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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

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

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

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

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%

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

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%

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

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

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

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.