Carcinoma della Cervice Uterina CronoprogrammaDiagnostico-Terapeutico.
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Transcript of Carcinoma della Cervice Uterina CronoprogrammaDiagnostico-Terapeutico.
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Carcinoma della Cervice UterinaCarcinoma della Cervice UterinaCronoprogramma Cronoprogramma
Diagnostico-TerapeuticoDiagnostico-Terapeutico
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Pap-test Anormale
Bethesda System, 2001
L-SIL
H-SIL
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Pap-test Anormale
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ASC-USASC-US61%61%
L-SIL 31%L-SIL 31%
H-SIL 8%H-SIL 8% ICC ICC 0% 0%
Pap-test Anormale
Davey, 2004
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Solomon (ALTS Group), 2001 Stoler, 2001
Sherman, 2001Kristen (ALTS Group), 2006
INCIDENCE: 1.3-5.0%INCIDENCE: 1.3-5.0%
CYTOLOGIC REVISION
Downgraded to neg 40%
Upgraded to L-SIL 20%
Upgraded to H-SIL 2%
• Low reproducibility level• Low PPV
ASC-US
NEGATIVE 75-85%
RISK OF CIN2+ 12%
RISK OF CIN3+ 5%
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CIN 2-3CIN 2-3 CancerCancer
Microinv. Inv.Microinv. Inv.
ASC-USASC-US 5-175-17
ASC-HASC-H 24-9424-94
CIN 3 CIN 3 6-126-12 1-21-2
% Upgrading% Upgrading
0.2 0.2
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ASC-US – HPV-test Triage
SICPCV, 2006
HPV-testHPV-test
HR +HR + HR -HR -
ColposcopiaColposcopia Pap-test Pap-test a 12 mesia 12 mesi
++ --
ColposcopiaColposcopia ScreeningScreening
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Statement on HPV DNA test utilization, 2009
HPV-test Triage – Raccomandazioni
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p16 Triage (sperimentale)
HPV-test (screening)HPV-test (screening)
HR -HR - HR +HR +
p16-testp16-test
++ --
ColposcopiaColposcopia HPV-test a un annoHPV-test a un anno
Carozzi, 2008
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ASC-US - ASC-H - L-SIL
SICPCV, 2006
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H-SIL – Carcinoma squamocellulare
SICPCV, 2006
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AGC
SICPCV, 2006
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• Citologia e colposcopia ogni 6 mesi per 2 anni• Controllo annuale per altri 5 anni• Ritorno a screening
Follow-up
SICPCV, 2006
Colposcopia, citologia e HPV-testColposcopia, citologia e HPV-test
Colposcopia Colposcopia e/o citologia +e/o citologia +
--
Percorso Percorso sec. lesionesec. lesione
Pap-test e HPV-test Pap-test e HPV-test a 12 mesia 12 mesi
++ --
ColposcopiaColposcopia ScreeningScreening
Colposcopia Colposcopia e/o citologia -e/o citologia -
HPV +HPV +
Controllo Controllo a 6 mesia 6 mesi
A 6 mesi da trattamento
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• • Carcinoma squamoso Carcinoma squamoso in situin situ• • Carcinoma squamoso inf.Carcinoma squamoso inf. cheratinizzante, non-cheratinizzante, verrucosocheratinizzante, non-cheratinizzante, verrucoso
• • Adenocarcinoma Adenocarcinoma in situ / in situ / tipo endocerv. tipo endocerv. • • Adenocarcinoma endometrioideAdenocarcinoma endometrioide• • Adenocarcinoma a cellule chiareAdenocarcinoma a cellule chiare• • Ca. adenosquamosoCa. adenosquamoso• • Ca. adenoide cisticoCa. adenoide cistico• Ca. a piccole celluleCa. a piccole cellule• • Ca. indifferenziatoCa. indifferenziato• Ca. neuroendocrinoCa. neuroendocrino
IstotipiIstotipi
FIGO, 2006FIGO, 2006
~10%~10%
~80%~80%
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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 ≤5mm and largest extension ≤7mmIA1 Measured stromal invasion ≤3mm in depth and horizontal extension ≤7mmIA2 Measured stromal invasion >3mm and not >5mm with an extension of not >7mmIB Clinically visible lesions limited to the cervix or pre-clinical cancers > Stage IAIB1 Clinically visible lesion ≤4cm in greatest dimensionIB2 Clinically visible lesion >4cm in greatest dimensionII Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to
the lower third of the vaginaIIA Without parametrial invasionIIA1 Clinically visible lesion ≤4cm in greatest dimensionIIA2 Clinically visible lesion >4cm in greatest dimensionIIB With obvious parametrial invasionIII The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or non-functioning kidneyIIIA Tumor involves lower third of the vagina (No extension to the pelvic wall)IIIB Extension to the pelvic wall and/or hydronephrosis or non-functioning kidneyIV 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 IVIVA Spread of the growth to adjacent organsIVB Spread to distant organs
Cervical Cancer - FIGO Staging (2009)
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Microinvasive CC
• IA
Early CC
• IB1
• IIA1
Locally Advanced CC
(LACC)
• IB2
• IIA2
• IIB
• III
• IVA
Metastatic CC
• IVB
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CONIZZAZIONE CERVICALE
EVISCERAZIONE PELVICA
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FIGOIA1: stromal invasion ≤ 3 mm in depth, horizontal extension ≤ 7 mm IA2: stromal invasion 3-5 mm in depth, horizontal extension ≤ 7 mm
SGOStromal invasion ≤ 3 mm in depth, no LVSI
Microcarcinoma – Staging Criteria
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Microcarcinoma – Treatment
• Total abdominal or vaginal hysterectomy (if VAIN, appropriate cuff of vagina should be removed)
• Observation after cone biopsy (particularly if fertility is desired)
FIGO, 2006
IA1
• Modified RH (Type 2) and pelvic LND• Consider extrafascial H and pelvic LND (if no LVSI)
If fertility is desired:• large cone biopsy + extra-perit. or lpsc pelvic LND• rad. trachelectomy and extra-perit.or lpsc pelvic LND
IA2
Mainly with Pap smears annually after two normal smears at 4 and 10 mos
Follow-up
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Cone: Positive margin
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In patient with positive margins:
• Vaginal Strict Follow-Up
• Endocervical Repeat Conization or or Stromal Hysterectomy
Microcarcinoma – Cone Positive Margin
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Fertility-sparing surgeryCervical Cancer
Radical Trachelectomy
Eligibility criteria
Dargent, 1994
43% of cervical cancer in women <45y (10-15% during childbearing years)
• Vaginal• Abdominal• Laparoscopic• Robotic
• Age < 40-45 years & Strong fertility desire• Diagnosis of invasive cancer (ideally, disease located
primarily on the ectocervix)• Exclusion of unfavorable histology• Stage IA1 with LVSI, IA2, IB1<2 cm• No evidence of pelvic N met and/or distant met• Gynecologic oncologist experienced in laparoscopic
and radical vaginal surgery
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Fertility-sparing surgeryRVT & Cancer prognosis
Overall recurrence and death rates comparable to early-stage cervical cancer treated by RH or RT
Plant, 2004; Seli, 2005
Review n Recurrence Rates
DeathRates
Darsun, 2007 520 4.2 2.8
Sonoda, 2008 548 4.0 2.6
Plante, 2008 603 4.5 2.5
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Fertility-sparing surgeryRVT & Pregnancy outcome
Pregnancy rate Pregnancy rate 70%70%
11stst-2-2ndnd trimester loss trimester loss 30%30%
Review (16 studies: 355 RVT / 161 pregnancies)
Boss, 2005
Pregnancy rate Pregnancy rate 62%62%
TAB/EUP TAB/EUP 5% 5%11stst-2-2ndnd trimester loss trimester loss 27%27%Deliveries <32 ws Deliveries <32 ws 12%12%
Deliveries >37 ws Deliveries >37 ws 65%65%Currently pregnant Currently pregnant 6% 6%
Review (8 studies : 603 RVT / 256 pregnancies)
Plante, 2008
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CK ConizationCK Conization
Follow-upFollow-up
Margins +Margins +
Repeat coneRepeat coneLVSI +LVSI +
Margins -Margins -
Pelvic LNDPelvic LND
N +N +RHRH N -N - Follow-upFollow-up
No Res TNo Res T
Invasive Res TInvasive Res T
RH + pelvic LNDRH + pelvic LND
Cerv Microca – Conservative Treatment Cerv Microca – Conservative Treatment Algorythm Algorythm
IA2IA2
LVSI -LVSI -
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CERVICAL CARCINOMA
Clinical AssessmentClinical Assessment
Histotype & Grade
Bladder/Rectum involvement
Parametrial infiltration
FIGO StageFIGO Stage
Vaginal infiltration
Lymphnode mets
T size
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• Esame vaginale bimanuale e vagino-rettale (in narcosi)
• Colposcopia, biopsia / conizzazione
• Currettage endocervicale
• Cistoscopia
• Retto-sigmoidoscopia
• Rx torace (2 proiezioni)
• TAC/RMN (PET)
FIGO, 2006
Stadiazione Clinica
CC localmente avanzatoCC localmente avanzatoCC apparentemente inizialeCC apparentemente iniziale
• RX torace
• RMN addome/pelvi
• Visita ginecologica in narcosi• RX torace• RMN addome/pelvi• Uretrocistoscopia• Retto-sigmoidoscopia
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Cervical Cancer Cervical Cancer Comparison of Diagnostic Procedure UtilizationComparison of Diagnostic Procedure Utilization
ACRIN 6651/GOG 183 (n=208 ;Stage ≥ IB)ACRIN 6651/GOG 183 (n=208 ;Stage ≥ IB)
1978 1978 19831983 1988-19891988-1989 20022002
Cystoscopy Cystoscopy 64%64% 80% 80% 52% 52% 8.1%8.1%
Sigmoidoscopy Sigmoidoscopy 44% 44% 58%58% 49% 49% 8.6%8.6%
Barium enema Barium enema 58% 58% 60% 60% 32% 32% 00
Intravenous urogram Intravenous urogram 86% 86% 91% 91% 42% 42% 1.0%1.0%
Lymphangiography Lymphangiography 18% 18% 11% 11% 14% 14% 00
CT/MRI CT/MRI 16% 16% 54% 54% 70% 70% 100%100%
Montana, 1995Montana, 1995Amendola, 2005Amendola, 2005
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Narayan K, 2003
MRI staging for cervical cancer is now widely accepted as an optimal method for evaluation of tumor volume, uterine corpus involvement, parametrial invasion, …
Cervical CancerMRI
… but prediction of parametrial, bladder and rectal involvement is correct in 75% of cases at best
Bipatt, 2003Narayan, 2005
Follen, 2003
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Cervical Cancer Detection of Advanced Stage (>IIB) Cancer
by Retrospective Readers of CT & MRI
ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)
CTCT MRIMRI P ValueP Value
Mean sensitivity (%)Mean sensitivity (%) 2828 47 47 0.1040.104
Mean specificityMean specificity (%)(%) 9090 7979 0.0990.099
Mean PPV (%)Mean PPV (%) 5555 3636 0.0010.001
Mean NPV (%)Mean NPV (%) 8383 8585 0.3050.305
Hricak, 2007
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Cervical Cancer Performance of CT & MRI in Detecting
Lymph Node Involvement
ACRIN 6651/GOG 183 (n=208 – Stage ≥ IB)
CT CT MRIMRI
Sensitivity (%)Sensitivity (%) 3131 37 37
Specificity (%)Specificity (%) 8686 94 94
Hricak, 2005
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FIGO, 2006
Treatment – Stage IB1, IIA1
• Modified RH (Type 2) or RH (Type 3) and pelvic LND • Adjuvant pelvic RT plus BRT• Adjuvant concurrent CTRT (Cisplatin±5FU) ↑ survival in such patients
In younger patients, if post-operative radiation is likely to be given:• ovaries may be preserved and suspended outside the pelvis
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• RH tipo III + LA pelvica + sampling N aortici
• RT pelvi + BRT
Se desiderio di prole (solo per IB1):
• trachelectomia radicale + LA pelvica ± sampling N aortici
NCCN, 2009
Treatment – Stage IB1-IIA1
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Wertheim (1900)
Okabayashi (1921)
Meigs (1951)
Nerve-sparing (1990s)
Robotics (2000s)
Piver-Rutledge (1974)
Mota-EORTC (2008)
Querleu-Morrow (2008)
Radical Hysterectomy – History & Classification
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• Type I (Extrafascial hysterectomy): simple hysterectomy to remove the entire cervical tissue
• Type II (Modified RH): basically, the RH described by Wertheim, to remove more paracervical tissue while still preserving the blood supply to the distal ureters and bladder
• Type III (RH): first described by Meigs in 1944, with the purpose of a wide excision of parametrial and paravaginal tissue
• Type IV (Extended RH): complete removal of the periureteral tissue and a more extensive resection of the paravaginal tissue
• Type V (Partial exenteration): radical removal of disease involving the distal ureter and/or bladder
Radical Hysterectomy – Piver-Rutledge Classification
Piver, 1974
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THE POINT OF TRANSECTION OF THE UTEROSACRAL AND CARDINAL LIGAMENTS IN CLASS II AND III RH
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Type 3 RHType 3 RH Type 2 RH
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Radical Hysterectomy – Querleu-Morrow Classification
• Type A (Minimum resection of paracervix): extrafascial hysterectomy, corresponds to the type I RH, with a <10 mm vaginal resection
• Type B (Transection of paracervix at the ureter): corresponds to the type II RH, with (B2) or without (B1) additional removal of the lateral paracervical lymph nodes, and >10mm vaginal resection
• Type C (Transection of paracervix at junction with internal iliac vascular system): corresponds to type III RH, with the ureter completely mobilized, 15-20mm of vagina and corresponding paracolpos resected routinely; with (C1) or without (C2) autonomic nerve preservation
• Type D (Laterally extended resection): ultraradical procedures mostly indicated at the time of pelvic exenteration, with the entire paracervical resection at the pelvic sidewall including the hypogastric vessels (D1); type D2 includes the resection of adjacent fascial-muscular structures
Querleu, 2008
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It is recommended to include the following information in the operative report:
• All parts defining the type of RH (transection of paracervix and vagina, uterine artery)
• Surgical (fresh sample) and pathological (fixed sample) length of ventral, dorsal and lateral extent of paracervix resection
• Surgical/pathological minimum length of vagina resected
• Minimum distance between tumor and resection margins (when applicable)
Quality control and results comparison in RH
The term paracervix replaces others such as cardinal or Mackenrodt’s ligament, or parametrium, and includes that usually named as paracolpium
Querleu, 2008
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Type AType A
Type B1Type B1 Type C2Type C2
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Surgery-related Complications
Rad. Hysterectomy Rad. Hysterectomy (type III) (type III)
+ Pelvic Lymph.+ Pelvic Lymph.
10-15% Severe 10-15% Severe Perioperative Compl.Perioperative Compl.
20-30% Early/Late 20-30% Early/Late Bladder/Rectal Disf.Bladder/Rectal Disf.
75% vs 10% (III vs II) 75% vs 10% (III vs II) Temp. Bladder Disf. Temp. Bladder Disf.
Literature Review
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FIGO, 2006
LN Involvement by Stage
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FIGO, 2006
Treatment – Stage IB2, IIA2
• Primary CTRT• Primary RH and pelvic LND + Adjuvant RT• Neoadjuvant CTRT (3 courses of platinum based CT) + RH and pelvic LND ± Adjuvant post-operative CT or RT
If positive common iliac or paraaortic nodes:• extended field radiation should be considered
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Treatment – Stage ≥ IIB
• Primary CTRT (RT plus BRT) • Primary pelvic exenteration (Stage IVA not involving pelvic sidewall)
If positive common iliac or paraaortic nodes:• extended field radiation should be considered
• Primary CT (Cisplatin)
Unclear impact of CT on palliation and survival
FIGO, 2006
IIB-IVA
IVB
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• RH tipo III + LA pelvica + sampling N aortici
• CTRT (RT pelvi + Cisplatino + BRT)
• CTRT (RT pelvi + Cisplatino + BRT) + isterectomia adiuvante
IB2-IIA2
NCCN, 2009
Treatment – Stage IB2-IVA
• CTRT (RT pelvi + Cisplatino + BRT)IIB-IVA
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• RT pelvi (volume, invasione stromale, LVSI) ± CT(P)
• Follow-up N -
RT pelvi + CT(P) ± BRT (margini vaginali +)N pelvici +Margini +Parametrio +
NCCN, 2009
Terapia Adiuvante & Follow-up
• ogni 3 mesi (1° anno)• ogni 4 mesi (2° anno)• ogni 6 mesi (3-5° anno)• annuali (> 6° anno)
EO gen & gin Pap-test
Rx Torace
Laboratorio
CT/MRI/PET
ogni anno (opzionale)
ogni 6 mesi (opzionali)
su indicazione clinica
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(Neo)adjuvant Setting
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NACT
SHRINKAGE OF PRIMARY TUMOR
TREATMENT OF LOCO-REGIONAL AND DISTANT MICROMETASTASES
ADDITIONAL LOCAL TREATMENT
BETTER DISEASE CONTROL
SURVIVAL BENEFIT
NACT – Rationale
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Italian Multicenter Randomized Study, 2001
NACT + Surgery vs Exclusive RT (LACC)
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Stage
IB2-IIB
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Stage
III
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Endpoint Nr. of events / patient
HR
(p value)
Survival
DFS
Loco-regional DFS
Metastases-free survival
368/872
414/872
402/872
381/872
0.65 (0.00004)
0.68 (0.0001)
0.68 (0.0001)
0.63 (0.00001)
NACT & Radical Surgery (Locally Advanced Cervical Cancer)
Review & Meta-analysis
The absolute improvement in survival of 15% (8-21%) at 5-years obtained by NACT is of the same magnitude as that achieved with the standard cisplatin-based CTRT
Cochrane Coll., 2009
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EORTC Trial 55994EORTC Trial 55994Study Coordinators:Study Coordinators:
S. GreggiS. GreggiG. KenterG. Kenter
F. LandoniF. Landoni
IB2; IIA2; IIBIB2; IIA2; IIB
Cervical Cancer Cervical Cancer (age 18-75)(age 18-75)
RANDOMRANDOM
NACT + NACT + Radical SurgeryRadical Surgery
ExclusiveExclusiveCTRTCTRT
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Flow-Chart
IR tipo B o C +LA pelvica o
CTRT
IB1
FU
MRC -Parametri -
N -
RT
MRC + parametri + N + Inf stroma cerv >90%
CT +/- RT
CTNA + IR tipo C + LA pelvica o
CTRT
IB2 - II
CTRT oPelvectomia +LA pelvica
III - IVA
CT sistemica
IVB
RMN addome / pelvi Colposcopia, Rx torace,
SCC Ag, Visita gin. in narcosi,Cistoscopia e Rettoscopia
Stadiazione clinica
Ca invasivo
Ca invasivo
FU
IA1 (margini -)
Vedi algoritmo dedicato
IA2
Ca microinvasivo
Conizzazione Cervicale
Ca microinvasivo Ca non definito / CIN III
Biopsia cervicale
Sospetto K cervice uterina
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Carcinoma della Cervice non Radiotrattato
1° e 2° anno 3° e 4° anno 5° anno > 5° anno
A 30 gg
Ogni 3 mesi
Ogni 6 mesi
Ogni 6 mesi
Ogni 12 mesi
Ogni 12 mesi
Ogni 12 mesi
Visita ginecologica X X X X X
E.O. generale X X X X X
Colposcopia X X X X
Pap-Test X X X X
Rx torace X X X
RMN addome-pelvi* X X X
Urinocoltura (+ ev. Abg) X X X
CA125 X X X
SCC X X X
Follow-up
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Carcinoma della Cervice Radiotrattato1° e 2° anno 3° e 4° anno 5° anno > 5° anno
A 45 gg
Ogni 3
mesi
Ogni 6 mesi
Ogni 6 mesi
Ogni 12 mesi
Ogni 12 mesi
Ogni 12 mesi
Visita ginecologica X X X X X
E.O. generale X X X X X
Colposcopia X X X X X
Pap-Test X X X X
Rx torace X X X
RMN addome-pelvi* X X X X
Urinocoltura (+ ev. Abg) X X X
CA125 X X X
SCC X X X
Rettoscopia X X
*TAC addome/pelvi qualora RMN controindicata
Follow-up