care for these patients.

Recurrent Pelvic Disease
Concurrent CT + RT
Post-surgery
Re-surgery***
Recurrent Surgery
Central Pelvic Exenteration/
Plevic Disease
Hysterectomy
Palliative
Chemotherapy
Post - RT
Side wall or extra pelvic Pelvic RT/

CT/ Care
Relapse in the pelvis following primary surgery may be treated by radical radiation therapy with
concomitant chemotherapy.
Radical irradiation (with concurrent chemotherapy) may cure a substantial proportion of those with
isolated pelvic failure after primary surgery depending on the extent of disease.
Radiotherapy is usually a combination of external beam pelvic radiation and appropriate intracavitary/
interstitial or combination brachytherapy (Low dose rate/ High Dose rate / Pulse dose rate) depending
on the available expertise. However, referral for interstitial brachytherapy to appropriate centers with
expertise and experience is encouraged wherever feasible.
Radiation treatment planning and dose prescription should be similar to locally advanced cervical
cancer protocols. Patient not suitable for brachytherapy after external beam radiation, further external
radiation boost with small fields up to a dose of 64 66 Gy.
For Post RT central recurrence, pelvic exenteration (particularly if a fistula is present) in selected
patients without pelvic sidewall involvement may be offered.
This surgery should be undertaken only in centres with facilities and expertise and only by teams
who have the experience and commitment towards management of post-operative short and long-
term rehabilitation of these patients.
Palliative Chemotherapy has limited efficacy in pelvic recurrences that have been heavily irradiated
earlier. It should only be used in highly selected patients with this presentation on an individualized
basis. Grade C Recommendation
The choice of chemotherapy schedules and frequency is similar as detailed in treatment of FIGO IV
B section.

6
CHAPTER
Special Situations
6.1 Pregnancy
Stage I A1
Decision at 6
weeks of
peurpeurium
(Pap HPV test)
*NTZ: Follow up only
Colposcopy
+
Colposcopy **ATZ: Biopsy
Observation
(every 3 monthly)
Suspicious growth
Biopsy & further
*NTZ-Normal Transformation zone
**ATZ-Abnormal Transformation zone
Colposcopy for IA1 and observation every 3 months

Anytime suspicious lesions should be biopsied
IB1 IIA1
1st Trimester RH III + PLND

( 12 wks)
RH III + PLND up to 20 weeks
2nd Trimester
(12 - 27 wks)
Wait for fetal lung maturity

RH III + PLND
3rd Trimester Induce lung maturity

Ceasarean section followed
(28-40 wks) > 34 weels by RH III + PLND

IIA2 IIIB
Radical Radiation with concomitant

1st Trimester
chemotherapy
(-12 wks)
Termination of Radical Radiation with concomitant

2nd Trimester
Pregnancy chemotherapy
(12-27 wks)
3rd Trimester Induce lung maturity Caesarean section followed

by Radical Radiation with
(28-40 wks)
> 34 weeks concomitant chemotherapy
Either surgery or radiotherapy is used, depending on the stage of the disease in the first trimester.
In the third trimester, definitive treatment is usually delayed until the foetus is mature.
A multidisciplinary team approach is essential in making decisions with every effort made to maximize
the treatment.
6.2 -Retroviral Positive:
In patients with retroviral positive, there is higher incidence of in situ and invasive cervical cancer. In
general, cervical cancer is diagnosed at an earlier age in the retroviral positive patient 23. Antiretroviral
therapy (ARV) reduces AIDS related causes of death by 75%. The medical management of retroviral
positive and AIDS patients diagnosed with cervical cancer should follow the general guidelines for the
treatment of carcinoma cervix.
Women should be offered curative treatment for cervical cancer according to the stage of disease and
the general medical condition, irrespective of their retroviral status. The indication for chemotherapy is
tailored to the performance status and immune status of the patient. No chemotherapy is recommended
if the CD4 count is below 200 cells/mm3. Myelosuppression should be carefully monitored. During
treatment, patients require close monitoring in the same manner as in the retroviral negative setting.
Retroviral positive patients are particularly at risk of developing increased acute and possibly long term
toxicity from radiation and, especially, from concurrent radiation and chemotherapy 23.
6.3: Neuroendocrine tumor
Neuroendocrine tumor comprises of family of tumors ranging from well differentiated neoplasms
(carcinoids and atypical carcinoid) to high grade neuroendocrine carcinomas (small cell and large cell)
having a common origin from the diffuse neuroendocrine cell system24. The biology, clinical outcome and
treatment of high grade neuroendocrine carcinomas are different from well differentiated tumors. Most
common neuroendocrine of cervix (NCC) is small cell carcinoma, comprising around 1-5% of all cervical

neoplasms25. Behavior of small cell carcinoma cervix (SCCC) is similar to small cell carcinoma lung so
that lymph node spread is very common, propensity of vascular invasion, tendency for hematogenous
dissemination at relapse. Large cell carcinoma cervix though uncommon has similar clinical features and
behavior compared to SCCC.
Epidemiology
Risk factors for NCC have not been elucidated. HPV-18 seems to be associated with this tumor in various
reports26. Unlike small cell carcinoma of lung its association with smoking is not yet proven. Incidence of
neuroendocrine carcinoma seems to be on rise probably attributed to increased diagnostic recognition.
Clinical features
Though there is wide range of ages involved, this most commonly presents in fifth decade. Patients
usually present with abdomino-pelvic symptoms such as vaginal bleeding or discharge, pelvic pain, or
pelvic pressure. Only few asymptomatic patients are detected with abnormal Pap smear. Patients may
rarely present with paraneoplastic syndromes like cushings syndrome, SIADH, carcinoid syndrome and
other neurological disorders. Patients may also present with metastatic disease at presentation and most
common sites of metastasis are liver, adrenals, bone, bone marrow, and the brain.
A pelvic mass is most common finding on physical examination. On examination only it is impossible to
distinguish NCC from squamous cancer of cervix.
Diagnosis and staging
A diagnostic biopsy with histopathological examination and immunohistochemistry are mandatory to
diagnose neuroendocrine carcinoma. It is important to differentiate it from other small blue cell tumors
arising in cervix including basaloid squamous cell carcinoma, embryonal rhabdomyosarcoma, and rarely
lymphoma.
Neuroendocrine carcinomas are staged similar to squamous cell cervical cancer. Since neuroendocrine
carcinomas are associated frequently with disease outside cervix so all patients should undergo computed
tomography (CT) of the chest, abdomen, and pelvis for assessment of locoregional disease as well as
distant spread. Since metastatic disease accounts for 20-40% of cases in different series so some guidelines
suggest doing PET-CT though prospective evidence for the same is not available 27. In view of very low
incidence of brain metastasis in upfront setting CT head is not required in absence of symptoms or lung
metastasis.
Prognostic factors
Advanced stage is the most consistent and probably strongest prognostic factor in most of the studies.
Other prognostic factors are tumor size, presence and number of lymph node metastasis, pure small cell
histology and smoking28. Lymph node involvement is present in around 50% of patients at presentation. In
a retrospective series(n=188) 5-year disease-specific survival in stage I-IIA, IIB-IVA, and IVB disease was
36.8%, 9.8%, and 0%, respectively (P<.001)29.
Treatment
For the sake of simplicity treatment can be divided according to extent of the tumor. Disease can be
divided into limited stage resectable disease, non metastatic locoregionally advanced unresectable disease
and metastatic disease. Also most of the strategies for treatment of small cell cancer of cervix have been
extrapolated from small cell cancer lung.
Limited stage resectable (stage I-IIA)

Since, there is no evidence showing superiority of either of surgery (radical hysterectomy with regional
lymphadenectomy) or primary chemo-radiation. So either of them can be used to treat limited stage
resectable disease. Post surgery as in lung cancer adjuvant chemotherapy should be given in all cases.
Post operative chemotherapy has been shown to be associated with increased survival in various
retrospective studies. Out of various chemotherapy regimens used in these studies EP regimen is preferred
over other regimens because of less toxicity. There is no role adjuvant radiation as no advantage has been
seen in various retrospective studies in terms of recurrences or survival. Some guidelines recommend
upfront surgery for tumor size less than 4 cm and neoadjuvant chemotherapy or chemoradiation for
tumor size more than that but prospective evidence for this stratification is lacking27. Data for neoadjuvant
therapy is sparse so treatment should be individualized.
Loco-regionally advanced disease
For advanced unresectable disease definitive chemoradiation like small cell lung cancer is recommended.
Hoskin et al. reported results at British Columbia cancer agency for SCCC treated between 1988-2002
treated with platinum based chemoradiation and showed clinical stage as the only independent predictor
of outcome. Distant failure rates were 28% with their regimen as compared to 13% local failure rates.
Metastatic disease
For patients with metastatic disease or recurrent disease patients should be treated with EP or VAC based
chemotherapy as in small cell neuroendocrine carcinoma of lung.
Conclusion
Though data regarding treatment strategy of NCC is sparse but multimodality therapy with chemotherapy,
radiotherapy and surgery seems to improve outcome. More prospective data is needed for this rare but
potentially curable tumor.
6.4 -Anaemia
Low hemoglobin level is frequently observed in these patients because of prolonged vaginal bleeding,
poor nutrition, advanced disease, bone marrow toxicities during treatment and lack of supportive care.
A low hemoglobin level during radiotherapy/ chemo-radiotherapy reflects lower local control and survival
30
.There is not enough evidence to recommend routine use of agents stimulating erythropoiesis31.

7
CHAPTER
Follow-up Strategies
After completing the treatment patients require regular clinical follow-up to detect possible recurrence and
evaluate the potential complications.
1. Since the recurrence is common during first two years following treatment. Patient should follow once
in four months for first two years and every six months for 3 years and yearly thereafter.
2. Role of annual PAP smear is controversial. In absence of symptoms it is not warranted. Local recurrence
has to be established histologically and should not be based on PAP cytology alone.
3. Evaluation with radiology, cystoscopy, recto-sigmoidoscopy, chest x-ray, CT scan may be done if
clinically indicated, however general history and physical examination is recommended at each follow-
up visit.
4. Patients should be educated regarding symptoms suggestive of recurrence and metastasis for early
diagnosis of recurrence.
5. The narrowing of vaginal causing dyspareunia and post coital bleeding. Patient should be educated to
use dilator or resume intercourse to avoid this complication.

8
CHAPTER
RESEARCH ISSUES
1. Treatment Related Complications and Outcome in Indian Women

2. Quality of Life Issues
3. Cervical Cancer Screening Program
4. Prevention: HPV Vaccination
5. Anti HPV Therapeutics and Targeted Delivery.
6. Incorporation of neoadjuvant chemotherapy in primary treatment
7. Role of adjuvant chemotherapy following chemo-radiation
8. Cervical cancer stem cell
9. Minimal access surgery
10. Biomarkers and Genomics for prognostication
11. Determination of node metastasis by newer techniques

9
CHAPTER
APPENDIX
Appendix A
BIOMARKERS AND CERVICAL CANCER
The biomarkers offer great potential for improving management of cancer at every point from screening and
detection, diagnosis, staging, prognosis to assessment of treatment response. A significant advancement
in understanding causes of cervical cancer and identification of several biomarkers have been achieved
for its early diagnosis, prevention and treatment.
1. Primary Biomarkers:
i. HPV DNA testing as the primary biomarker for early detection of precancer lesions and triaging. Direct
detection of HPV DNA in cervical specimens may offer an alternative or complementary to population-
based cytological screening. It has been reported that HPV test results are more sensitive than Pap
smears in detecting high-grade lesions in older women32-33. A population-based study demonstrated for
the first time the impact of single round of HPV DNA testing as an effective primary screening tool with
better efficacy than other conventional methods 34. In a large population-based cytological screening from
Costa Rica, a cut-off point of 1.0pg/mL using the second generation assay allowed sensitive detection
of cervical high-grade lesions and cancer, giving a seemingly optimal trade-off between high sensitivity
and reasonable specificity rates for this test. PCR detection of HPV DNA by L1 consensus primers and
typing by HPV type-specific primers should be performed to detect the presence of high-risk HPVs. Most
widely used My9 and MY11 consensus primers are capable of detecting about 27 HPV types which
include all 15 High Risk HPVs (HPV 16, 18, 31, 35, 39, 45 etc) and 6 low Risk-HPVs35. Since most HPV
infections in women are transient and only a minority of women infected with HPV develops persistent
infection that may evolve into squamous intraepithelial lesions, triaging of women infected with HR-HPV
and management of co-factors such as inflammation and infection of RTIs is recommended. Studies also
support the potential utility of HPV testing for effective triaging of Pap smears of atypical squamous
cells of undetermined significance (ASCUS) and atypical glandular cells of undetermined significance
(AGUS) and therefore have a potential role in primary screening of populations in which pap smears have
been inconclusive. DNA probes of high-risk HPV types in different formats have been fully validated as
primary screening tests, as secondary triage tests and as a prognostic marker following treatment of high
grade squamous intraepithelial lesions (HSIL). They consistently showed significant superiority over the
conventional Pap smears.
ii. HPV E6 and E7 protein detection in the severe dysplastic and invasive carcinoma cases. Since two
early genes E6 and E7 are the two main viral transforming genes that are invariably retained in almost all
cervical cancers, detection of these two viral oncoproteins can serve as important biomarkers of severe
dysplastic and invasive cervical cancers and progression of the disease. HPV E6 and E7 oncogenes play
an essential role in HPV-induced carcinogenesis by interfering with two essential tumor suppressor genes

p53 and Rb that regulate normal cellular events and are possible protein biomarkers for early detection
of cervical cancer. Studies show that detection of E6/E7 mRNA expression could predict the risk of
cervical cancer better than HPV DNA testing36 and currently the commercially available mRNA-based
assays (e.g., NucliSENSEasyQ HPV Test and APTIMA HPV mRNA Assay) are being used. Arbor Vita
Corporation has developed a rapid diagnostic test, AV Avantage HPV E6 test in collaboration with
PATH (the Program of Appropriate Technology in Health) with FDA approval expected in 2013. AV
Avantage HPV E6 test uses a high-affinity monoclonal antibody for the detection of E6 oncoprotein from
high risk HPV-16, -18, and -45 responsible for approximately 90% of cervical cancers.
i. Viral load and Integration. There exists a close link between HPV viral copy number and integration
of viral genome into the host cell and is considered as a risk factor for the progression of pre-cancer
to invasive cancer 37. The significantly higher HPV load detected in women with high-grade cervical
dysplasia, as well as the dramatic difference in the load after surgical removal of the lesion, suggest that
HPV load is a possible prognostic marker of high-grade squamous intraepithelial lesion. Integration of the
viral DNA to host cell genome is yet another biomarker as persistent HPV infection leads to integration of
viral DNA into the host cell genome, leading to tumorigenic transformation of cervical epithelium.
2. Secondary Biomarkers
A number of molecular markers have been found to show an early sign of alteration at the onset of disease
which may be useful in predicting the disease course at an early stage.
Tumor suppressor genes and proto-oncogenes
i. p53 has been found to be deregulated with the progression of lesions, suggesting that p53 abnormality
is an early event in cervical carcinogenesis. The E6 protein of oncogenic HPV types has been shown
to complex with p53 and targets it for rapid degradation. As a consequence, p53s growth-arrest and
apoptosis-inducing activities are abrogated. This suggests the potential importance of the E6 - p53
interaction for therapeutic intervention.
ii. p16, the cyclin D/cdk inhibitor is overexpressed as the lesions proceed to a more aggressive
one. This tumor suppressor p16INK4A plays an important role in regulating the cell cycle and is
overexpressed in the presence of the HPV E7 oncoprotein. Several studies reported p16INK4A
as a useful diagnostic marker for squamous and glandular epithelial dysplasia in the uterine cervix
38-39 and a valuable surrogate marker for high risk and malignant cervical lesions in the presence
of HPV40. Furthermore, expression of p16INK4A appears to correlate with the degree of cervical
neoplasia41-42. A recent study showed that a p16INK4A immuno-cytochemical assay has better
specificity than HPV testing to predict underlying high-grade dysplastic lesions43. Currently, clinical
trials are underway to assess the diagnostic and prognostic value of p16INK4A expression in atypical
glandular cells and low-grade squamous intraepithelial lesions of the cervix.
iii. c-fos protein specifically shows exclusive high expression with the increasing severity of lesion and in
cancer. The transcription factor AP-1, which is composed of heterodimers of members of the c-Jun
and c-Fos families, regulates various cellular processes such as enhanced proliferation, apoptosis, and
tumor metastasis. c-fos acts as a tumor promoter, and its upregulation causes cellular transformation
and when c-fos binds to c-jun contributes to the potentiating of malignancy.
iv. Fra-1 is expressed in normal cervical tissue and its expression was diminished as the lesion progressed
from precancer to cancer. Thus in cervical cancer it acts like a tumor suppressor gene 44.

v. p50 subunit of NF-kB shows enhanced expression in high grade cervical lesions and changes in
relation to disease progression 44.
vi. NOTCH 1 family of proteins are found to be highly expressed from CIN III onwards. Thus, Notch1
exerts specific protective effects against HPV-induced transformation through suppression of E6/
E7 expression, and down-modulation of Notch1 expression is likely to play an important role in late
stages of HPV-induced carcinogenesis45.
vii. R-bprotein has been found to be deregulated in poorly differentiated carcinoma, suggesting its
important role in differentiation. pRB is a negative regulator of the cell cycle that normally prevents
S-phase entry by associating with the E2F family of transcription factors. E7 binding to pRB release
E2F, irrespective of the presence of external growth factors leading to the expression of proteins
necessary for DNA replication46
viii. Telomerase activation is a relatively early event in cervical carcinogenesis and mostly correlated
with the grade of cervical lesion, HR-HPV status (HPV 16 and 18 subtypes) and clinical staging.
Upregulated hTR and hTERT subunits of telomerase have also been observed in cervical cancers 47
ix. Ki-67 is a nuclear protein that is expressed during all active phases of the cell cycle, and its expression
is used to determine the cell proliferation status 48. In cervical intraepithelial neoplasia (CIN), Ki-67
expression is increased in the upper layers of cervical epithelium compared to normal cervices 48.
Several studies have also suggested that Ki-67 can be used as an independent prognostic marker to
identify women with high risk for progression and/or recurrence of cervical squamous precancerous
lesions 49.
x. E cadherin, cadherins are glycoproteins of 120 to 130 kDa that are involved in the cell adhesion
and is considered as an important biomarker for tumor development 50,51. The squamous cells of
cervix epithelium are strongly attached to each other and to the basement membrane through a
large number of adhesion molecules. Thus, E-cadherin is one of the key molecules of adhesion. The
decrease or loss of expression of these molecules can be correlated with aggressive behavior and
progression of cancer. The decrease in the expression of E-cadherin seems to be a useful parameter
in evaluating the potential for malignancy of cervical cancer50.
Potential serum markers
i. SCC (Squamous cell carcinoma antigen) For cervical cancer, the discovery of useful serum biomarkers
for its early detection has been a priority nowadays. Such tumor markers are the molecules arising
due to presence of the tumor, which can appear in the surrounding tissue, and then within the
blood and excretions. Diagnostic serum markers for cervical cancer in clinical use are SCC antigen
(squamous cell carcinoma antigen)52.
Cell Adhesion Matrix proteins
i. Cell adhesion matrix proteinsCD44, and its variant forms, are integral membrane proteins that
have been implicated in tumorigenesis. They act as both a lymphocyte homing mechanism and cell
adhesion molecule, as well as being involved with tumor growth, spread, and invasion53. CD44 is
generally used as an epithelial cancer stem cell marker and thus provide novel approaches to the
diagnosis and treatment of cancer.

MiRNA
i. Micro ribonucleic acids (miRNA) is released and circulated in the blood of cancer patients. Changes
in the levels of circulating nucleic acids have been associated with tumor burden and malignant
progression. The area of metastasis-associated miRNA markers in relation to oncogenesis is expanding
rapidly and these markers have recently been referred to as metastamirs. miRNA can act as a
tumor suppressor as well as an oncogene. This emphasizes the potential application of miRNAs
as biomarkers, In the past decade, huge number of publication on the potential use of circulating
nucleic acids for cancer screening, prognosis and monitoring of the efficacy of anticancer therapies
has emerged. Mir 21 is upregulated in solid tumors and participates in oncogenic signaling. MiR-21
is transcriptionally induced by AP1 which is essential for HPV transcription. Another miRNA, miR-
29 restrains cell cycle progression and induce apoptosis and promotes malignant transformation
induced by HPV 54

Appendix-B
REPORTING FORMAT FOR CERVICAL CANCER IN CONE BIOPSY HISTOPATHOLOGY
EXAMINATION
GROSS EXAMINATION:
Specimen type: LEEP / CONE
Dimensions ...x.. x...mm
Resection margins :
Number of sections studied :
MICROSCOPY:
Description:
.
Diagnosis (Select one or more as appropriate):
CIN 2/ CIN-3
Focuses unifocal / multifocal
Number of sections involved # ..
Endocervical glandular involvement Present / Absent
CGIN (Cervical Glandular Intraepithelial Neoplasia): low grade / high grade
Microinvasive Carcinoma*
Depth of Invasion ... mm
Lateral extent of Invasion ... mm
Early Invasive Squamous Cell Carcinoma
Depth of invasion mm
LVSI (Lympho-Vascular Space Invasion) Present / Absent
Adenocarcinoma-in-situ
Early invasive adenocarcinoma
Resection margin-
Upper resection limit: Involved / Not Involved
Lower resection limit Involved / Not Involved
In case of invasive carcinoma, Deep resection limit: Involved / Not Involved
* Note on Measurement of invasion:
Depth of invasion: Measurement is taken from the base of the epithelium (surface or glandular) from which the carcinoma arises, to
the deepest point of invasion, as specified in the FIGO classification.
If the invasive focus is not in continuity with the dysplastic focus, measure depth from the nearest dysplastic crypt / surface
epithelium or from the adjacent non-neoplastic surface epithelium / crypt base.
Lateral extent of invasion: The maximum horizontal extent of invasion should be measured in mm.
The number of sections showing invasion must be mentioned in the report.

REPORTING FORMAT FOR CERVICAL CANCER IN BIOPSY SPECIMEN
GROSS EXAMINATION:
Specimen type: Wedge / Punch
Number of fragments # ..
Resection margins
Size of each fragment in three dimensions
1. x .. x...mm
2. x .. x...mm
3. x .. x...mm
4. x .. x...mm
5. x .. x...mm
MICROSCOPY:
Description:
.
Diagnosis
Histological types (as WHO classification)
Presence of associated CIN / CGIN Present / Absent

REPORTING FORMAT FOR CERVICAL CANCER IN HYSTERECTOMY SPECIMEN
GROSS EXAMINATION:
Specimen type: Hysterectomy/ Radical Hysterectomy
Tumor site- anterior posterior right left circumferential
Cx. Involvement- ectocervix endocervix
Tumor size- cm x .. cm
Tumor description- (colour of tumor, polypoidal, infiltrative, ulcerative):
..
...
Extent of tumor- stromal invasion / upward extension :
Uterine corpus- Dimension, Endometrium, Myome- :
trium
Vaginal cuff- Dimension, Involved or not :
Parametrium- Dimension, Involved or not :
Other Organs: :
Rt. Ovary Dimension, Patho- :
logic macroscopic findings
Lt. Ovary Dimension, Patho- :
logic macroscopic findings
Rt. Fallopian tube Dimension, :
Pathologic macroscopic findings
Lt. Fallopian tube Dimension, :
Pathologic macroscopic findings
Lymph Nodes- Site :
Size :
Approximate number :
Gross appearance: : involved/ Not involved
MICROSCOPY:
Histological type (WHO Classifica- :
tion)
Histological grade :
Extent of invasion :
Margins (check all that apply)
Vaginal cuff (tumor extension) : Cannot be assessed/ uninvolved / involved
: Distance from resection margin ..
: In-situ changes at margin present / absent
Parametrium(tumor extension) : Cannot be assessed/ uninvolved / involved
: Distance from resection margin ..
: In-situ changes at margin present / absent
LVSI (Lympho-Vascular Space Inva- : Present / Absent/ indeterminate
sion)
Additional pathological findings : None/ Intraepithelial neoplasia/ Others
Endometrium :
Myometrium :
B/L Fallopian tubes & Ovaries :
Lymph nodes : Involved / Not involved

Site / size :
Perinodal spread : Yes / No
Immunohistochemistry : Not done / Done
If done, specify : .
..
Comments: ..
DIAGNOSIS :
Pathologist.

Appendix - C
PRINCIPLES OF SURGERY
Stage IA1 patients are usually diagnosed after histological examination of the conization specimen. For
these patients with stage IA1 disease, extrafascial (Piver class I) hysterectomy is recommended55. However,
if the conization specimen shows presence of lymphovascular emboli, Piver class II radical hysterectomy is
preferred. For patients desiring fertility preservation, radical trachelectomy with pelvic lymphadenectomy
is an option. In patients with compromised performance status or severe co-mobidities, surveillance may
be advised if the margins of the cone are free of tumour 56,57.
Stage IA2-IIA:
The surgery that is recommended is radical hysterectomy (Piver Class III) with pelvic lymphadenectomy
(Piver Classification)55. The aim of surgery is to remove the cervical disease with a wide tumour free
margin that includes a wide parametrial and paracervical excision and a wide vaginal cuff. Surgery results
in survival rates of 70-90% at 5 years 58 and identifies high risk patients needing adjuvant therapy.
Surgery may be carried out by the abdominal, vaginal or laparoscopic approach with equally good
outcomes.
In selected patients with small tumours (IA2-IB1), where the risk of parametrial involvement is low 59-60,
a modified radical hysterectomy (Piver class II) with adjuvant radiation therapy for high risk patients has
been shown not to compromise survival and reduce the treatment related morbidity especially the bladder
related and sexual morbidity 61-63.
The other option for these patients with small volume tumours, elective nerve sparing radical hysterectomy
wherein the hypogastric nerves and the pelvic splanchnic plexus are identified and separated before
resection of the parametrial tissue, may be carried out 64. Although there are no randomized trials
of nerve sparing versus standard radical hysterectomy class III, numerous authors have demonstrated
oncological equal efficacy, safety and reduced morbidity with this procedure 65.
In young premenopausal women, bilateral ovarian preservation may be done with transposition of the
ovaries in the paracolic gutters, as the rate of ovarian metastasis is very low 66,67.
In young women with cervical cancer, who are desirous of child bearing, in a select group of patients with
tumour size <2 cm, radical trachelectomy with pelvic lymphadenectomy may be done. This may be done
by the vaginal, abdominal or laparoscopic approach. Oncological safety and good fertility preservation
& pregnancy rates have been reported, although the risk of abortions and premature delivery are higher
68-71
. The relapse rate in well selected patients is low and the survival figures are equivalent to those of
radical hysterectomy 72.
A complete pelvic lymphadenectomy from the level where the ureter crosses the bifurcation of common
iliac artery is recommended. Sentinel node sampling is under investigation for its usefulness in cervical
cancer surgery73. False negative rates of about 10% have been reported using a combined blue dye and
lympho-scintigraphy technique and the negative predictive value of the procedure is not sufficient to
warrant its routine use to replace standard lymphadenectomy at present74. In the absence of sufficient
validation data, this remains an area of research.
Stage IB2 patients may be treated with radical hysterectomy Piver class III with pelvic lymphadenectomy
with or without para-aortic lymph node sampling. Pelvic lymph node dissection may be done first and if

negative, radical hysterectomy may be done. If the nodes are positive, then the hysterectomy should be
abandoned and these patients should receive chemo-radiation.
Minimal access surgery: The role of minimal access surgery in management of cervical cancer is presently
investigational. Laparoscopic radical hysterectomy with pelvic lymphadenectomy can be offered to
patients with stage IB1 cervical cancer as an alternative to the open abdominal radical hysterectomy.
For optimizing results of the procedure, it should be done only by surgeons trained in the application of
advanced laparoscopic surgery to gynecological cancer management and in specialized cancer centers
with large volume gynecologic oncological work. Initial results showed safety and feasibility of Robotic
radical hysterectomy. However data on long term oncological outcome is lacking. Advantages of Minimal
access surgery include less intra-operative blood loss, early post-operative recovery, shorter hospital stay
and better cosmesis.

Appendix - D
PRINCIPLES OF RADIATION THERAPY
Conventional External Radiation Techniques:
Radiation Planning: Conventional planning is fluoroscopy guided with patient in supine position. Under
fluoroscopy guidance, bony landmarks are used to mark the portals. The whole pelvis treatment fields
typically extends from the L4-5 or L5-S1interspace superiorly to the mid-pubis or to a line 2 cm below the
lowest vaginal disease. Radio-opaque markers may be placed in the vaginal cavity to identify the disease
at cervix or vagina. The fields may be extended superiorly if the para-aortic nodes are to be treated
prophylactically (high risk) or known to be involved. Lateral borders are placed at least 1.5 cms lateral
to the bony pelvic brim. The lateral margins and shielding should be more generous if massive obesity
reduces the reproducibility of the treatment setup.
In four field technique (antero-posterior and bilateral portals), the anterior border of the field usually
includes the pubis to adequately cover the tumor with margins, the posterior border at S3 vertebra
to include presacral nodes and uterosacral ligaments. Customized blocks to shield small bowel region
anterio-superiorly and, low ano-rectum on the lateral fields in special situations. Additionally, inguinal
nodes should be included if the disease is extending into/ beyond lower third of the vagina.
Using conventional fractionation, a dose of 40-50 Gy in 20-25 fractions over a period of 4-5 weeks is
recommended. Use of two filed or four-field beam arrangement, corner shields and a special midline block
(after 20 Gy), helps in reducing the dose to rectum, bladder and small bowel during external radiation.
IntracavitaryBrachytherapy: Brachytherapy plays a very important role in obtaining high cure rates with
minimum complications. A good intracavitary insertion delivers a very high radiation dose to the cervix,
upper vagina and medial parametria without exceeding the tolerance doses for rectum and bladder. The
randomized trials comparing low dose rate (LDR) with high dose rate (HDR) brachytherapy in carcinoma
cervix have shown that the two modalities are comparable in terms of local control and survival 75,76.
Thus, either LDR or HDR brachytherapy may be used, taking into account the availability of equipment
and other logistics of treatment delivery. HDR brachytherapy can be done as a day procedure in contrast
to approximately 20 hours of continuous LDR treatment requiring overnight inpatient stay. However, due
to radiobiological considerations, 3-5 applications of HDR are required in contrast to 1-2 applications of
LDR (for stage I and II) to maintain low complication rates. HDR is being increasingly used now as the
control rates are comparable and the toxicity is slightly less. Grade A recommendations
The task force committee strongly recommends that the use of low dose rate intracavitary brachytherapy
may be gradually phased out.
The recommended brachytherapy schedules are either LDR 1-2 fractions of 25 - 30 Gy to point A each 1
week apart, or HDR 3 - 5 fractions of 6 - 7.5 Gy to point A each once weekly. Other HDR fractionation
schedules are still investigational.
A combination of external-beam pelvic irradiation covering the uterus, parametria and pelvic nodes and
intracavitary irradiation primarily for the central disease is used. The aim is to deliver a dose equivalent
of 80Gy to point A. The planned radical radiation /concomitant chemo-radiation should be completed
within 8 weeks without significant treatment breaks. Prolonged overall treatment time result is poor
outcome 77 (Grade C recommendations)

Radiation therapy doses:
Stage IB-IIB: Using conventional fractionation, an external radiation dose of 40-45 Gy in 20-25 fractions
over a period of 4-5 weeks is recommended interspersed with brachytherapy applications of 1-2fractions
of LDR or 3-5 fractions of HDR applications once weekly.
Stage IIIA: The dose of external beam radiation therapy is 50Gy to the whole pelvis over 5 weeks with
1.8 - 2 Gy fractionation. Whenever possible, a midline block should be used after 40Gy. The radiation
portals are similar except that the inferior border is placed 2 cm beyond the lower vaginal disease or
at introitus. An LDR Intracavitary application with tandem and ovoids to a dose of 30Gy to point A is
recommended. Patients, in whom standard ICA is not feasible due to residual disease extending below
upper third vagina, intracavitary application using tandem and cylinders to a dose of 15 - 25 Gy to point
A (depending on rectal dose) is recommended.
Stage IIIB: The dose of external beam radiation therapy is 50 Gy to the whole pelvis over 5 weeks with 2
Gy fractionation. Whenever possible, a midline block should be used after 40 Gy. Intracavitary application
with Low dose rate (one application of 30 Gy to point A) or High dose rate (3 applications of 7Gy to point
A each every week, starting from 3rd or 4th week of external radiation) is recommended.
Para-Aortic nodes: Extended field radiation therapy has been reported to produce long term disease control
in women with microscopic or small volume (<2cm) lower para-aortic nodes (below L3) with acceptable
complications rates when radiation dose was not exceeded beyond 50 Gy and the lymphadenectomy
was performed by extraperitoneal rather than transperitoneal route 78. In the RTOG randomized trial
reported recently, the 10 year overall survival was improved from 44% with pelvic radiation to 55% with
pelvic plus prophylactic para-aortic radiation in 367 women with stage IB1 and IIA disease. Grade 4 and
5 radiation toxicities at 10 years however increased from 4% to 8% with para-aortic irradiation. Patients
with positive common iliac or para aortic nodes may be treated by extended field radiation with or
without chemotherapy 79,80,81. Grade C Recommendations.
Radiation therapy related side effects: During pelvic radiotherapy, most patients experience mild fatigue
and mild to moderate diarrhea that respond to anti-diarrheal medications and few may experience bladder
irritation. These acute symptoms are increased when combine with concurrent chemotherapy or on
extended fields. Patients receiving concurrent chemotherapy may additionally have hematological and
nephro-toxicities especially with the use of cisplatin 82.
The late sequelae following radiation therapy commonly seen are rectal, bladder and small bowel. These
depend on the duration of follow-up, type of treatment modalities and estimated radiation doses to these
organs. The reported grade III/IV late sequelae (toxicities requiring hospital admission or Intervention)
range from 5-15%.
Late Rectal Sequelae in the form of chronic tenesmus, telangiectasia and profuse bleeding, rectal ulceration
and strictures have been reported (5-8%). These are usually seen during 18-36 months follow-up period.
The treatment options include sucralfate enema, steroid enema, argon plasma coagulation (APC), laser
therapy, or formalin applied to affected mucosa, diversion colostomy.
Late Bladder complications may occur in the form of continuous hematuria, necrosis and rarely vesico-
vaginal or urethra-vaginal fistula. The incidence of symptomatic Grade III/IV late toxicities after radical
radiation is 4-8%. HBOT therapy within 6 months of hematuria onset results in a good therapeutic
response rate.

Late small bowel sequelae in the form of chronic enteritis, sub-acute intestinal obstruction, perforation,
strictures etc. can be encountered. The incidence of symptomatic Grade III/IV late toxicities after radical
radiation reported is 3-12%. These sequelae are higher in patients undergoing radical surgery esp. trans-
peritoneal pelvic lymphadenectomies and adjuvant radiation +/- chemotherapy.
Most patients treated with radical radiotherapy have telangiectasia and fibrosis of the vagina, resulting
in significant vaginal shortening especially in elderly, postmenopausal women and those with extensive
tumors treated with a high dose of radiation. These to some extent can be prevented by counseling for
regular sexual activity and vaginal dilatation exercises.
Newer External Radiation Techniques:
In the past 10-15 years, there has been a rapid progress in radiation delivery techniques in parallel
to advances in technology and imaging. Newer external radiation techniques like Intensity Modulated
Radiation Therapy (IMRT), Image Guided Radiation Therapy (IGRT), PET-CT Guided Radiation etc. have
also been explored in cervical cancers 83-87.
These techniques require thorough knowledge regarding CT or MRI anatomy, disease pathology and natural
history. This helps to translate the understanding of conventional fields of 2D based on bony landmarks
to 3D imaging like CT and MRI. Oncologist needs to contour (draw) the target volume and normal tissue
so that radiation doses can be prescribed. The target in cervix cancer includes Gross tumour volume
(GTV; which includes disease involving cervix and extensions when applicable to parametrium, vaginal
wall, uterus, lymphnodes), Clinical target volume (CTV; includes whole of cervix, uterus, parametrium up
to lateral pelvic wall and upper 2 cm of vagina below the lowermost gross involvement and lymphatics)
and Planning target volume (PTV includes appropriate margins over CTV). Recently many authors have
proposed guidelines to contour nodal/ lymphatic CTV in cervical cancer. Similar to identification of target
volume, identification and contouring of normal tissue is vital because newer techniques like IMRT can
achieve optimal sparing of normal tissues without compromising the doses to target. Various normal
tissues contoured are bladder, rectum, sigmoid, small and large bowel and bone marrow 87,88.
There are potential advantages with use of IMRT over conventional 2D treatment. Most of these
advantages have been described dosimetrically or have been used in small clinical series and need wider
clinical testing and implementation with generation of supporting evidence. These advantages include:
Limiting doses to normal tissues: This factor is of paramount importance and is going to be more and
more relevant in coming days with increasing intensity of treatments used routinely. The conventional
normal tissues include rectum, bladder, sigmoid and bowel; but this list is ever increasing. Bone
marrow sparing IMRT is one of the recent concept that is evolving fast with clinical data. This is
crucial development to be able to give safely high doses of RT to pelvis, concurrent and adjuvant
aggressive chemotherapies and para-aortic radiation 87,88
Dose escalation to central tumor is theoretically important application of IMRT in any site. In cervical
cancer brachytherapy excludes most of such need but still in locally advanced stages inappropriate
geometry and size of residual disease after EBRT can lead to omission of brachytherapy. In such
cases proper initial doses in EBRT are vital to get proper anatomy suitable for brachytherapy, also
in cases where brachytherapy is still not feasible IMRT boost can be used to increase local control 83,
89
.
Concomitant boost application to special target regions can be achieved using IMRT. These regions
may include pelvic or para-aortic lymphnodes or lateral one third of parametrium 79-81.

Prophylactic Extended field radiation with increasing stage risk of para-aortic lymphnodes
involvement increases and would benefit with prophylactic treatment. Conventional treatments with
2D have been long criticized for increased bone marrow and bowel toxicity. But with IMRT the doses
of 50 Gy can be safely delivered to these regions 79-81.
Radical treatments for para-aortic lymphnodes (PALN) Although FIGO staging does not change
with identification of PALN identified in imaging alone but the treatment should. Recently several
authors have tried giving radical doses of 60-66Gy with concurrent chemotherapy radically and
demonstrated good local controls and acceptable toxicities 79-81.
Recent advances in Cervical Brachytherapy:
Historically, there were systems like Manchester, Paris, Stockholm derived from rich clinical experience
which was used to deliver specified dose to the tumor fairly accurately in the absence of treatment
planning systems. Later with development of various manual and after-loaded applicators and different
Radium substitutes like Cs-137, Co-60, Ir-192, potential of brachytherapy became evident. High Dose
Rate (HDR) remote after-loading coupled with advances in treatment planning systems has ensured well
defined protocols and methods for brachytherapy dose analysis. However, the imaging modality used in
Brachytherapy was largely limited to 2D orthogonal radiographs. The major limitation of the conventional
imaging modalities is applicator and point based and there is a lack of information on the tumor volumes
and organs at risk (OAR). Conventionally, point doses are calculated for rectum and bladder according to
ICRU-38 recommendations. But, point doses do not represent the dose received by the entire volume of
the organs. Due to which the doses to the OARs are not accurately known. Hence there is no significant
correlation between the point doses and incidence of toxicities especially bladder. In addition, tumor
cannot be seen in the radiographs, hence local control of the disease also is a challenge especially in
larger tumors. In last 2 decades, significant technological advances have resulted in use of newer imaging
modalities, planning algorithms and treatment delivery. This has resulted in use of imaging techniques
for 3-D data acquisition, contouring for both target and various organs and optimizes treatment planning
for brachytherapy applications.
Various imaging modalities like Ultrasound, CT, MRI and PET scans etc have been explored. Among
all the imaging modalities, MR Imaging is becoming increasingly popular for diagnosis and treatment
planning for EBRT and brachytherapy. Image Based Brachytherapy (IBBT) has been mainly possible due
to MR imaging, where it is possible to image the applicator with tumor volume and other normal tissues.
MR based IBBT is practiced mainly in Europe and few US centers, as compared to robust 2D outcome
data, it is still evolving. GYN GEC-ESTRO network has published guidelines for the practice and reporting
of image based brachytherapy, which has been widely accepted so that a unified approach is formed
among the users of Image Based Brachytherapy 90,91.These recommendations describe a gross tumour
volume, which encompasses T2 bright areas in the cervix; the high-risk clinical target volume (HR-CTV),
which encompasses the entire cervix and all visible or palpable disease at the time of brachytherapy; and
the intermediate-risk (IR-CTV), which is a 1 cm margin around this high-risk CTV plus the initial sites of
involvement. The intermediate-risk CTV includes vaginal extension at the time of diagnosis that may have
significantly decreased over time, and requires subtracting the normal tissues. The group also recommends
starting with the standard method of dose prescription, either point A or the 60 Gy reference volume, and
then adjusting the loading pattern and dwell times to ensure comprehensive target coverage. All patients
should have the D90, D100, and V100 recorded for the high-risk CTV91. At this time, treatment of the
full length of the tandem with some modification of only the top dwell position based on sigmoid dosage
is recommended. One of the largest series published so far is from Vienna group, who have reported

the clinical outcome of 156 patients treated with image guided adaptive brachytherapy combined with
3D conformal external beam radiotherapy (EBRT)chemotherapy 92. The results are promising with
excellent local control rates of 95-100% at 3 years in limited/ favourable (IB/IIB) and 85-90% in large/
poor response (IIB/III/IV) groups with an acceptable treatment related morbidity rates. Compared to
their historical series there is relative reduction in pelvic recurrence by 65-70% and reduction in major
morbidity. Other outcome data published from Paris and Mumbai endorse the same93. This is being tested
further in an ongoing multicentric study involving several institutes in Europe, US, and Asia.
The potential of Ultrasonography (US) as an alternate imaging modality for guidance of intracavitary
brachytherapy in cervical cancer is also being explored now [94,95]. The advantages of universal
availability of US, its cost effectiveness, advances in 3D & real time US imaging and small learning curve
may be a potential area for clinical research especially in developing countries. Similarly CT has also been
compared with MRI in few small dosimetric studies and need validation in larger clinical studies 9698.
Radiotherapy with Concurrent Cisplatin Chemotherapy
Five randomized phase III trials of radical RT alone versus concurrent cisplatin-based chemotherapy and
RT, and meta-analyses subsequently have shown an absolute benefit in overall survival and progression
free survival with concomitant chemo-radiotherapy in patients with stage IB2 to IVA disease as well as
high risk patients after hysterectomy 99 - 106.
While chemo-radiotherapy is perhaps the new standard of care, it is worth remembering that these
results were obtained in a trial setting, in women from affluent countries who had better nutritional
or performance status and renal parameters as compared to the majority of our patients from lower
socioeconomic status and advanced disease. Therefore in women with medical or social reasons for
doubtful compliance or tolerance to combined modality treatment, radical radiotherapy alone without
compromising the doses and duration can still be considered as the gold standard treatment approach in
our setting.
Management of patients who relapse after primary treatment:
Treatment decisions should be based on the performance status of the patient, the site of recurrence and/
or metastases, the extent of metastatic disease and the prior treatment.
Therapeutic options for local relapse after Primary Surgery
Relapse in the pelvis following primary surgery may be treated by either radical radiation or in selected
patients pelvic exenteration. Radical irradiation (+/-with or without concurrent chemotherapy) may cure
a substantial proportion of those with isolated pelvic failure after primary surgery.Radiation dose and
volume should be tailored to the extent of disease. Fifty Gray in 25# @ 1.8 Gy per day should be delivered
to microscopic disease and using field reductions 64 to 66 Gy should be delivered to the gross tumour
volume.
Pelvic Exenteration may be an alternative (particularly if a fistula is present) to radical radiotherapy and
concurrent chemotherapy in selected patients without pelvic sidewall involvement.
Local Recurrence after Primary Radiotherapy: Selected patients with resectable recurrences should
be considered for pelvic exenteration. The only potentially curative treatment after primary irradiation
is pelvic exenteration. Patients should be selected carefully; those with resectable central recurrences
that involve the bladder and/or rectum without evidence of intraperitoneal or extra pelvic spread and
who have a dissectabletumour-free space along the pelvic sidewall are potentially suitable. The triad of
unilateral leg edema, sciatic pain and ureteral obstruction almost always indicates unresectable disease

on the pelvic sidewall, and palliative measures are indicated. This surgery should be undertaken only in
centres with facilities and expertise for this surgery available and only by teams who have the experience
and commitment to look after the long-term rehabilitation of these patients. The prognosis is better for
patients with a disease-free interval greater than six months, a recurrence 3 cm or less in diameter, and
no sidewall fixation. The five-year survival for patients selected for treatment with pelvic exenteration is
in the order of 30 60% and the operative mortality should be < 10%. In carefully selected patients, a
radical hysterectomy may be performed. Suitable patients are mainly those whose central tumour is not
more than 2 cm in diameter. Grade C Recommendations.
Since the institutions are different phases of development and infrastructure available. It is envisaged that
they will improve over the period of time.
Minimum Optimal
External RT
Technique Conventional Conformal
Machine Cobalt / low energy Linac Linac with MLCs
Brachytherapy
LDR / HDR TPS planning atleast once with or- TPS planning for all Intracavitary ap-
thogonal X-rays / Images plications

Appendix - E
PRINCIPLES OF CHEMOTHERAPY
INTRODUCTION:
Chemotherapy is the use of drugs to kill cancerous cells, which can be administered either intravenously,
orally or locally at the tumour site. In haematological malignancies chemotherapy solely and in solid
tumours chemotherapy in combination with surgery or radiotherapy has rendered many cancers curable.
The practice of medical oncology primarily deals with the appropriate use of chemotherapy drugs and
its success depends upon using the right drugs at sufficient doses so as to derive a good response with
minimum toxicity.
TYPES OF CHEMOTHERAPY:
Induction: High-dose, usually combination, chemotherapy given with the intent of inducing complete
remission when initiating a curative regimen. The term is usually applied to hematologic malignancies but
is equally applicable to solid tumors.
Consolidation: Repetition of the induction regimen in a patient who has achieved a complete remission
after induction, with the intent of increasing cure rate or prolonging remission.
Intensification: Chemotherapy after complete remission with higher doses of the same agents used for
induction or with different agents at high doses with the intent of increasing cure rate or remission
duration.
Maintenance: Long-term, low-dose, single or combination chemotherapy in a patient who has achieved
a complete remission, with the intent of delaying the regrowth of residual tumor cells.
Adjuvant: A short course of high-dose, usually combination chemotherapy in a patient with no evidence
of residual cancer after surgery or radiotherapy, given with the intent of destroying a low number of
residual tumor cells. Adjuvant chemotherapy has shown to improve the overall survival in cancer patients
107
and prevents recurrence of chemo-sensitive tumours 108.
Neoadjuvant: Adjuvant chemotherapy given in the preoperative or perioperative period. It helps in
reducing the size of the primary tumour. Another rationale is that if chemotherapy is administered prior
to surgery, the reaction at the primary tumor site may be a predictive marker of micrometastatic systemic
disease response 109. Based upon the response in the primary tumour we also can predict the nature of
the disease and identify patients who may require aggressive therapy in the future 110.
Palliative: Chemotherapy given to control symptoms or prolong life in a patient in whom cure is
unlikely.
Salvage: A potentially curative, high-dose, usually combination, regimen given in a patient who has failed
or recurred following a different curative regimen.
COMBINATION CHEMOTHERAPY: It is the use of combination of two or more drugs from different
classes used to treat a malignant disease e.g. the use of paclitaxel and carboplatin in ovarian malignancy.
The rationale for combination chemotherapy is to minimise toxicity due to high dose of a single drug,
synergistic effect of the combination drugs and thus greater anti neoplastic effect and to minimise drug
resistance due to tumour cell heterogeneity as the disease progresses due to DNA instability and mutations
111
.

CELL CYCLE:
In human body there are mainly three types of cells 112:
1. Actively dividing cells
2. Terminally differentiated cells which can no longer divided
3. Resting cells, but which have potential to divide
The cell cycle has 5 phases:
1. G0 phase: In this phase the cells are in resting state.
2. G1: This is the phase, where the cells prepare for DNA synthesis
3. S phase: DNA synthesis takes place, to form tetraploid forms
4. G2 phase: This is the phase where cells prepare for mitosis and repair of the defective genetic
material takes place
5. M phase: this is the active mitotic phase where two daughter cells are formed
The basic understanding of this cell cycle is important because chemotheraputic drugs can be classified
broadly into two categories:
A. Cell-cycle phase specific: eg G0 phase specific- e.g. corticosteroids
G1 phase specific- e.g. asparaginase
S phase specific- e.g. 5fluorouracil, methotrexate
G2 phase specific- e.g. bleomycin, irinotecan
M phase specific- e.g. vinca alkaloids, taxanes
These drugs act only if the cells are in that specific phase of cell cycle. Hence above a certain dose further
increase in the drug level will not enhance cell kill, but if the same concentration is maintained over a
longer time then more cells can enter into that particular phase.
B. Cell-cycle phase non specific: e.g. alkylating agents
These drugs have a linear dose response curve; more the concentration more is the cell kill
TUMOR CELL KINETICS: Tumour growth depends on the fraction of cells dividing actively, tumour
doubling time and the host immune system and destruction of tumour cells by apoptosis or necrosis.

When there is an increased fraction of actively dividing cells the tumour rapidly increases in size and after
it has reached a particular size the growth ceases due to decrease in blood supply and hypoxia. A tumour
becomes detectable when there are 109 cells or 1 gram of tissue and 1012 cells leads to death.
Tumour growth is best depicted by the Gompertzian model which suggests that uncontrolled growth
eventually leads to a plateau phase of slow growth and eventually the tumour maintains a stable size. This
important fact is important as most of the chemotherapy drugs act effectively at the fast dividing fraction
as proposed in the Norton and Simon hypothesis that cell kill is proportional to the growth fraction.
Hence smaller size tumours are more chemosensitive than larger size tumours.

MAJOR CLASSES OF ANTI NEOPLASTIC DRUGS: Anti cancer drugs are divided into the following
classes
CLASS EXAMPLE MECHANISM OF IMPORTANT TOXICITY
ACTION
Alkylating agents Busalfan Cross linking of Lung fibrosis
Cyclophosphamide DNA strands Haemorrhagic
Cystitis
Neurotoxicity,
Cisplatin Nephrotoxicity
myelosuppression
Antimetabolites 5 fluorouracil Interferes with DNA synthesis Diarrhea
Methotrexate by blocking necessary enzymes Myellosuppression
Antitumour Bleomycin Intercalates with Pneumonitis
Antibiotics DNA and prevents its Hypersensitivity
replication and Myelosuppression
Actinomycin D Messenger RNA cardiomyopathy
Doxorubicin Production
Mitotic spindle Paclitaxel Bind microtubular Neuropathy
Agents dosetaxel Proteins and Hypersensitivity
Vincristine Disrupt the mitotic Neuropathy
Vinblastine Spindle myelosuppression
Topoisomerase Etoposide Inhibits topoisomer- Myelosuppression
Inhibitors irinotecan Se which is essential diarrhea
To repair DNA
Strand breaks
Tyrosine kinase Imatinib BCR-ABL TKI Myelosuppression
Inhibitors (TKI) Erlotinib EGFR TKI Acneiform rash
Lapatinib EGFR & Her 2 TKI diarrhea
Monockonal Rituximab Anti CD 20 Infusion related
Antibodies Bevacizumab ANTI VEGF Cytokine release
Hormonal agents Tamoxifen Anti estrogen Hot flushes, vaginal
Aromatase inhibitor Bleeding
osteopenia
Anastrazole
DRUG RESISTANCE: Failure of chemotherapy has been a great concern and has led to discovery of
more and more new drugs to treat cancer. Drug resistance can be inherited or acquired 114. Acquired
resistance is of more concern; as such tumours may be cross resistant to chemotherapy drugs of other
classes in addition. The main causes of drug resistance are 115:
1. increased drug efflux due to a protein called p glycoprotein encoded by multi drug resistance (MDR)1
gene
2. drug inactivation
3. alterations in drug target
4. repair of drug-induced damage, and evasion of apoptosis
5. mutations and development of resistant clones of cancer cells
RESPONSE FOR CHEMOTHERAPY: Objective response of the tumour to chemotherapy and overall
survival are two important predictors of the efficacy of any chemotherapy regimen. Hence to have a fair

and objective response assessment RECIST (Response evaluation criteria in solid tumours) has been
formulated, which specifically helps in a clinical trial setting. The important definitions under RECIST are
as follows 116:
Complete Response (CR): Disappearance of all target lesions.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as
reference the baseline sum diameters
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
The appearance of one or more new lesions is also considered progression.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify
for PD.
The clinical application of RECIST by the help of imaging helps in making treatment decisions regarding
continuation of the existing chemotherapy regimen or changing into next line of chemotherapy. However,
patients symptomatic improvement and quality of life are also important factors for such decisions.

10
CHAPTER
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11
CHAPTER
ABBREVIATIONS
5-FU 5-Fluorouracil
AIDS Acquired Immune Deficiency Syndrome
APC Argon Plasma Coagulation
ARV Antiretroviral Therapy
ATZ Abnormal Transformation Zone
CGIN Cervical Glandular Intraepithelial Neoplasia
CIN Carcinoma in-situ
CT Chemotherapy
CT Scan Computed Tomography Scan
CTV Clinical Target Volume
DNA Deoxyribonucleic acid
EBRT External Beam Radiation Therapy
EP Etoposide and cisPlatinum chemotherapy
FOGO International Federation of Gynecology and Obstetrics
GEC-ESTRO Groupe Europeen de CurietherapieEuropean Society for Therapeutic Radiology and
Oncology
GTV Gross Tumor Volume
Gy Gray
GYN Gynecology
HBOT Hyperbaric Oxygen Therapy
HDR High Dose Rate
HPV Human Papilloma Virus
HR-CTV High Risk Clinical Target Volume
IBBT Image Based Brachytherapy
ICA Intracavitary Application
ICRU International Commission on Radiation Units and Measurements
IGRT Image Guided Radiation Therapy
IMRT Intensity Modulated Radiation Therapy
IR-CTV Intermediate Risk Clinical Target Volume
LDR Low Dose Rate
LEEP Loop Electrosurgical Excision Procedure
LVSI Lympho-Vascular Space Involvement
MDR Multi Drug Resistance
MLC Multileaf Collimator

MRI Magnetic Resonance Imaging
NCC Neuroendocrine cancers of Cervix
NTZ Normal Transformation Zone
OAR Organs at risk
OS Overall survival
PALN Para-Aortic Lymph Node
Pap test Papanicolaou test
PCR Polymerase Chain Reaction
PET-CT Positron Emission Tomography-Computerised Tomography
PFS Progression Free Survival
PLND Pelvic Lymph Node Dissection
PTV Planning Target Volume
RECIST Response Evaluation Criteria in Solid Tumors
RH Radical Hysterectomy
RNA Ribonucleic acid
RR Relapse Rate
RT Radiation Therapy
RTOG Radiation Therapy Oncology Group
SCCC Small Cell Carcinoma of Cervix
SIADH Syndrome of Inappropriate Antidiuretic Hormone
TPS Treatment Planning System
US Ultrasonography
VAC Vincristine, Dactinomycin, Cyclophophamide
WHO World Health Organisation
Wks Weeks

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CONSENSUS DOCUMENT FOR THE

Indian Council of Medical Research,

Dr. Soumya Swaminathan

Dr. V. K. Srivastava : Head (Publication & Information)

Compiled & Edited by : Dr Tanvir Kaur, Dr. S Shrisvastava

Production Controller : JN Mathur

(Dr. G.K. Rath)

Shyam Kishore Shrivastava

(Dr. R.S. Dhaliwal)

Dr G.K. Rath Dr Hemant Tongaonkar,

Dr Partha Basu, Dr BC Das,

Dr Uma Devi, Dr Sudeep Gupta,

Dr Lalit Kumar, Dr Sunesh Kumar Jain,

Dr A. Selva Lakshmi, Dr Umesh Mahantshetty

Dr Amita Maheshwari Dr Firuza Patel,

Dr S. Radhika, Dr T.Subramanyshwar Rao,

10 Consensus Document for the Management of Cancer Cervix

11 Consensus Document for the Management of Cancer Cervix

Pre-Treatment Evaluation for Cervical Cancer

12 Consensus Document for the Management of Cancer Cervix

13 Consensus Document for the Management of Cancer Cervix

14 Consensus Document for the Management of Cancer Cervix

FIGO Staging 2009

Salient features of FIGO 2009 Staging

15 Consensus Document for the Management of Cancer Cervix

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(If fertility desired

17 Consensus Document for the Management of Cancer Cervix

Modified Radical Hysterectomy

Stage IA2 Radical Trachelectomy or Radical cone

Brachytherapy External beam

Stage IA2: The treatment options are

18 Consensus Document for the Management of Cancer Cervix

Stage IB1and IIA1:

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Stages IB2 &

Stage IB2 and IIA2:

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High risk (any one)

Intermediate risk (any two)

21 Consensus Document for the Management of Cancer Cervix

Radical Radiotherapy (External +

Para-aortic LN+ve Extended field RT* + Concurrent

Stage IIB and III: The options are

22 Consensus Document for the Management of Cancer Cervix

Stage IV A Pelvic Exenteration**

Individualized Rx Concurrent CT + RT**

23 Consensus Document for the Management of Cancer Cervix

24 Consensus Document for the Management of Cancer Cervix

Side wall or extra pelvic Pelvic RT/

25 Consensus Document for the Management of Cancer Cervix

*NTZ-Normal Transformation zone

**ATZ-Abnormal Transformation zone

Colposcopy for IA1 and observation every 3 months

1st Trimester RH III + PLND

RH III + PLND up to 20 weeks

Wait for fetal lung maturity

3rd Trimester Induce lung maturity

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