1. Cervical cancer is the third most common cancer in women worldwide and the second leading cause of cancer death in women globally, with most cases occurring in developing countries. 2. Screening programs have helped lower cervical cancer incidence rates in developed countries by enabling early detection. The human papillomavirus (HPV) is the most important risk factor for cervical cancer. 3. Treatment for cervical cancer depends on the stage and includes surgery, chemotherapy, radiation therapy, or concurrent chemoradiation. Concurrent chemoradiation has been shown to improve outcomes compared to radiation alone or radiation with chemotherapy for locally advanced cervical cancer.

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2. Anatomy
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3. Incidence
— Worldwide:
— Third incidence (~500, 000 anually)
— Second cause of cancer death (~ 275, 000)
— 75% of cases occur in developing countries
— Why incidence is low in developed countries?
— Screening
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4. NCI-Egypt
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5. Risk factors
— HPV: most important
— High incidence areas: HPV 10-20%
— Low incidence areas: HPV 5-10%
— Immunization:
— Gardasil FDA approved in 2006
— Cervarix
— Other:
— Smoking, parity, contraceptive use,
— Early coitus, many sexual partners, history of STDs
— chronic immunosuppression
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6. HPV and cervical cancer
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7. Vaccination Against HPV
— Gardasil and Cervarix (C>G)
— Protein of HPV 6, 11, 16, 18 (G) 16, 18 (C)
— 3 IM injections over 6 Months (G 0,2,6), (C 0,1,6)
— Age
— most effective if given before sexual intercourse is initiated
— Girls and women ages 9 -26 years
— Not recommended for older than 26 years.
— Best for 11-12 years
— Effectiveness after 3 years (no CIN):
— No prior HPV infection: 99%
— Prior HPV infection: 44%
— Why to continue screening?
— Not all HPV strains
— Not 100% effective
— Males:
— Penile cancer and anal cancer
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8. Screening
— Age:
— 3 years after onset of vaginal intercourse
— No later than 21 years
— Till 70 y
— Methods:
— Cytology:
— conventional smears annually
— liquid based every 2 y
— HPV DNA testing: for age >30 y
— Every 3 y in combination with cytology if –ve
— If +ve at the discretion of the physician
— HPV vaccination: screened as usual, why?
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9. Cytology needed
— Uterine cervix is accessible to physician
— Histology is needed
1. Cervical cytology or
2. Papanicolaou (Pap) smears or
3. Cervical biopsy
4. Cone biopsy: if others are inadequate or if degree of
invasion needed.
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10. Cervical (pap) smear
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11. Cone biopsy
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12. CT
Parametrial extension
Pelvic wall extension Bladder and rectum
and uerter encasement
invasion
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15. 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

16. 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

17. Histology
— Normal epithelial lining of cervix
— Cancer:
— Squamous cell carcinoma (80%)
— Adenosquamous
— Adenocarcinoma
— Others :
— Neuroendocrine carcinoma,
— small cell tumors,
— glassy-cell carcinomas,
— sarcomas,
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18. Clinical picture
— Asymptomatic
— Watery vaginal discharge
— Postcoital bleeding or
— Intermittent spotting.
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19. Workup
— History and physical examination
— Routine lab:
— CBCD, liver and renal function tests.
— Radiologic imaging :
— Chest x-ray, CT, MRI, or PET;
— Cystoscopy and proctoscopy examination under
anesthesia
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20. Staging of cervical CA
T1=FI (T2=FII) (T3=FIII) (T4=FIVA) N1 M1=FIVB
Confined to uterus Outside uterus but not T3 Outside uterus to Outside uterus to: Regional Distant spread
A: Microscopic A: Parametrium negative A: Vagina lower 1/3 A: Bladder or LN Including
A1: 7H x 3D mm A1: <= 4 cm B: Pelvic wall, rectal mucosa peritoneal
A2: 7H x 5D mm A2: > 4 cm Causing HN of NFK B: Extrapelvic
B: Macroscopic B: Parametrium positive extension
B1: <= 4 cm
B2: > 4 cm
No stage grouping
F =FIGO stage
HN:hydronenphrosis
NFK: non-functioning
kidney
M1=FIVB
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21. Treatment modalities
— Surgery:
— Limited: radical trachelectomy for tumors up to 2 cm if
fertility preservation is desired
— Extensive: radical hystrectomy +/- pelvic +/- PA LND
— Concomitant chemo-radiotherapy; CCRT: (Cisplatin)
— Palliative chemotherapy: cisplatin-based
— BSC
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22. Treatment of Cx CA
Stage stage Surg CCRT Chemo
Localized micro IA1 Micro 7Hx3D Yes* No No
micro IA2 Micro 7H x 5D Yes* ORà RT alone** No
<=4cm IB1 <=4cm Yes * ORà RT alone** No
IIA1 Parmet -/ <=4cm
>4cm IB2 >4cm Yes ORà CCRT*** No
IIA2 Parmet -/ >4cm
Locally IIB Paramet + No CCRT No
advanced IIIA/B LVag/Pel W
IVA Blad/Rect/HN
Metastatic IVB Mets No No Pall’tve
* 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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23. Surgery and CCRT
— If surgery was used first:
— Post op CCRT can be given to high risk patients:
— positive lymph nodes, or
— parametrial extension, or
— positive margins)
— If CCRT was used first: surgery is not recommended
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24. RT and surgery are equal in
Treatment of stage IB and IIA
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%
— Landoni Eet al, Lancet. 1997 Aug 23;350(9077):535-40.
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25. Concurrent CRT
— CCRT
— Improves DFS and OS compared to RT alone or RT+HU
— Cisplatin : standard
— 40 mg/sm weekly up to 6 weeks (Max 70 mg)
— Less toxic than 5FU/Cisplatin
— Cisplatin and 5FU: more toxic
— 3 cycles:
— (1st and 2nd )D1-5, D22-26: during EBRT
— (3rd ) D1-5 during second brachytherapy course
— Cisplatin 20 mg/sm/d x 5 d, FU 1000 mg/sm/d x 5d
— 5FU alone is not optimal
— Intolerance to ciaplatin: àcarboplatin or xeloda
— Cb: 100mg/m or UC 2 weekly
— Novel regimen: weekly x 6 CCRT à adjuvant gem cis
— CCRT: Cisplatin 40 mg/sm followed by Gem 125 mg/m2
— 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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26. Adding Gemcitabine to cisplatin in
CRT
— Dueñas-González et al, 2011, JCO
— Patients and Methods Eligible chemotherapy- and
radiotherapy-naive patients with stage IIB to IVA disease
and Karnofsky performance score ≥ 70 were randomly
assigned to:
— 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) :
— or to arm B (cisplatin and concurrent XRT followed by BCT
only; dosing same as for arm A)
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27. — Results Between May 2002 and March 2004, 515 patients
were enrolled (arm A, n = 259; arm B, n = 256).
— PFS at 3 years was significantly improved in arm A versus
arm B (74.4% v 65.0%, respectively; P = .029),
— as were overall PFS (log-rank P = .0227; hazard ratio [HR],
0.68; 95% CI, 0.49 to 0.95),
— overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49
to 0.95),
— and time to progressive disease (log-rank P = .0012; HR,
0.54; 95% CI, 0.37 to 0.79).
— 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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28. CCRT is better than RT alone in
Stage IB2-IVA
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29. CCRT is better than RT alone in
Bulky stage IB2 and IIA (=> 5cm) & IIB-IVA
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
— Moris et al N Engl J Med. 1999 Apr 15;340(15):1137-43.
— Conclusions: CCRT > RT
— Cisplatin 20 mg/sm/d &FU 1000 mg/sm/d [x 5d x 3 courses]
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30. CCRT is better than RT alone in
Bulky stage IB and IIA (=> 4cm)
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%
— Keys HM et al, N Engl J Med. 1999 Apr 15;340(15):1154-61.
— Conclusions: CCRT > RT
— Cisplatin 40 mg/sm q w x 6 max 70 mg
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31. CCRT with cisplatin is standard in
Bulky stage IIB-IVA
RT+ cisplatin RT+ cis+5FU+HU RT+HU
SCC, adeno, `175 `175 ~175
AdenoSquamous
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
— Rose et al, N Engl J Med. 1999 Apr 15;340(15):1144-53.
— Conclusions: CCRT > RT, Cis = cis/5FU > HU
— Cis 40 mg/sm/w x 6
— Cisplatin 50mg/sm d1 &FU 1000 mg/sm/d [x 4d x 2 courses]
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32. Chemotherapy for Rec/mets
— First-line combination therapy
— Cisplatin/paclitaxel
— Carboplatin/paclitaxel
— Cisplatin/topotecan
— Cisplatin/gemcitabine (category 2B)
— Possible first-line single agent therapy
— Cisplatin (preferred as a single agent)
— Carboplatin
— Paclitaxel
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33. Chemotherapy for Rec/mets
— Second-line therapy††
— Bevacizumab
— Docetaxel
— 5-FU (5-fluorouracil)
— Gemcitabine
— Ifosfamide
— Irinotecan
— Topotecan
— Pemetrexed (category 3)
— Vinorelbine (category 3
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34. Treatment of metastatic disease
— Systemic chemotherapy and
— Individualized radiotherapy.
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35. Relapse
— Locoregional
— Systemic
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36. Relapse
— Locoregional therapy
— After surgery: CCRT
— After RT: possible surgery
— After surgery and CCRT: platinum-based CT/BSC
— Systemic therapy
— Extrapelvic or para-aortic recurrence(s) at multiple sites
or with unresectable recurrence
— Platinum-based CT/BSC
— Surgery has limited role for isolated sites
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37. Palliative chemotherapy
— Recurrent or metastatic disease
— Not candidate for surgery or RT
— Platinum-based (most active, RR 20-30%)
— Compared with cisplatin:
— Combinations :
— Same QOL, little or no OS advantage
— cisplatin/paclitaxel and
— cisplatin/topotecan (category 1 for both)
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38. Cisplatin-paclitaxel
cispaltin Cisplatin - pacliatxel
IVB recurrent or 134 130
persistent SCC
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
— Moore et al, J Clin Oncol 2004;22:3113-3119
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39. Cisplatin- topotecan
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
— Long HJ et al, J Clin Oncol. 2005 Jul 20;23(21):4626-33.
— Cis 50 mg/sm q 3w
— Topo 0.75 mg/sm/d x 3 d q 3w
— MVAC third arm was closed due to high mortality
— Fisrt to show OS advantage
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40. — PATIENTS AND METHODS:
— RCT of 3 regimens every 3 weeks doses in mg/m2
— paclitaxel 135 over 24 hours plus Cis 50 day 2 (PC);
— vinorelbine 30 days 1 &8 plus Cis 50 day 1 (VC);
— gemcitabine 1,000 day 1 &8 plus Cis 50 day 1 (GC);
— topotecan 0.75 days 1, 2, &3 plus Cis 50 day 1 (TC).
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43. 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.
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