ROLE OF CHEMOTHERAPY IN GYNAEC MALIGNANCIES

DR. R. RAJKUMAR M.D., D.M.

OVARIAN CANCER

Leading cause of death from gynecologic cancer 75% present in advanced stage Improvement in 5yr survival – 36% in 1977 39% in 1986 45% in 2002 More effective chemotherapy options Surgical techniques

OVARIAN CANCER – CLINICAL FINDINGS

Usual features : Abdomino –pelvic mass, ascites, left supraclavicular

lymph node Unusual presentations: Right supraclavicular or axillary lymph nodes with

abdominal mass Isolated pleural effusion Isolated ascites without any ovarian mass

OVARIAN CANCER - EVALUATION

Detailed history and clinical exam Pelvic exam including per rectal exam to assess POD

- EUA Endometrial biopsy in selected cases Complete blood counts Renal function tests Liver function tests Tumor markers Chest x ray & other imaging studies Genetic counseling

OVARIAN CANCER - EVALUATION Tumor markers: CA 125 –most commonly elevated in 80% of serous tumors not elevated in 50% of early stage tumors, mucinous and clear

cell carcinomas Not a reliable diagnostic test Post operatively ca125 levels –sensitive –to monitor response

to chemo Normalization after 3 cycles –favorable outcome Nadir <10u/ml – favorable Useful in follow up for detecting recurrence CEA , CA 19-9 - mucinous tumors & in krukenbergs tumor

OVARIAN CANCER – TUMOR MARKERS

Sr.VEGF levels HE4 (human epididymis 4)-WFDC gene product MCS-F in serum & ascitic fluid Proteomic spectral analysis of serum SELDI-TOF –MS : Surface enhanced laser desorption

and ionization time of flight MS

OVARIAN CANCER - IMAGING

USG abdomen with colour doppler study –transvaginal sonography

Complex mass with increased vascularity Ascites Enlarged para aortic nodal masses Omental and peritoneal deposits larger than 1cm Matted bowel loops

Ultrasonography &Colour Doppler

OVARIAN CANCER - IMAGING

CT SCAN abdomen & pelvis:

Extent of disease in upper abdomen Helps to decide on primary surgery or neoadjuvant chemotherapy Attachment of omentum to splenic hilum Disease/tumor nodules >2cm in mesentery, liver surface or parenchyma,

diaphragm, gall bladder fossa, suprarenal para aortic nodes Pulmonary or pleural nodules

CT Scan

OVARIAN CANCER - IMAGING

MRI abdomen – not superior to CTscan except in pregnant women where USG is inconclusive

PET-CT scan : not for diagnosis Useful in rec.disease with isolated CA125 elevation

OVARIAN CANCER - INVESTIGATIONS

UPPER GI SCOPY& COLONOSCOPY – NOT INDICATED ROUTINELY

Symptoms s/o gastric disease or lower GI symptoms or fecal occult blood positive

4% have associated GI malignancy

Mammography Genetic counseling in pts with positive family history

EPITHELIAL OVARIAN CANCER

DIAGNOSISSymptoms

Clinical Examination

Investigations

Ca125 Imaging

USG Colour Doppler CT/MRI

FNAC contraindicated

OVARIAN CANCER STAGING

Stage I - Limited to ovaries

A. Unilateral ovary

B. Bilateral ovaries

C. Positive cytology

Stage II - Limited to pelvis

A. Extends to uterus or tubes

B. other pelvic organs

C. Positive cytology

Stage III – Spread to upper abdomen or regional lymph nodes

A. Microscopic spread

B. Macroscopic < 2 cm

C. Macroscopic > 2 cm

Stage IV - Spread outside peritoneum, pleura or parenchymalliver metastases

OVARIAN CANCER FIGO STAGING SYSTEM

Stage Description Incidence Survival I Confined to ovaries 20% 73%

II Confined to pelvis 5% 45%

III Confined to abdomen/ 58% 21%lymph nodes

IV Distant metastases 17% <5%

Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France.

Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007.

FIGO = International Federation of Gynecology and Obstetrics

HOW TO PROCEED AFTER INVESTIGATIONS ?

Decision to proceed directly to surgery is a clinical one – in advanced stage :

based on extent of disease

Performance status

Nutritional status

Comorbid illness

HOW TO PROCEED AFTER INVESTIGATIONS?

Operable tumors – laparotomy and proceed

Avoid percutaneous FNA of localised masses or complex cysts – upstage disease

WHO NEEDS NEOADJUVANT CHEMOTHERAPY?

Presence of gross ascites,

huge fixed pelvi-abdominal mass,

nodules in POD PS III-IV

Supraclavicular nodes

Pleural effusion – bilateral

USG abdomen showing

extensive peritoneal,omental deposits and liver sec, bilateral pleural effusion

CT SCAN FINDINGS

Diffuse peritoneal thickening(DPT) >4mm – involving atleast 2 of the 5 areas

lateral colic gutters Lateral conal fascia Anterial abdominal wall Diaphragm and splenic peritoneal reflection

Sean C.Dowdy et al, CANCER - 2004

FOR NEOADJUVANT CHEMOTHERAPY

Cytologic evidence of malignancy – ascitic fluid

FNA of the mass ( transvaginal –preferably)

Laparoscopy before NACT:

- to assess disease extent and for biopsy in cases where repeated cytology is negative for malignancy

OVARIAN CANCER SURGICAL DEBULKING AND STAGING

Exploration

Washings/Ascites

(Staging)

TAH/BSO

Biopsies(Staging)

Goals (Debulking)•Assessment of extent of disease

•Optimal tumor reduction

TAH = total abdominal hysterectomy

BSO = bilateral salphingo-oophorectomy

Cytoreductive Surgery

Goal is elimination of all tumor• No gross residual (microscopic)• Optimal (<1 cm)• Suboptimal (>1 cm)

Operative Technique• Resection of urinary or intestinal tract

Surgical Outcomes• Optimal in ~75% of cases• Does it matter?

Does Cytoreduction Matter?

Optimal Suboptimal

Response Rate

Clinical CR 95% 75%

Pathologic CR 50% 25%

Progression free interval (mo) 34 13

Survival (mo) 50 36

10-yr survival 35% 15%

PROGNOSTIC FACTORS

Volume of residual disease after surgery Stage Histologic subtype Histologic grade Performance status Age Ovarian cancer prognostic profile(OCPP) Chemotherapy response profile (CRP) Gene expression profiling

PRIMARY TREATMENT OF OVARIAN CANCER

1995 1997 1999

Cyclophosphamide + Cisplatin

STANDARD OF CARE

GOG 111 establishes Taxol-CDDPas standard 1st line

2001

GOG 158 shows Taxol-carboplatin = Taxol-CDDP, with improved toxicity and QoL

GOG 178 demonstrates improved DFS with longer duration of maintenance Taxol – No

data on overall survival

GOG 172 confirms IP therapy leads to a survival

advantage compared with IVNEW STANDARD OF CARE?

SWOG 8501 demonstrates improved survival with IP therapy

2003 2005 2008

GOG 182 demonstrates no survival advantage to triplet or sequential

doublet therapy

FIRST-LINE THERAPY – Standard Treatment Options

Platinum + Taxane Chemotherapy(Carboplatin + Paclitaxel)

Surgery with maximum cytoreduction effort <1cm

residual disease

CHEMOTHERAPY• Standard front-line chemotherapy today is

carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles

• Result of several studies over last decade– GOG 1111 and OV 102 - paclitaxel/cisplatin

vs cyclophosphamide/cisplatin

– GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin

1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6.2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200.4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329.

GOG = Gynecologic Oncology GroupAGO = ArbeitsgemeinschaftGynaekologische Onkologie

The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma

Study # Pts RegimenMedian PFS

(mo)Median OS

(mo)

GOG 1321

377III suboptimal-IV

Cisplatin/Paclitaxel (24 h) x 6

14.1 26.3

Cisplatin 100 mg/m2 x 6 16.4 30.2Paclitaxel 200 mg/m2 (24 h)* 10.8 25.9

ICON32

2074I-IV

Carboplatin/Paclitaxel (3 h)

17.3 36.1

Carboplatin or CAP 16.1 35.4

CAP = cyclophosphamide, doxorubicin, cisplatinGOG = Gynecologic Oncology GroupICON = International Collaborative Ovarian Neoplasm Group OS = overall survivalPFS = progression-free survival

1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515.

*CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001

OVARIAN CARCINOMA: CLINICAL COURSE

Symptoms

Diagnosis

Chemotherapy #1

StagingPrimary cytoreduction

Interval Cytoreduction

Progression

Chemo #2 Chemo #3+

SupportiveCare

Death

Consolidation/Maintenance

Cure

SecondaryCytoreductionSecond-Look

EPITHELIAL OVARIAN CANCERPLAN OF MANAGEMENT

Resectable

Primary cytoreductive surgery (Max)

Chemo 6 cycles

Unresectable

Chemo 3 cycles

Interval cytoreductive Surgery (Max)

Chemo 3 cycles

Stage III/IV

CHEMOTHERAPY – EARLY STAGE DISEASE

High risk early stage: stage I, gr III, Ic,any stage II

Stage Ia,Ib –gr I & II can be observed

ICON I(International Collborative Ovarian Neoplasm Trial I) &

ACTION (Adjuvant Chemotherapy in Ovarian Neoplasm Trial) –chemo improves progression free & OS in high risk early stage disease(925 pts – os – superior for platinum based chemo

GOG study -3 vs 6 cycles – 33% reduction in risk of rec in high risk disease who received 6cycles of chemo

Patients with suboptimal surgery benefit from platinum based chemo

Chemotherapy in advanced stage

GOG 111: paclitaxel+cisplatin superior to cisplatin + cyclophosphamide

RR 73% vs 60%

Median PFS 18 vs 13mo

Median os 38mo vs 24mo p<001

60mo of follow up – 20% reduct. In risk of progression & 34% reduction in risk of death

OV10,ICON 3

GOG 132 –sequential administration of pacli or cisplatin is therapeutically equivalent

Chemotherapy in advanced stage

GOG 158,AGO,NETHERLANDS-DENMARK: Carboplatin+paclitaxel vs cisplatin +paclitaxel is equivalent – PFS &OS

Carbo+paclitaxel – preferred – favorable toxicity profile

Reduced emesis,neutropenia,nephrotoxicity

Short infusion time

Marginal PS,Comorbid medical condition – start with single agent carboplatin – add paclitaxel later

No benefit for 12 vs 6 cycles

No benefit for addition of 3rd cytotoxic agent – PLD,EPI,TOPO,GEM

Addition of bevacizumab

Interventions to Mortality?

Time

Dis

ea

se V

olu

me

Prevention

Screening

Current point of diagnosis and initiation of treatment

Prevention– Pedigree Analysis– Medical: Oral Contraceptives– Surgical: Risk-Reducing Oophorectomy

Screening– Pelvic Examination– Ultrasonography– CA125 and other (OvaSure) Serum Testing– Proteomics (OvaCheckTM)

Interventions to Mortality?

NIH Consensus Development Panel

“…there is no evidence available yet

that the current screening modalities

of CA 125 and ultrasonography can

be effectively used for widespread

screening to reduce mortality from

ovarian cancer…”

Screening – US and CA 125

Goals of Treatment:Relapsed Ovarian Cancer

• Prolong Survival

• Delay Time to Progression

• Control Disease-Related Symptoms

• Minimize Treatment-Related Symptoms

• Maintain or Improve Quality of Life

Surveillance Options for Ovarian Cancer Patients in Remission• Second-look laparotomy• Physical examination

– Include pelvic examination• CA-125• Imaging

– CT scan– MRI?– PET scan?

CT = computed tomographyMRI = magnetic resonance imaging PET = positron emission tomography

Ovarian Cancer:How is Relapse Defined?

• Continuous rise in CA-125• CA-125 above 100• Radiographic recurrence• Symptomatic recurrence• Physical examination findings• Combination of above

Effect of Platinum-Free Intervalon Response Rate% Response to Second-line

Platinum Therapy

Platinum-Free Interval (mos) Markman Gore Blackledge

0-617%

10%

7-12 27% 29%

13-1833% 27%

63%

19-24 94%

>24 59% 57%

Non-Platinum Therapy

15%

20%

30%

30%

Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211.Blackledge G, et al. Br J Cancer. 1989;59:650-653.

Refractory

PRI

MARY

TREATMENT

Resistant

Sensitive

0 3 6 12 18 24Months

“Very Sensitive”

Ovarian Cancer at First RelapseDefinition of Sensitivity

Defined as measurable recurrence, not biochemical (CA-125) recurrence

Active Agents in Ovarian CancerFDA approved

Altretamine Carboplatin Cisplatin

Gemcitabine/Carboplatin

Paclitaxel Pegylated liposomal doxorubicin

Topotecan

Not FDA approved, compendium listedChlorambucil Cyclophosphamide Docetaxel

Doxorubicin Epirubicin Etoposide

5-FU/LV Gemcitabine Ifosfamide

Irinotecan Melphalan Methotrexate

Thiotepa Vinorelbine

Not FDA approved, not compendium listedAromatase inhibitors Bevacizumab Pemetrexed

Tamoxifen

Secondary Cytoreduction

• Controversial • Inconsistent definitions• Benefit appears confined

to patients likely to respond to additional chemo:

• >12 month PFI• Isolated site of

recurrence• Disease

completely resectable Kidney

Resected LiverDiaphragm

Kidney

Vena Cava

Tumor Mass

Renal Vein

PFI = progression-free interval

Advanced Ovarian Cancer

cisplatin paclitaxelmulti-drug Alkeran

Median Survival: 1975 - 2005

IP therapy

(optimal)(optimal)

months

12 1424

3752

5766

0

20

40

60

80

1975 1983 1986 1996 1998 2003 2005

The tumor extends to the pelvic wall and/or involves lower third of the vagina and or causes hydronephrosis or non-functioning kidney **

Stage IIIA: Tumor involves lower third of the vagina, with no extension to the pelvic wallStage IIIB: Extension to the pelvic wall and/or hydronephrosis or non-functioning kidney

The carcinoma is strictly confined to the cervix(extension to the corpus would be disregarded)

Stage IA: Invasive carcinoma which can be diagnosed only by microscopy, with deepest invasion ≤5 mm and largest extension ≤7 mmStage IA1: Measured stromal invasion of ≤3.0 mm in depth and extension of ≤7.0 mm.Stage IA2: Measured stromal invasion of >3.0 mm and ≤5.0 mm with an extension of not >7.0 mm

Stage IB: Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than stage IA*

Stage IB1: Clinically visible lesion ≤4.0 cm in greatest dimension Stage IB2: Clinically visible lesion >4.0 cm in greatest dimension

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

Stage IVA: Spread of the growth to adjacent organs. Stage IVB: Spread to distant organs.

Stage II

Stage I

FIGO staging system, 2009

Cevical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina

Stage IIA: Without parametrial invasionStage IIA1: Clinically visible lesion ≤4.0 cm in greatest dimensionStage IIA2: Clinically visible lesion >4 cm in greatest dimension

Stage IIB: With obvious parametrial invasion

Stage III

Stage IV

*All macroscopically visible lesions—even with superficial invasion—are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissue—superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with “early (minimal) stromal invasion” (~1 mm). The involvement of vascular/lymphatic spaces should not change the stage allotment.** 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.

Diagnosis is based on conization!

Recommended work-up• Vaginal and rectal examination, exfoliative cytology (Papanicolaou smear), colposcopy, biopsy and/or endocervical curettage (ECC), conization or Loop electrosurgical procedure (LEEP) • Histopathological finding with all standard tumor parameters• Laboratory analyses: WBC, biochemical analyses• Imaging: Chest X-ray, pelvic and abdominal ulstrasound

ConizationNecessary HP parameters:2• Depth of invasion• Width of the tumor• Tumor differentiaion• Lympho-vascular space invasion (LVSI)• Resection margins

Margins and/orECC positive for dysplasia

Margins clearECC negative

Stage Ia1LVSI negative

•Stage Ia1 with extensive LVSI Stage Ia2

• Repeated conisation• Modified radical hysterectomy (type B6) if re-conisation is not possible± pelvic lymphadenectomy

Conization if preservation of fertility is desiredorSimple (extrafascial, type A6) hysterectomy with or without salpingoophorectomy

Conization or radical trachelectomy if preservation of fertility is desiredorModified radical hysterectomy (type B6)andPelvic lymphadenectomy

Recommended follow-upEvery 3 months after completed therapy during the first year; every 6 months up to 5 years. Annually afterwards. Investigations in addition to gynaecological examination, including cytology and colposcopy, should be performed depending on symptoms, local findings and general condition of the patient

Cervical cancerFIGO Stage I a

Microinvasive carcinoma (invasion ≤ 5 mm)

Recommended work-upNeccessary investigations:• Vaginal and rectal examination, colposcopy, biopsy and/or endocervical curettage (ECC); conization or loop electrosurgical procedure (LEEP) if needed for definitive diagnosis• Histopathological finding with all standard tumor parameters• Laboratory analyses: WBC, biochemical analyses including check for renal function and Hb• Imaging: Chest X-ray, abdominal and pelvic ultrasound (size and position of the tumor and tumor volume/cervix ratio)Optional investigations:Pelvic NMR, CT of the abdomen (PET/CT if possible), cystoscopy, rectoscopy, IVU or sonographic renal examination. Involvement of the bladder or rectum should be confimed histologically

Radical surgery

• Uterus with paracervical tissues and upper part of vagina (radical, type C6 hysterectomy) + pelvic lymphadenectomyor• Entire cervix with paracervical tissues (radical trachelectomy) if fertility is desired + pelvic lymphadenectomyor• Upper part of vaginal cuf, paracervical tissues + pelvic lymphnodes in case of previous simple hysterectomy * At least 2 cm distance from the resection margins is desirable ** In premenopausal women ovaries can be retained; if so tranposition is advised.*** For the desision of further management, all neccesary histopathologic parameters4 should be requested

Chemo-radiation

Neoadjuvant chemotherapy followed by radiation or surgery is an option for locally advanced tumors (Ib2 and IIa2) but awaits confirmatory evidence from controlled clinical trials.

Recommended follow-upEvery 3 months after completed therapy during the first year; every 6 months up to 5 years. Annually afterwards. Investigations in addition to gynaecological examination should be performed depending on symptoms, local findings and general condition of the patient

• Positive resection margins• Involvement of parametria• Residual tumor• Multiple positive nodes (>3)

• Positive nodes (1-3)• Poorly differentiated or undifferentiated tumor (G3)• LVSI present• Primary tumor (tumor-cervix volume) >3 cm• Endocervical invasion (barrel shaped cervix)• Inadequate surgery• Insufficient HP (if report of all necessary parts is missing)

• Medical contra-indications for surgery• Ib2/IIa2 tumors in selected cases• Anterior vaginal extension• Invasive cancer after simple hysterectomy• Choice of the patient

ConcomitantChemo-radiation

Radiation± Chemotherapy

Radiation± ChemotherapyFollow up

Negative nodes

GOG score**consider using GOG score as a guide for adjuvant treatment5

Low risk(GOG score < 120)

Low risk(GOG score < 120)

or

Cervical cancerFIGO Stage Ib - IIa

Squamocellular, Adenocarcinoma, Adenosquamous

Recommended work-up• Vaginal and rectal examination, biopsy or endocervical curettage (ECC)• Histopathological finding with all standard tumor parameters• Laboratory analyses: WBC, biochemical analyses including check for renal function and Hb • Imaging: Chest X-ray, abdominal and pelvic ultrasound• Pelvic NMR, CT of the abdomen (PET/CT if possible), cystoscopy, rectoscopy, IVU or sonographic renal examination. Involvement of the bladder or rectum should be confimed histologically

Recommended follow-upEvery 3 months after completed therapy; every 6 months up to 5 years. Annually afterwards. Investigations in addition to gynaecological examination should be performed depending on symptoms, local findings and general condition of the patient

Pelvic MRI andAbdominal CT

Paraaortic nodes (PALN) negative(=not enlarged)

Pelvic or paraaortic nodes (PALN) positive (enlarged ≥2 cm))

Pelvic (± paraaortic) radiation+ brachytherapy+ concomitant chemotherapy

CT of the lungs & mediastinum

CT negative CT positive

Pelvic radiation (with paraaortic if PALN are positive) + brachytherapy + concomitant chemotherapy

* Consider: • resection of adnexal mass and/or extraperitoneal resection of enlarged nodes • Sequential chemoth and Concomitant ChemoRadioTherapy /External Beam RadioTherapy (CCRT/EBRT)

Palliative pelvic RT± Palliative chemotherapy

*Stage IVa• with vesicovaginal fistula: if pelvic, abdominal and chest imaging exclude distant metastases primary pelvic exenteration can be considered• NACT may be offered to large bulky tumors to downsize tumor prior to CCRT

Cervical cancerFIGO stage IIb- IV

Recommended work-up•• Vaginal and rectal examination, biopsy - histopathological confirmation of recurrence• Laboratory analyses: WBC, biochemical analyses including check for renal function and Hb• Imaging: Chest X-ray, pelvic and abdominal ultrasound, pelvic NMR and CT of the lungs and abdomen; (PET/CT if possible)• Cystoscopy, rectoscopy, IVU or sonographic renal examination

Recommended follow-upEvery 3 months for two years or more often if clinically indicated. Every 4-6 months thereafter. Annually afterwards. Investigations in addition to gynaecological examination should be performed depending on symptoms, local findings and general condition of the patient

Lungs & abdominal CT

Pelvic recurrence Extrapelvic recurrence

Options include:• Palliative radiotherapy or chemo-radiation• Systemic therapy• Supportive care

* Resection in selected cases(in particular paraaortic nodes)may be considered

Previous radiationNo previous radiation

Options include:• Chemo-radiation• Neoadjuvant chemotherapy (NACT)• Supportive care

Central pelvicrecurrence

Sidewall pelvicrecurrence

Options include • Radical hysterectomy in tumor <2 cm • Pelvic exenteration • Neoadjuvant chemotherapy (NACT) + surgeryOther options if surgery is not possible: • Re-irradiation • Neoadjuvant chemotherapy (NACT) + radiation • Systemic therapy • Supportive care

Options include: • Resection of isolated disease • Systemic therapy • Supportive care

Cervical cancer- recurrence -

Recommended work-upNeccessary investigations:• Vaginal and rectal examination, colposcopy, biopsy and/or endocervical curettage (ECC); conization or loop electrosurgical procedure (LEEP) if needed for definitive diagnosis• Histopathological finding with all standard tumor parameters• Laboratory analyses: WBC, biochemical analyses including including check for renal function and Hb • Imaging: Chest X-ray, abdominal and pelvic ultrasound (size and position of the tumor and tumor volume/cervix ratio)

Optional investigations:• Pelvic NMR, CT of the abdomen (PET/CT if possible), cystoscopy, rectoscopy, IVU or sonographic renal examination. Involvement of the bladder or rectum should be confi rmed histologically

*Stage of the disease is determined using FIGO classification1

Recommended follow-upEvery 3 months after completed therapy during the first year; every 6 months up to 5 years. Annually afterwards. Investigations in addition to gynaecological examination should be performed depending on symptoms, local findings and general condition of the patient

FIGO Ia FIGO Ib-IIa FIGO IIb-IV

• Diagnosis is based on conization; resection margins should be clear• Further decision depends on the presence of poor histologic prognostic factors2

Surgery Chemo-radiation Concomitant chemoradiationor Radical radiation only if unfit for chemotherapy

* Stage IV1 with vesicovaginal fistula: if pelvic, abdominal and chest CT exclude distant metastases, primary pelvic exenteration can be considered

• Medical contra-indications for surgery• Ib2/IIa tumors • Anterior vaginal extension• Invasive cancer after simple hysterectomy• Choice of the patient

• Radical hysterectomy (type C6)or • Radical trachelectomyor • Resection of the upper part of vagina and parametrectomy in case of previous simple hysterectomy and • Pelvic lymphadenectomy* Decision about further therapy is based on the presence of adverse histological factors

Neoadjuvant chemotherapy followed by radiation or surgery is an option for locally advanced tumors, but awaits confirmatory evidence from controlled clinical trials.

FIGO Ia1LVSI negative

• Conization/radical trachelectomyor • Modified radical hysterectomy(type B6)and • Pelvic Lymphadenectomy

• Conizationor • Simple hysterectomy (type A6)

Follow-up No adverse prognostic factors Adverse prognostic factors4 present

Follow-up Adjuvant therapy(Radiation ± Chemotherapy)

FIGO Ia1, LVSI positive

or

Cervical cancerSquamocellular, Adenocarcinoma,

Adenosquamous

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