cervical cancer 10 2011
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This is a comprehensive overview of Cervical cancer: Diagnosis, staging and treatmentTRANSCRIPT
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Ahmed Zeeneldin
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Anatomy
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Incidence ó Worldwide:ó Third incidence (~500, 000 anually)ó Second cause of cancer death (~ 275, 000)ó 75% of cases occur in developing countries
ó Why incidence is low in developed countries?ó Screening
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NCI-Egypt
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Risk factorsó HPV: most importantó High incidence areas: HPV 10-20%ó Low incidence areas: HPV 5-10%ó Immunization: ó Gardasil FDA approved in 2006ó Cervarix
ó Other:ó Smoking, parity, contraceptive use, ó Early coitus, many sexual partners, history of STDs ó chronic immunosuppression
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HPV and cervical cancer
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Vaccination Against HPVó Gardasil and Cervarix (C>G)ó Protein of HPV 6, 11, 16, 18 (G) 16, 18 (C)ó 3 IM injections over 6 Months (G 0,2,6), (C 0,1,6)ó Age
ó most effective if given before sexual intercourse is initiatedó Girls and women ages 9 -26 yearsó Not recommended for older than 26 years.ó Best for 11-12 years
ó Effectiveness after 3 years (no CIN):ó No prior HPV infection: 99%ó Prior HPV infection: 44%
ó Why to continue screening? ó Not all HPV strainsó Not 100% effective
ó Males: ó Penile cancer and anal cancer
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Screeningó Age:ó 3 years after onset of vaginal intercourseó No later than 21 yearsó Till 70 y
ó Methods:ó Cytology: ó conventional smears annually ó liquid based every 2 y
ó HPV DNA testing: for age >30 yó Every 3 y in combination with cytology if –veó If +ve at the discretion of the physician
ó HPV vaccination: screened as usual, why?
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Cytology neededó Uterine cervix is accessible to physicianó Histology is needed
1. Cervical cytology or 2. Papanicolaou (Pap) smears or3. Cervical biopsy4. Cone biopsy: if others are inadequate or if degree of
invasion needed.
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Cervical (pap) smear
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Cone biopsy
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CT
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Parametrial extension and uerter encasement Pelvic wall extension Bladder and rectum
invasion
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Figure 2. Clinical and imaging stage IIIB cervical cancer in a 37-year-old woman with hydronephrosis at diagnosis
Pannu H K et al. Radiographics 2001;21:1155-1168
©2001 by Radiological Society of North America
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Figure 4. Tumor extension into the vagina in a 50-year-old woman with clinical stage IIIB and imaging stage IIIA cervical cancer
Pannu H K et al. Radiographics 2001;21:1155-1168
©2001 by Radiological Society of North America
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Histologyó Normal epithelial lining of cervix
ó Cancer: ó Squamous cell carcinoma (80%)ó Adenosquamousó Adenocarcinomaó Others :ó Neuroendocrine carcinoma, ó small cell tumors, ó glassy-cell carcinomas, ó sarcomas,
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Clinical pictureó Asymptomaticó Watery vaginal dischargeó Postcoital bleeding oró Intermittent spotting.
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Workup ó History and physical examinationó Routine lab: ó CBCD, liver and renal function tests.
ó Radiologic imaging : ó Chest x-ray, CT, MRI, or PET;
ó Cystoscopy and proctoscopy examination under anesthesia
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Staging of cervical CAT1=FI (T2=FII) (T3=FIII) (T4=FIVA) N1 M1=FIVB
Confined to uterus A: Microscopic
A1: 7H x 3D mmA2: 7H x 5D mm
B: MacroscopicB1: <= 4 cmB2: > 4 cm
Outside uterus but not T3 A: Parametrium negative
A1: <= 4 cmA2: > 4 cm
B: Parametrium positive
Outside uterus toA: Vagina lower 1/3 B: Pelvic wall, Causing HN of NFK
Outside uterus to:A: Bladder or rectal mucosaB: Extrapelvicextension
RegionalLN
Distant spreadIncludingperitoneal
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No stage groupingF =FIGO stageHN:hydronenphrosisNFK: non-functioning kidneyM1=FIVB
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Treatment modalitiesó Surgery: ó Limited: radical trachelectomy for tumors up to 2 cm if
fertility preservation is desiredó Extensive: radical hystrectomy +/- pelvic +/- PA LND
ó Concomitant chemo-radiotherapy; CCRT: (Cisplatin)ó Palliative chemotherapy: cisplatin-basedó BSC
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Treatment of Cx CAStage stage Surg CCRT Chemo
Localized micro IA1 Micro 7Hx3D Yes* No No
micro IA2 Micro 7H x 5D Yes* ORà RT alone** No
<=4cm IB1IIA1
<=4cmParmet -/ <=4cm
Yes * ORà RT alone** No
>4cm IB2IIA2
>4cmParmet -/ >4cm
Yes ORà CCRT*** No
Locally advanced
IIBIIIA/BIVA
Paramet +LVag/Pel WBlad/Rect/HN
No CCRT No
Metastatic IVB Mets No No Pall’tve
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* Surgery can be extensive or limited for fertility preservation*Post op CCRT can be given in : LN+, SM+, Parametrium +** No surgery after CCRT *** adjuvant surg can be done after CCRT
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Surgery and CCRTó If surgery was used first: ó Post op CCRT can be given to high risk patients:ó positive lymph nodes, oró parametrial extension, or ó positive margins)
ó If CCRT was used first: surgery is not recommended
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RT and surgery are equal in Treatment of stage IB and IIA
ó Landoni Eet al, Lancet. 1997 Aug 23;350(9077):535-40.
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RT Surgery
IB & IIA 171 172 *(PO RT to => pIIB ~ 100 pt)
5-y DFS 74% 74%
5-y OS 83% 83%
Recurrence 26% 25%
Severe morbidity* 19% 28%
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Concurrent CRTó CCRTó Improves DFS and OS compared to RT alone or RT+HU
ó Cisplatin : standardó 40 mg/sm weekly up to 6 weeks (Max 70 mg)ó Less toxic than 5FU/Cisplatin
ó Cisplatin and 5FU: more toxicó 3 cycles: ó (1st and 2nd )D1-5, D22-26: during EBRT ó (3rd ) D1-5 during second brachytherapy course
ó Cisplatin 20 mg/sm/d x 5 d, FU 1000 mg/sm/d x 5dó 5FU alone is not optimaló Intolerance to ciaplatin: àcarboplatin or xelodaó Cb: 100mg/m or UC 2 weekly
ó Novel regimen: weekly x 6 CCRT à adjuvant gem cisó CCRT: Cisplatin 40 mg/sm followed by Gem 125 mg/m2ó Adj: Gem (1,000 mg/m2 on Days 1 and 8) plus Cis (50 mg/m2 on
Day 1) x 2 cycles q 21 d
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Adding Gemcitabine to cisplatin in CRTó Dueñas-González et al, 2011, JCOó Patients and Methods Eligible chemotherapy- and
radiotherapy-naive patients with stage IIB to IVA disease and Karnofsky performance score ≥ 70 were randomly assigned to:ó arm A (cisplatin 40 mg/m2 and gemcitabine 125 mg/m2
weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m2 on day 1, plus gemcitabine, 1,000 mg/m2 on days 1 and 8) :ó or to arm B (cisplatin and concurrent XRT followed by BCT
only; dosing same as for arm A)
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ó Results Between May 2002 and March 2004, 515 patients were enrolled (arm A, n = 259; arm B, n = 256). ó PFS at 3 years was significantly improved in arm A versus
arm B (74.4% v 65.0%, respectively; P = .029), ó as were overall PFS (log-rank P = .0227; hazard ratio [HR],
0.68; 95% CI, 0.49 to 0.95), ó overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49
to 0.95), ó and time to progressive disease (log-rank P = .0012; HR,
0.54; 95% CI, 0.37 to 0.79). ó Grade 3 and 4 toxicities were more frequent in arm A than
in arm B (86.5% v 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A.
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CCRT is better than RT alone inStage IB2-IVA
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CCRT is better than RT alone in Bulky stage IB2 and IIA (=> 5cm) & IIB-IVA
ó Moris et al N Engl J Med. 1999 Apr 15;340(15):1137-43.ó Conclusions: CCRT > RTó Cisplatin 20 mg/sm/d &FU 1000 mg/sm/d [x 5d x 3 courses]
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RT CCRT
193 193
5-y DFS 40% 67% (P<0.001)
5-y OS 58% 73% (P<0.004)
Recurrences and mets higher
Hem toxicity Higher but reversibel
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CCRT is better than RT alone in Bulky stage IB and IIA (=> 4cm)
ó Keys HM et al, N Engl J Med. 1999 Apr 15;340(15):1154-61.ó Conclusions: CCRT > RTó Cisplatin 40 mg/sm q w x 6 max 70 mg
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RT+Surgery CRT+Surgery
186 183
RR of progression 1 0.51 (P<0.001)
RR of death 1 0.54 (P=0.008)
G3-4 Hem Toxicity 2% 21%
GI toxicity 5% 14%
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CCRT with cisplatin is standard in Bulky stage IIB-IVA
ó Rose et al, N Engl J Med. 1999 Apr 15;340(15):1144-53.
ó Conclusions: CCRT > RT, Cis = cis/5FU > HUó Cis 40 mg/sm/w x 6ó Cisplatin 50mg/sm d1 &FU 1000 mg/sm/d [x 4d x 2 courses]
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RT+ cisplatin RT+ cis+5FU+HU RT+HU
SCC, adeno, AdenoSquamous
`175 `175 ~175
PFS Higher (P<0.001) higher (P<0.001) Lower
OS Higher (P=s) Higher (p=s) lower
RR of progression 0.57 0.55 1
RR of death 0.61 0.58 1
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Chemotherapy for Rec/metsó First-line combination therapyó Cisplatin/paclitaxeló Carboplatin/paclitaxeló Cisplatin/topotecanó Cisplatin/gemcitabine (category 2B)
ó Possible first-line single agent therapyó Cisplatin (preferred as a single agent)ó Carboplatinó Paclitaxel
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Chemotherapy for Rec/metsó Second-line therapy††ó Bevacizumabó Docetaxeló 5-FU (5-fluorouracil)ó Gemcitabineó Ifosfamideó Irinotecanó Topotecanó Pemetrexed (category 3)ó Vinorelbine (category 3
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Treatment of metastatic diseaseó Systemic chemotherapy and ó Individualized radiotherapy.
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Relapseó Locoregionaló Systemic
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Relapseó Locoregional therapy ó After surgery: CCRTó After RT: possible surgeryó After surgery and CCRT: platinum-based CT/BSC
ó Systemic therapy ó Extrapelvic or para-aortic recurrence(s) at multiple sites
or with unresectable recurrenceó Platinum-based CT/BSC
ó Surgery has limited role for isolated sites
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Palliative chemotherapyó Recurrent or metastatic diseaseó Not candidate for surgery or RTó Platinum-based (most active, RR 20-30%)ó Compared with cisplatin:ó Combinations :ó Same QOL, little or no OS advantageó cisplatin/paclitaxel and ó cisplatin/topotecan (category 1 for both)
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Cisplatin-paclitaxel
ó Moore et al, J Clin Oncol 2004;22:3113-3119
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cispaltin Cisplatin - pacliatxel
IVB recurrent or persistent SCC
134 130
RR (CR) 19 (6)% 36 (15)%
Median PFS 2.8 m 4.8 m (P < .001)
Median OS 8.8 m 9.7 m (PNS)
QOL same same
Anemia/neutropenia more
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Cisplatin- topotecan
ó Long HJ et al, J Clin Oncol. 2005 Jul 20;23(21):4626-33.ó Cis 50 mg/sm q 3wó Topo 0.75 mg/sm/d x 3 d q 3wó MVAC third arm was closed due to high mortalityó Fisrt to show OS advantage
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Cispaltin Cisplatin - topotecan
146 147
RR 13% 27%
Median PFS 2.9 m 4.6 m (P=0.014)
Median OS 6.5 m 9.4 m (P=0.017)
QOL same same
Anemia/neutropenia more
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ó PATIENTS AND METHODS: ó RCT of 3 regimens every 3 weeks doses in mg/m2ó paclitaxel 135 over 24 hours plus Cis 50 day 2 (PC); ó vinorelbine 30 days 1 &8 plus Cis 50 day 1 (VC); ó gemcitabine 1,000 day 1 &8 plus Cis 50 day 1 (GC); ó topotecan 0.75 days 1, 2, &3 plus Cis 50 day 1 (TC).
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Conclusions•VC, GC, and TC are not superior to PC in terms of overall survival (OS). •However, the trend in RR, PFS, and OS favors PC. •Differences in chemotherapy scheduling, pre-existing morbidity, and toxicity are important in individualizing therapy.