Cervical Dysplasia and Invasive Cervical Cancer

Cervical Dysplasia and Faculty Invasive Cervical Cancer

Satellite Conference and Live Webcast Friday, October 10, 2008 Michael A. Finan, M.D., F.A.C.S. 1:00 - 3:00 p.m. Chief, Gynecologic Oncology

Produced by the Alabama Department of Public Health Video Communications and Distance Learning Division

Objectives Objectives

• Overview of cervical cancer • Understand staging of cervical cancer • Understand Role of HPV • Describe treatment of various stages of • Apply algorithms from www.asccp.org cervical cancer • Apply methods of diagnosis of cervical • Understand roles of surgery, radiation cancer therapy and chemotherapy for the management of cervical cancer

1 Cervical Dysplasia Epidemiology • Schauenstein (1908) first proposed that SCC • Abnormal Pap = 3.5 million per year (7%) of cervix evolves by a progression of a • CIS = 50,000 per year preinvasive lesion (carcinoma in situ) • CXCA = 13,000 per year – 4,500 deaths per year • Overall incidence: 8.7/100,000 women Papanicolaou described CIS and less • • Second most common female cancer anaplastic lesions called dysplasia worldwide • Among top 5 causes cancer death in developing countries (20-30% of female • WHO defines dysplasia as “lesion in which cancers) part of the epithelium is replaced by cells – Pap decreased cancer by 50% in showing varying degrees of atypia.” U.S.!

Risk Factors • Age first intercourse • Low • Multiple partners (>2) socioeconomic status • STD > 3 years pap • HPV • High risk partner • High risk HPV • Other • Immunosuppression • • Smoking – Contraceptive hormones – Radiation

HPV Human Papilloma Virus • Non-enveloped DNA encased in capsid > 80 subtypes (31 anogenital) • E2 transcriptional regulation of HPV • HPV stronger association with cancer genes E2 E5 Integration Epidemic past 20 yrs disrupts E2 • E4 leading to L2 • HPV DNA found > 95% of SCC E1 increased E6/E7 Late genes encode capsid HPV-16 transcription • Not only factor proteins E7 L1 E7 binds pRb • 43% college women HPV+ (but <5% E6 LCR CIN) E6 binds p53

2 HPV Types Cervical Dysplasia Schematic High Risk HPV Testing

Low Risk Intermediate High Outer 1/3 Risk Risk 31, 33, 35, Middle 1/3 6, 11, 26, 39, 51, 52, 16, 18, 42, 44, 54, Inner 1/3 55, 58, 59, 45, 56 70, 73 66, 68

• Low Risk: never found alone in invasive cancer • HPV-16: more common in squamous lesions • HPV-18: more common in endocervical lesions

“In The Zone” Understanding The Cervical • Cervix mullerian duct origin Transformation Zone

• Lined by columnar epithelium E2 • 18-20 wks. gestation colonized by

squamous epithelium E2 • Squamocolumnar Junction =

Transformation Zone E2 • Zone changes position depending on

hormonal influence From: Practical Gynecologic Oncology 3rd Ed. Berek & Hacker

Screening Is Good Bethesda 2001 • Cervical cancer #1 in incidence & • Specimen type mortality in women prior to 20th century • Specimen Adequacy • Screening for premalignant lesions – Satisfactory knocked it down to #2 worldwide – Unsatisfactory due to… (yipee) • General Categorization • Dichotomy b/t developing & developed – Negative, Epithelial cell abnormality, countries other • “Preventable disease”

3 Bethesda 2001 Bethesda 2001 • Interpretation and Result • Squamous Cell – Negative for Intraepithelial Lesion or – Atypical Squamous Cells Malignancy • ASC-US • Organisms • ASC-H –Trich, Candida, BV, HSV, etc – LSIL (HPV, mild dysplasia) • Other – HSIL –Reactive inflammation, IUD, • Moderate dysplasia radiation, Atrophy • Severe dysplasia

Bethesda 2001 Bethesda 2001 Abnormalities • Squamous Cell • Squamous Cell – Squamous Cell Carcinoma – Atypical Squamous Cells ASC-US • Glandular Cell • • ASC-H (can’t r/o high grade lesion) – Atypical Endocervical, Endometrial, – LSIL (HPV, mild dysplasia) Glandular cells – HSIL AG-NOS • • Moderate dysplasia • AG-favor neoplasia • Severe dysplasia – Adenocarcinoma – Squamous Cell Carcinoma

Bethesda 2001 Abnormalities Dysplasia Natural History

• Glandular Cell Progress Progress Biopsy Regress Persist to – Atypical Endocervical, Endometrial, to CIN 3 Cancer Glandular cells CIN1 57% 32% 11% <1% • AG-NOS • AG-favor neoplasia CIN2 43% 35% 22% 5% – Adenocarcinoma CIN3 32% 56% N/A 12%

Ostor AG. Int J Gyn Path. 1993

4 Infectious Or Neoplastic? Bottom Line

Normal Infection Neoplasia Differentiate

• No Neoplasia • Infection (HPV) • Neoplasia • No Infection • No Neoplasia • Infection normal from infectious

Pap Normal Normal ASCUS ASCUS ASCUS LSIL and LSIL LSIL HSIL HSIL infectious from neoplastic

Colposcopy The Colposcope • Adequacy? – visualize entire TZ and entire lesion (if any) • Visualize with Green filter- atypical vascularity • 3-5% acetic acid solution – Dries cells, neoplastic cells with higher nuclear:cytoplasmic ratio

Colposcopy Colposcopy

• Lugol’s Solution (1/4 strength)- Shiller’s Test • Endocervical Curettage (ECC) – Taken up by glycogen containing normal – Identify dysplasia within endocervical epithelium canal – Not taken up by atrophic or neoplastic – Controversial epithelium or columnar epithelium – Some studies show cytobrush sampling more sensitive although less specific

5 Colposcopic Findings Normal? Acetowhite Acetowhite • Acetowhite Changes – Increased N:C ratio – Abnormal intracellular keratins – Intracellular dehydration

Before Acetic Acid After Acetic Acid

Colposcopic Findings Punctation And Mosaicism • Abnormal vascularity Punctation Mosaicism – Punctation and Mosaicism • HPV capillary proliferative effect • Intraepithelial pressure created by expanding neoplastic tissue • Tumor angiogenesis factor – Atypical blood vessels • Margins Rolled, peeling edges or internal – • Epithelial proliferation squeezes demarcation between areas of differing appearance are abnormal capillaries up to surface

Where’s the Dysplasia? Abnormal Vascularity

Punctation

Coarse Mosaicism & Punctation

6 Colposcopic Warning Colposcopic Warning Signs Of Invasion Signs Of Invasion

• Friable epithelium with contact • Extremely abnormal punctation and bleeding mosaicism

• Irregular surface contour • High grade lesions occupying 3 or 4 quadrants • Surface ulceration or erosion • High grade lesions extending into canal • Atypical blood vessels either >5mm or beyond colposcopic view

Lugol’s Tischler Biopsy Instrument Is this Normal? Nabothian Cyst

Cancer

Lugol’s Iodine Application

Interventional Techniques Biopsy Diagram • Excision – Cold Knife Cone – Loop Electrosurgical Excision Procedure (LEEP, LLETZ, LOOP) – Laser Cone • Ablation – Cyrotherapy – Laser vaporization therapy

7 Cold Knife Cone Cold Knife Cone • Lugol’s to delineate lesion • Tag 12 o’clock for orientation • Stay sutures at 3 and 9 o’clock for • +/- ECC or D&C traction & hemostasis • Cauterize base • Intracervical vasopressin for – Sturmdorf sutures not advisable hemostasis because of risk of burying residual • Sound endocervical canal to guide disease excision • Conical excision with #11 blade

LEEP Cold Knife Cone Illustration • Visualize cervix with non-conductive speculum with suction attachment • Lugol’s to define lesion • Paracervical and intracervical block with Lidocaine • 35-55W or either cutting or blend

LEEP LEEP Diagram • Excise area 7-10mm deep at center – Maximum depth of involved glands 5.2mm • Ball electrode cautery to base and periphery with coag current • +/- ECC • Monsel’s as needed for hemostasis

8 ASC-H Slide HPV Testing- ALTS Side Effects Of LEEP LSIL Algorithm Distribution • Bleeding (now & later) All Paps

Pap normal ≥ ASCUS • Infection 92% 8% CIN2+ 15% • Damage to adjacent organs HSIL LSIL ASCUS 0.5% 2% 5% • Cervical incompetence

High risk High risk High risk • Cervical stenosis HPV pos CIN2+ HPV pos HPV pos 25% 97%* 89% 53% HPV Triage reduces *Missing or false neg values Colpo of ASCUS by 50%

ASC-US Summary ASC-US Algorithm • If using Thin Prep/HPV testing – ASC-US HPV test and colpo if (+) • If (-) then repeat HPV test only in 1 yr. (or repeat Pap) – >ASC-US Colpo • If not using ThinPrep/HPV – Colpo for ASC-US*2 – If ASC-H or greater Colpo See www.asccp.org

Atypical Glandular Cells of Undetermined Significance AGUS Algorithm (AGUS) • Where are glandular cells? • Endometrium • Endocervix

9 AGUS Mgmt of AGUS

HSIL

AGUS

Difficult to differentiate HSIL from AGUS on Pap

Significance Of AGUS AGUS Summary

High Any HSIL • Colpo with ECC for everyone Grade Pap (including Glandular squamous) Lesion • Endometrial Bx if >35 or history of AGUS 5-39% 1-8% Reactive irregular bleeding (suspicion of AGUS NOS 9-41% 0-15% endometrial hyperplasia or CA) AGUS favor 27-96% 10-93% neoplasia See www.asccp.org

Special Circumstances- ASC-US Adolescent Postmenopausal

• Vaginal atrophy causes cells to resemble HSIL or ASCUS – Predominance of smaller basal cells

• If atrophy present, treat with vaginal Estrogen for 6 weeks and re-evaluate See www.asccp.org

10 ASC-H ASC-High Grade • ASC- Can’t rule out high grade All Paps lesion – 87% High-risk Pap normal ≥ ASCUS HPV positive 92% 8% – 30% CIN2 or CIN3 on CIN biopsy HSIL LSIL ASCUS 2+ 0.5% 2% 5% 15%

• Immediate HPV HPV HPV CIN pos pos Colposcopy pos 2+ 97%* 89% 53% 25% See www.asccp.org

LSIL HSIL- “See & Treat” • HSIL Severe Dysplasia (in multiparous All Paps • Almost all women) High Risk – Who doesn’t get LEEP? HPV positive Pap normal ≥ ASCUS – HPV 92% 8% – If negative or CIN1 on colpo- where’s testing CIN the HSIL coming from? useless HSIL LSIL ASCUS 2+ 0.5% 2% 5% 15% • LEEP for diagnosis (not if • 30% CIN2/3 nulliparous)

• Immediate – If CIN2/3 on colpo then LEEP for HPV HPV HPV Colpo pos CIN2 treatment pos pos + 97%* • Management may differ in 89% 53% 25% See www.asccp.org See www.asccp.org pregnancy, adolescence

HSIL LSIL Algorithm • HSIL Moderate Dysplasia – 75-85% CIN2/3 • Immediate Colpo

See www.asccp.org

11 LSIL Special Circum. LSIL Pregnant

HIV Patients HSIL Algorithm • Pap every 6 months • Colpo for all abnormalities ≥ASCUS • Higher risk for severe dysplasia and cancer • More likely to have abnormal cytology ≥ ASCUS 42%

HSIL LSIL ASCUS 5% 17% 20%

Pregnant Patients Treatment of Dysplasia • Referral to Colpo same as non- • CIN1 pregnant – Expectant management if colpo • Colposcopy satisfactory • Preferably by examiner experienced with pregnant colpos • 10% risk of CIN2/3 progression • Biopsy if lesion suspicious for high – Consider ablative or excisional grade or invasive disease procedure if persistent (But • NO ECC recommend conservative f/u) – No treatment unless invasive cancer • Sample endocervix prior to ablative found procedure

12 Treatment of Dysplasia CIN2 or CIN3 • CIN1 • Excision or Ablation – Follow-up (if colpo satisfactory) • Repeat Pap 6mo or HPV test at – Excision preferred if CIN recurrent 12mo • Observation acceptable in very select • Refer back to colpo for ≥ASCUS circumstances

Normal Infection Neoplasia

CIN2 or CIN3 CIN2 or CIN3 • Special Circumstances BX Regress Persist CIN 3 Cancer – Pregnancy- observation of CIN2/3 ok – Adolescent- observation of CIN2 ok & CIN1 57% 32% 11% <1% very selectively CIN3

• Repeat Pap 6 mo. or HPV at 12 mo. CIN2 43% 35% 22% 5% – Refer to colpo for ≥ASCUS CIN3 32% 56% N/A 12%

Positive Endocervical Margin Excisional Procedure

After CIN2/3 Excision • Inadequate colposcopy • 15-30% rate of recurrence • + ECC • Colpo at 6 mo. preferred (according to • 2 step difference (Pap , CXBX) guidelines) • HSIL – Repeat Pap at 6 & 12 mo. likely ok • Hysterectomy acceptable if repeat cone • Microinvasion ( +/-) not possible • Persistent dysplasia • Hysterectomy for recurrent CIN2/3 acceptable

13 Candidates For Candidates For Excision Or Ablation Excision Or Ablation • Ablation therapy • Excision – Visualization of entire transformation zone – Unsatisfactory colpo – No suggestion of invasive disease – Suspicion of invasion or glandular abnormality – No suspicion of glandular disease – Corresponding cytology and histology (≤1 grade difference) • ie HSIL-Mod Pap and CIN1

Cryosurgery • Nitrous Oxide Cryosurgery Diagram – -65 to -85ºC at cryotip – Cell death at –20 to -30ºC • Lethal Zone – 2mm proximal to start of iceball – Thus to ensure 5mm depth of freeze, lateral spread freeze of 7mm required • Water-soluble gel to tip • Freeze-thaw-freeze technique

Treatment Success Treatment Success • Persistence • Complications – 3-5% for CIN2/3 – Cervical stenosis (Cryo) – No difference b/t treatments – Cervical incompetence (large • Recurrence specimens) – 13-19% • Preterm labor • Higher if age>30, HPV16 or 18, or – Infection (<1%) prior treatment – Bleeding (2-5%)

14 “You tell them I’m coming, and I’m bringing Lugol’s Invasive Cervical Cancer with me!!!”

-Wyatt Earp

Invasive Cervical Cancer: Symptoms Of Typical Patient Advanced Disease • 45 – 55 y.o. woman • First child delivered before the age of 20 • Heavy continuous bleeding • Vaginal discharge: thin, watery, blood • Foul smelling discharge tinged • Flank or leg pain, sciatic pain Intermittent painless metrorrhagia or • • Dysuria, hematuria, rectal bleeding spotting • Unilateral leg edema • Postcoital bleeding • Last pap was several years ago • Massive hemorrhage

Diagnosis

15 Differential Diagnosis LEEP

• Vaginitis • Ectropion • Cervical Polyp • Primary Herpes • Infection/Cervicitis • MUST DO BIOPSY OF ANY SUSPICIOUS LESION

Cervical Cancer Poor Prognostic Factors • Depth of invasion • Parametrial involvement • CLS involvement • Gross vs occult • Pelvic node involvement • Adenocarcinoma • Size of tumor (> 3-4 cm)

Delgado et al, GOG study, Gynecologic Oncology, 35:314-320, 1989 Kamura et al, Cancer, 69:181-186, 1991

Cervical Cancer Cervical Cancer

FIGO STAGING FOR STAGE I CERVICAL CANCER Routes of Spread I Carcinoma confined to the cervix • Pelvic lymphatics IA Identified only microscopically, no gross disease IA1 Depth ≤ 3.0 mm, horizontal spreads ≤ 7.0 mm • Direct extension: IA2 Depth ≤ 5.0 mm (> 3.0 mm) Vagina Horizontal spread ≤ 7.0 mm Parametrium IB Clinical lesions confined to the cervix (or microscopic lesions > IA) Bladder, Rectum IB1 Clinical lesions ≤ 4.0 cm in size • Hematogenous IB2 Clinical lesions > 4.0 cm in size

Creasman WT, Gynecol Oncol; 58, 157-158 (1995), FIGO, Montreal (1994) • Intraperitoneal

16 Cervical Cancer Cervical Cancer Pretreatment Evaluation Pretreatment Evaluation • History and Physical examination • Staging (EUA) - Lesion size • Histology of Lesion (review slides) - Configuration • Cystoscopy/Proctoscopy selectively CBC, liver function studies • • PET/CT Fusion Selectively • CXR • IVP • CT scan abdomen and pelvis?

Microinvasive <1mm Depth Cervical Conization • Of 3683 patients reported with < 1mm invasion: – Incidence of Lymph Node Metastases was essentially 0% – Death rate <0.1% – Invasive recurrences approx 0.4%

Ostor AG, Rome RM: Int J Gynecol Ca 4:257, 1994

Management of Microinvasive Management of Microinvasive Cervical Cancer Cervical Cancer 3-5 mm invasion: 0-3 mm invasion: • 2 – 6% risk of nodal metastases • Conization is reasonable if patient desires preservation of childbearing • 4% risk of invasive recurrence • Hysterectomy is also reasonable • 2% of patients die of the disease • Preservation of ovaries • LND not indicated Creasman WT, Zano, RJ et al;Am J Obstet Gynecol:178;62,1998

17 Management of Microinvasive Cervical Cancer Cervical Cancer Management I-B – II-A 3-5 mm invasion: • Radical hysterectomy: • Management options include Uterus Conization with LND, Hysterectomy Upper third of vagina with LND, Radical Trachelectomy with LND or Radical Hysterectomy with LND Parametrial tissues Uterosacral ligament • Treatment individualized based on histology Cardinal ligament • Conservative management becoming Pelvic lymphadenectomy more common +/- para-aortic lymphadenectomy

Cervical Cancer Cervical Cancer Management I-B – II-A Management I-B – II-A • Most appropriate for younger, thin • Postoperative teletherapy still patients advisable in selected cases • Smaller tumors (< 4 cm) • Radical Trachelectomy with uterine • Reasonable for any medically fit, preservation may be an option in reasonably sized patient with a small select patients who want to preserve tumor fertility

18 Radical Trachelectomy

Radical Trachelectomy Radical Trachelectomy

Radical Trachelectomy IB1 VS IB2 CERVICAL CANCER COMPLICATIONS of Radical Hysterectomy

IB1 IB2 n (%) n (%) None 91 (50.3) 25 (52.1) Thromboembolic event 9 (5.0) 1 (2.1) Medical minor 78 (43.1) 19 (39.6) Surgical major 1 (0.5) 3 (6.2) Other major 2 (1.1) 0 (0.0)

p = 0.0775 (NS)

Finan MA et al, Gynecol Oncol 1996

19 Locally Advanced Cervical Cancer Cervical Cancer Pelvic Nodal Involvement Bulky Smaller Tumor Tumor Stage Patients% + Pelvic Nodes > 4 cm < 4 cm

Nodal metastases 80% 16% IB 1160 20 Local recurrences 40% 5 % IIA 90 26 Distant metastases 50% 1% IIB 341 36

Chung, et al: Am J Obstet Gynecol, 138, 1980 III 96 43 IVA 23 55

Cervical Cancer Para-aortic Nodes

Stage Patients % + Para-aortic Nodes

IB 1579 4 IIA 212 11 IIB 602 20 III 546 27 IVA 80 31

Tumor Diameter & Tumor Diameter & Recurrance Interval Recurrance Interval • 431 patients with IB and IIA cervical • Median time to recurrence is related to cancer treated with radical hysterectomy tumor size: • Overall survival = 82% Less than 2 cm: 44 mos. 85% with negative nodes 2-4 cm: 23 mos. 50% with positive nodes Greater than 4.0 cm: 17 mos. • Tumors greater than 4.0 cm assoc. with local recurrence

20 Tumor Diameter & IB Cervical Cancer Recurrance Interval • 98 patients underwent laparotomy for IB/IIA disease • Negative nodes assoc. with local • Bulky tumor (> 4 cm) 80% nodal recurrence metastases • Smaller tumor (< 4 cm) 16% nodal • Positive nodes: local and distant metastases recurrence • Factors associated with prognosis are: – Size of cervical lesion – Lymph node metastases – CLS involvement – Depth of invasion Fuller AF, et al. Gynecol Oncol 33, 34-39 (1989). Chung, et al. Am J Obstet Gynecol, 135: 550-556 (1980), Hershey, Pennsylvania

IB Cervical Cancer GOG study with 645 patients • IB, negative paraaortic nodes and grossly negative pelvic nodes • 3 independent prognostic factors: – Clinical tumor diameter – CLS involvement – Depth of invasion

IB Cervical Cancer Cervical Cancer GOG study with 645 patients Nodal Metastases Pelvic nodal status did not affect • • 185 patients treated with radical disease free interval (may be a result of careful patient selection) hysterectomy, all had nodal metastases • Tumor diameter and disease free • 150 Stage IB, 35 Stage IIA interval at 3 years: • 95 patients had single node involved, – Occult 94.6% remainder had multiple nodes – < 3 cm 85.5% – > 3 cm 68.4% Delgado G, et al. Gynecol Oncol, 38: 352-357 (1990)

21 Cervical Cancer Cervical Cancer Nodal Metastases (cont.) Nodal Metastases Risk Groups • Multivariate analysis Number of Lesion size Nodes < 1 cm 1.1 - 4 cm > 4 cm • Identified risk groups based on tumor ≤ 2 LR LIR HIR size and nodal disease > 2 LIR HIR HR 10 yr survival Postop XRT • Older age = poor survival Low Risk (n=13) 92% 61% Low Intermediate Risk (n=66) 70% 56% Alvarez RD, et al. Gynecol Oncol, 35: 130-135 (1989) High Intermediate Risk (n=66) 56% 50% High Risk (n=20) 13% 85% Alvarez RD, et al. Gynecol Oncol, 35: 130-135 (1989)

Treatment: Stage IB2 Treatment: Stage IB2 Treatment Options: Treatment Options: • Radical Hysterectomy • Radiation therapy plus adjuvant • Radical Hysterectomy plus chemotherapy postoperative adjuvant radiation • Neoadjuvant chemotherapy plus • Radiation therapy plus adjuvant definitive surgery ± XRT extrafascial hysterectomy • Neoadjuvant chemotherapy plus • Radiation therapy definitive radiation ± surgery

Controversy With 1B Rx Controversy With 1B Rx • Stage IB encompasses a wide range of • Cell type: squamous, adenocarcinoma tumor diameters vs adenosquamous

• Tumor diameter is related to survival • Wide range of treatment options: surgery, radiation, combined modalities

• IB ranges from less than 1 cm tumor to > 8 cm tumor • Which type of treatment is best?

22 IB Cervical Cancer IB Cervical Cancer • 100 patients, Radical Hysterectomy, 3 risk groups identified: randomly selected • Studied prognostic factors: Tumor diameter Depth of invasion Low Risk: < 2 cm any depth Histopathologic Clinical 2.1 - 3 cm depth ≤ 1.5 cm Grade Age Intermediate Risk: 2.1 - 3 cm > 1.5 cm Stromal Reaction Race > 3.0 cm ≤ 1.5 cm Depth of invasion Lesion size High Risk: > 3.0 cm > 1.5 cm CLS Pos Nodes Recurrence 5 yr % Character of Tumor - Stromal Border Risk Group (n) (%) (%) survival Number of mitoses Low 75 20 8 97 Intermediate 14 29 36 21 • Purpose was to define "risk groups" to High 11 36 64 31 classify patients Gauthier P, et al. Obstet & Gynecol, 66: 569 (1985) UAB, Birmingham Gauthier P, et al. Obstet & Gynecol, 66: 569 (1985)

Cervical Cancer IB1 VS IB2 Cervical Cancer SURVIVAL Management: I-B, II-A Large Tumors IB1 18/181 patients (9.9%) are dead • XRT 5 year survival 90.0% • Radical hysterectomy IB2 • Combined treatment 9/48 patients (18.7%) are dead • Neoadjuvant chemotherapy 5 year survival 72.8% p = 0.0265* Mantel-Cox test

Survival by Nodal Status Stage IB2 Cervical Cancer 1.1 XRT & Adjuvant Extrafascial

(%) 1.0 IB1 Hysterectomy 0.9 • GOG Prospective Study 1984-1991 0.8 Survival 0.7 • 282 patients randomized to IB2 0.6 conventional XRT versus XRT followed 0.5 by extrafascial hysterectomy 0.4 Cumulative 0.3 0 10 20 30 40 50 60 70 80 90 100 Follow - up (months) Finan MA, et al; Gynecol Oncol 1996

23 Stage IB2 Cervical Cancer Stage IB2 Cervical Cancer XRT & Adjuvant Extrafascial XRT & Adjuvant Extrafascial Hysterectomy Hysterectomy • Survival: • Substantial reduction in risk of local 61.4% for XRT alone recurrence in XRT plus surgery group at 5 years (25.8% versus 14.4%) 64.4% for XRT plus surgery (ns) • The addition of hysterectomy to • Recurrence: standard radiation therapy does not 43.3% for XRT alone improve survival but may reduce the 34.5% for XRT plus surgery (ns) risk of local recurrence (longer follow up is needed) Keys H, et al. GOG, Abstr. SGO 1997

Progression-Free Interval Survival Time

100 100

80 80

60 60 Rx: 40 40 RT

NED Probability 20 20 RT + Hyst. Survival Probability 0 0 0 12 24 36 48 60 Months on Study

Keys, H et al, GOG, Abstr, SGO, 1997 Keys, H et al, GOG, Abstr, SGO, 1997

IB1 VS IB2 Cervical Cancer IB1 VS IB2 Cervical Cancer • Patients with Stage IB2 disease did • Stage appears to impact survival have a significantly worse 5 year through nodal status survival when compared to Stage IB1 • Those patients with Stage IB2 tumors patients but with negative nodes had a • The current staging system is not an significantly better survival than those independent predictor of survival with positive nodes

Finan MA, et al; Gynecol Oncol 1996 Finan MA, et al; Gynecol Oncol 1996

24 Treatment: Stage IB1 Treatment: Stage IB2

• Appropriate treatment is either • Individualize treatment radiation or radical • Tailor treatment to patient hysterectomy/radical trachelectomy • Further study is needed for bulky

• Radical hysterectomy appropriate even tumors treat patients on protocol with positive lymph nodes

Cervical Cancer Cervical Cancer Adenocarcinoma: Is it really worse? Adenocarcinoma: Is it really worse? Stage IB analysis of survival by treatment: 5 year survival Conclusion from study of 11,157 patients: Surgery Surgery XRT • Multivariate analysis revealed that alone & XRT alone Squamous cell 93% 73% 76% histologic cell type had no impact on Adenocarcinoma 95% 66% 71% survival for patients with IB disease. Adenosquamous 69% 87% 79% • SCCa and Adenocarcinoma patients treated with Surgery alone • Tumor size, nodal mets and treatment had a significantly better survival than women treated with Surgery and XRT or XRT alone (p<0.001). other than surgery alone were all • Adenosq patients had similar survival in all treatment groups independent prognostic factors in Stage (p=0.5). Shingleton HM, et al. Cancer Suppl, 76: 1948-1955 (1995) IB disease.

Cervical Cancer Cervical Cancer Stage I Survival by Cell Type Adenocarcinoma: Is it really worse? 1.0 0.9 Conclusion from study of 11,157 patients: 0.8 • Patients with adenocarcinoma and 0.7 0.6 positive nodes had a very poor survival 0.5

(33.3%). 0.4 0.3 • Surgery and XRT seemed to result in Squamous (n=1871) Proportion Surviving 0.2 Adenocarcinoma (n=302) higher cure rate for patients with 0.1 Adenosquamous (n=81) adenosquamous tumors. 0 0 12 24 36 48 60 84 96 Months Shingleton HM, et al. Cancer Suppl, 76: 1948-1955 (1995) Shingleton et al, Cancer Suppl 76; 1948-55 (1995)

25 Cervical Cancer Stage I Squamous Carcinoma of Cervix Positive Lymph Nodes Stage Ib Survival by Treatment 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6

0.5 0.5 0.4 0.4 Surgery and Radiation 0.3 0.3 Squamous (n=86) (n=242) Proportion Surviving 0.2 Adenocarcinoma (n=12) Proportion Surviving 0.2 Radiation Only (n=589) Adenosquamous (n=8) Surgery Only (n=471) 0.1 0.1 0 0 0 12 24 36 48 60 84 96 0 12 24 36 48 60 84 96 Months After Diagnosis Months After Diagnosis

Cervical Cancer- Survival by Cell Type Post-Op Adjuvant Radiation 100 195 patients treated with radical 90 •

80 hysterectomy 70 • 164/195 (85%) with negative nodes, 60 7.3% recurred 50 • 30/195 (15%) had positive nodes 10/30 40 Cell Type Alive Failed Total (33%) recurred 30 Squamous 503 115 645 20 Adenocarcinoma 92 12 104 20/30 Postop XRT 10/30 No XRT

Proportion Surviving Adenosquamous 46 18 64 10 5/20 recurred 5/10 recurred 0 0 12 24 36 48 60 No pelvic recurrences 2 pelvic Months on Study 3 distant

Post-Op Adjuvant Radiation Cervical Cancer

• 90% of recurrences occur within 24 Surgery vs Radiation* months Stage Radiation Surgery • Patients with pelvic node metastases I 91.5 86.3 accounted for 45% of the recurrences IIA 83.5 75.0 IIB 66.5 58.9 yet they were only 15% of the study IIIA 45.0 group IIIB 36.0 IV 14.0 Larson D, et al. Obstet & Gynecol, 69, 378 (1987). *5 year survival

26 Cervical Cancer Cervical Cancer I-B, II-A: Surgery vs. XRT Primary Radiation Therapy Surgery: • Avoids permanent radiation injury to • Avoids a major operation normal organs (ovaries, vagina, bladder, • Potentially gives better “tumor-free” rectum, etc.) margin • Avoids possibility of XRT induced 2nd • Survival rates similar to surgery pelvic malignancies • Accurate staging • Can be used for stage I-B – IV • Pregnancy, IBS, prior XRT, PID, adnexal • Should always include weekly cisplatin mass chemotherapy

Brachytherapy For Cervical Cancer

Brachytherapy For Cervical Cancer

A = 2cm above os & 2 cm lateral, B = 3 cm lateral to A

27 Rectal / Bladder Points Dose Distribution

Brachytherapy Brachytherapy For Cervical Cancer For Cervical Cancer • Treatment options for cervical cancer: • Radiation Therapy: 2 components – Surgery (Stages 1A, 1B & 2A) – Radiation therapy + weekly cisplatin – External Radiation (Teletherapy) Chemotherapy - all stages – Internal Radiation (Brachytherapy) – Combined therapy

28 Brachytherapy Brachytherapy For Cervical Cancer For Cervical Cancer • Brachytherapy: • Important points for Brachytherapy: – Maximize dose directly to tumor site – Drain bladder – Minimize radiation dose to – Foley with 50% Hypaque in balloon surounding organs – The tandem and ovoids are NOT – Protect bladder, rectum, small bowel, RADIOACTIVE. etc. – Flange used on tandem to mark location of cervix

Brachytherapy Brachytherapy For Cervical Cancer For Cervical Cancer • Important points (continued): • Important points (continued): – Plastic caps used on ovoids – Tandem and ovoids must be “closed” (colpostats) to “push” normal tissues at end of case away from sources

– Lubricant used on racking to ease – Colpostats must contain “baskets” to removal of system hold radiation sources

Brachytherapy Brachytherapy For Cervical Cancer For Cervical Cancer • At end of Case: • At end of Case: – All patients MUST have Foley – Thighs are frequently marked with catheter pen or marker to document location – Suture occasionally placed in vulva of system to secure system to patient – When moving patient from OR table to bed, protect Brachytherapy System

29 Brachytherapy Cervical Cancer For Cervical Cancer Systemic factors contributing to complications • Postoperatively: • Age – Patients go to Radiation Oncology Radiation • Atherosclerosis (after recovery) to have X-Rays taken • Diabetes – System is loaded with radioactive seeds after patient arrives on floor • CHF postoperatively • Collagen vascular disease

Cervical Cancer XRT Plus Concomitant Chemotherapy For Cervical Adhesion factors contributing to Cancer complications • USF study, 67 patients (cervix n=56, vagina • Salpingitis Radiation n=7, vulva n=4) • Peritonitis • Cervix Stages IB-IVA (most were advanced • Appendicitis stages) • Diverticular disease • XRT combined with: Mitomycin-c and 5-Fu Cisplatin and 5-Fu • Previous pelvic surgery or 5-Fu alone

XRT Plus Concomitant Chemotherapy For Cervical Cancer • 57 (85%) complete clinical response 6 (9%) partial response 2 (3%) stable disease • Overall survival 22% at 5 years • GOG randomized study with Cisplatin 5-Fu and XRT vs XRT alone, results pending (IIB- IVA) Roberts WS, Hoffman MS, et al. Gynecol Oncol, 43: 233 (1991).

30 Cervical Cancer - Cervical Cancer - Neoadjuvant Chemotherapy Neoadjuvant Chemotherapy • Randomized, prospective trial of bulky • Patients randomized to NACT followed stage IB and IIA, IIB & III cervical cancer by radical surgery vs exclusive XRT

• Neoadjuvant chemo (NACT) consisted NACT & Radical Surgery XRT alone of cisplatin as single agent or n 199 187 Age (median) 48 51 2 combination total dose > 300 mg/m Stage IB-IIB 40% 41% over 6-8 weeks Stage III 60% 59% Tumor > 5 cm 53% 53% Benedetti-Panici P, et al. Abstr SGO 1997, Gynecol Oncol, 64 (2), 292 (1997).

Cervical Cancer - Cervical Cancer - Neoadjuvant Chemotherapy Neoadjuvant Chemotherapy (cont.) (cont.) • Complications of chemotherapy: • Median follow up only 20 months N & V 76% Severe in 15% (range 1-73) Myelotoxicity 69% Severe in 14% • 3 yr disease free survival: NACT & • Complications of radical surgery and/or Radical Surgery 47% & XRT alone 41% XRT: Lymphocyst 20% • 3 yr survival overall NACT & Radical Bladder dysfunction 12% Surgery 66% & XRT alone 60% Proctitis/cystitis 58% Benedetti-Panici P, et al. Abstr SGO 1997, Gynecol Oncol, 64 GI toxicity 36% (2), 292 (1997).

Locally Advanced Stages 2 – 4 Cervical Cancer (3 & 4) • Standard Rx includes both XRT and chemotherapy Neoadjuvant Chemotherapy • Whole pelvis +/- extended field • Brachytherapy Tumor resistance to neoadjuvant • Weekly Cisplatin chemotherapy: chemotherapy may imply cross Cisplatin 40 mg/m2 weekly X 5 – 7 resistance to radiotherapy doses

31 Summary Future Programs: • Stage 1a1 1a2: CKC vs Hyst +/- nodes Manage Your Stress • Stage 1B1: Surgery or XRT Before It Manages You • Stage 1B2: Multiple options – Thursday, October 23, 2008 individualize to the patient 2:00-4:00 p.m. Central Time • Stage 2 – 4: XRT + weekly cisplatin HIV Serology Update 2008 chemotherapy Tuesday, October 28, 2008 9:00-11:00 a.m. Central Time

32