Cervical Carcinoma

Chris DeSimone, M.D. Assistant Professor Division of Gynecologic Oncology Outline

 Cervical Carcinoma  Epidemiology  Clinical symptoms  Risk factors  Staging  Cell types  Prognostic factors  Treatment Cervical Cancer

 2nd most common cancer among women world wide  Estimated 493,000 new cases  293,000 deaths annually worldwide  7th most common cancer among women in the United States  Estimated 10,000 new cases each year  3700 deaths annually from cervical cancer

Parkin et al. Int J Cancer, 2005. Who Develops Cervical Cancer?

 50% of women diagnosed with cervical cancer have not had a Pap test in 5 years  25% of all cervical cancers are diagnosed in women older than 65  In women older than 65, it is estimated that over 50% have not had a Pap test in the past 10 years

 Bottom Line – the majority of women with cervical cancer fail to get annual Pap tests Symptoms

 Early stages  Vaginal bleeding  Post coital spotting  Foul smelling, yellowish discharge  Late stages  Back pain  Lethargy  Nausea/vomiting  Most symptoms attributable to renal failure from ureteral obstruction Classic Risk Factors for Cervical Cancer

 Early first age of sexual contact  Multiple sexual partners  Smoking  Multiple sexually transmitted diseases  Immunocompromised  Lower socio-economic class  Family history is not a risk factor Main Risk Factors for Cervical Cancer

 Human papillomavirus (HPV) is the cause of cervical cancer

 Estimated that 80% of men and women will have been exposed to the virus by the age of 50

 Smoking is an important cofactor for malignant transformation Staging of Cervical Cancer

 Clinically staged (at least partially)  Stage I is confined to the cervix

 Ia1  Stromal invasion < 3 mm and lateral spread < 7 mm

 Ia2  Stromal invasion 3-5 mm and lateral spread < 7 mm lateral spread

 Ib1  Clinically visible lesion ≤ 4 cm

 Ib2  Clinically visible lesion > 4cm in greatest dimension Staging of Cervical Cancer

 Stage IIa  Upper 2/3 of vagina

 Stage IIb  Parametrial involvement

 Stage IIIa  Lower 1/3 of vagina

 Stage IIIb  Pelvic sidewall or hydronephrosis

 Stage IVa  Rectal or bladder mucosa

 Stage IVb  Distant disease Cervical Anatomy Cell Types

 Squamous (80%)  Squamous cell  Large cell keratinizing  Large cell non-keratinizing  Grade 2 most common grade  Adenocarcinoma (20%)  Incidence is increasing ~30% (70’s to 90’s)  Adenocarcinoma  Mucinous (rare)  Endometrioid  Clear Cell (DES exposure)  Adenosquamous  malignant glandular and squamous cell types  Poor prognosis Cell Types

 Glassy Cell Carcinoma  Poorly differentiated adenosquamous carcinoma with eosinophilic cytoplasm  Poor prognosis  Adenoid Cystic Carcinoma  Cribriform gland pattern  Aggressive and poor prognosis  S100 immunohistochemistry  Adenoid Basal Carcinoma  Indolent and excellent prognosis  Neuroendocrine tumors  Carcinoid  Small-cell carcinoma  Strong association with HPV 18  Chemosensitive but recurrences likely  Surgical treatment best therapy  Chromogranin and neuronspecific enolase immunohistochemistry Survival Rates

 Ia 95%  Ib 80%  II 63%  III 36%  IV 15%

 Benedet J. Annual report on the treatment of GYN CA. J Epidemiol Biostat, 2001. Prognostic Factors

 Age  Women < 35 have a poorer prognosis?  No conclusive data to support this concept

 Race  African –American women are more likely to have numerous risk factors, advanced stage and less likely to undergo therapy

 Anemia  Grogan et al. Cancer; 1999.  475 patients evaluated  Presenting hemoglobin ≥ 12 g/L had a better prognosis  Significant on univariate analysis ONLY Prognostic Factors

 Tumor Invasion/Size

 Delgado et al. Gynecol Oncol; 1990. GOG 49.  Patients with minimal stromal invasion had better 3 year survival rates following radical hysterectomy  < 10 mm: 86-94%  11 to 20 mm: 71 to 75%  > 21 mm: 60%

 van Nagell et al. Cancer; 1979.  Recurrence rate for Ib cervical cancers: RAH vs. XRT  Tumor <2 cm: 5% recurrence for RAH or XRT  Tumor 2-5 cm: 24% recurrence with RAH, 11% with XRT Prognostic Factors

 Stage  Stehman et al. Cancer; 1991.  Confirmed that tumor burden is a poor prognostic factor  Clinical staging limits thorough evaluation of tumor burden such as tumor volume, nodal status etc; therefore stage not the best indicator of a patient’s prognosis

 Lymph Vascular Space Invasion  Delgado et al. Gynecol Oncol; 1990. GOG 49.  Disease free survival 77% with LVSI vs. 89% without LVSI Prognostic Factors

 Nodal Status

 The MOST significant negative prognostic factor  Tinga et al. Gynecol Oncol; 1990 and Delgado et al. Gynecol Oncol; 1990. GOG 49.  Higher 5 year survival rates among surgically treated patients with negative LN’s (90%), positive pelvic LN’s (50-60%) and positive para-aortic LN’s (20-45%)  Reported 87% survival rate for 1 involved LN vs. 53% for 2 or more involved LN’s (p<0.02) Parametrial, Pelvic and Para- aortic Lymph Node Involvement per Stage

Stage Parametrial Pelvic Para-aortic

Ia2 - 5% 1% Ib 11% 15% 5% IIa - 22% 15% IIb 22% 35% 20% III - 45% 35%

Hoskin's. 4th ED. 745. Treatment for Stage I

 Surgery is reserved for early staged cervical cancer

 Stage Ia1  Cervical cone  Hysterectomy

 Stage Ia2, Ib1 and some Ib2 or IIa  Radical hysterectomy (abdominal, vaginal or laparoscopic)  Fertility-sparing: radical trachelectomy Radical Hair Radical Hysterectomy

 Objective is to remove the cervical cancer, uterus and tissue adjacent to the uterus:  Parametrial tissue  Complete pelvic lymphadenectomy (internal, external, common iliac nodes and obturator nodes)  Upper 2 cm of the vagina  Higher morbidity than a simple hysterectomy Types of Radical Hysterectomies

Extrafascial Type I Modified Radical Type II Radical Type III

Cervical Fascia Completely removed Completely removed Completely removed

Vaginal Cuff Small rim removed Proximal 1-2 cm Upper ⅓ to ½ removed

Bladder Partially mobilized Partially mobilized Mobilized

Rectum Partially mobilized Partially mobilized Mobilized

Ureters Not mobilized Unrooted in ureteral tunnel Complete dissection to bladder entry Cardinal Ligament Resected medial to ureters Resected at level of ureter Resected at pelvic sidewall

Uterosacral Resected at level of cervix Partially resected Resection at post-pelvic Ligaments insertion Uterus Removed Removed Removed

Cervix Completely removed Completely removed Completely removed

Extended Radical - - Above plus, resection of Hysterectomy Type superior vesical artery and IV more vagina Type V - - Above plus, resection of ureter and bladder Radical Hysterectomy Anatomy Radical Hysterectomy Anatomy Radical Hysterectomy Anatomy Complications of Radical Hysterectomy

 Estimated that 10% of patients will have some form of bladder dysfunction or injury  Ueland et al. Gynecol Oncol, 2005.  Evaluated 290 RAH’s from 1965-2002  Since 1985, incidence of ureteral injury <2%, bladder injury <1% and fistulas <1%  These injuries were more common when EBL >1000 ml (p<0.01)  Pulmonary embolis  Transfusion Survival Rate from Radical Hysterectomy

 Related to size of the tumor  Generally 90% 5-year survival rate  Ueland et al. Gynecol Oncol, 2005.

 All size Ib1 tumors  98% 2-year, 96% 5-year, 94% 10-year  Gadduci et al. Anticancer Res, 1995.  ≤4 cm, 92% 5-year  >4 cm, 56% 5-year (p=0.001)  Hopkins et al. Am J Obstet Gynecol, 1991.  ≤3 cm, 91% 5-year  >3 cm, 76% 5-year (p=0.007) Positive Lymph Nodes Following RAH

 Positive lymph nodes equate to poor prognosis

 Ib1 survival with RAH and (-) LN’s 80-90%  Ib1 survival with RAH and (+) LN’s 50-60%  Several studies document decreased local recurrence with XRT; BUT no improvement in overall survival

 What about Chemo/XRT?

Delgado et al. Gynecol Oncol. 1990. Positive Lymph Nodes Following RAH

 Peters WA et al. J Clin Oncol, 2000. GOG 109.

 Randomized study for Ia2-IIa cervical carcinomas treated by RAH with positive lymph nodes  Treatment group consisted of XRT versus Chemo/XRT  XRT: 4900 cGy. No brachytherapy  Chemo: q 21 days  Cisplatin 70 mg/m2 D1  5-FU 1000mg/m2 D2-5 Positive Lymph Nodes Following RAH

 Majority of women stage Ib cervical carcinomas and majority had positive pelvic lymph nodes  Median follow up 42 months  4 year survival:  Chemo/XRT 81%  XRT 71% HR 1.96 (p=0.007)  Toxicity:  Chemo/XRT grade 4 toxicity (n=27) [Neutropenia 11]  XRT grade 4 toxicity (n=4) Radical Fashion High Risk Groups s/p RAH with (-) LN’s

 Risk factors significant for recurrence  Depth of invasion  Size of tumor  LVSI

 Estimated 25% of Ib tumors with negative pelvic lymph nodes have these factors  GOG 49- Delgado et al. Gynecol Oncol, 1990. High Risk Groups s/p RAH with (-) LN’s

 Sedlis et al. Gynecol Oncol, 1998. GOG 92

 Randomized study for Ia2-Ib2 cervical carcinomas treated by RAH with negative lymph nodes AND:  > ⅓ stromal invasion (>15 mm)  LVSI (positive)  Large clinical tumor (>4 cm)

 Treatment group consisted of XRT versus no further therapy (NFT)  XRT: 4600 to 5040 cGy. No brachytherapy High Risk Groups s/p RAH with (-) LN’s

 21 patients (15%) recurred with XRT versus 39 patients (28%) with no further therapy

 Majority of recurrences local 18/21 XRT vs. 27/39 NFT

 47% reduction in risk of recurrence: RR 0.53, p=0.008

 Recurrence free rate at 2 years 88% XRT vs. 79% NFT

 11 patients with Grade 3-4 toxicity with XRT vs. 3 with NFT (majority GI and/or GU complications) High Risk Groups s/p RAH with (-) LN’s

 Summary  Deep stromal invasion > 15 mm  LVSI  Tumor > 4 cm  Negative LN’s

 Tailor therapy per patient for XRT ± Cisplatin Radical Hippies

Arrow points to the hippy Neoadjuvant Chemotherapy and RAH for Bulky Cervical Disease

Reference FIGO Stage Chemo regimen NACT+S Control Median Overall follow up Survival (5 year)

Chang et al. J Clin Ib-IIa Cisplatin 50mg/m2 D1 68 52 39 months 70% vs. 62%, Oncol, 2000. Vincristine 1mg/m2 D1 p=0.77 Bleomycin 25 mg/m2 D1-3 q 10 days for 3 cycles

Benedetti-Panici et al. J Ib2-III Cisplatin 80 mg/m2 D1-2 152 144 79 months 56% vs. 44%, Clin Oncol, 2002. Bleomycin 15 mg/m2 D1,8 p=0.01 q 21 days for 2 cycles

Cisplatin 50 mg/m2 D1 Vincristine 1 mg/m2 D1 Bleomycin 30 mg D1 6 weekly cycles

Cisplatin 43 mg/m2 Ifosfamide 3.5mg/m2 on cycles 1,4,7 7 weekly cycles

Cisplatin 40 mg/m2 for 6 cycles Neoadjuvant Chemotherapy and RAH for Bulky Cervical Disease

 Too few studies to change standard of care  OK to tailor treatment  Awaiting more studies to determine if this option is feasible Radical Smokers Radical Laparoscopic Hysterectomy

 Ramirez et al. Gynecol Oncol, 2006.  Case series of 20 patients who underwent total laparoscopic radical hysterectomy

 18 cervical carcinomas (5 Ia2 and 13 Ib1)  Median age 41 (range, 25-76 years)  Median weight 70 kg (range, 49-112 kg)  Median blood loss 200 ml (range, 25-700 ml)  Median OR time 333 minutes (range, 275-442 minutes)  Median hospital stay 1 day (range, 1-5 days)  5 patients (25%) had complications (P.E., cystotomy, pneumomediastinum, vaginal evisceration and lymphocyst)  Median follow up 8 months all patients NED Radical Laparoscopic Hysterectomy

 Spirtos et al. Am J Obstet Gynecol, 2002.  Evaluated 78 patients with total laparoscopic radical hysterectomy

 78 cervical carcinomas (26 Ia2 and 52 Ib1)  Median age 41 (range, 26-62 years)  5 patients converted to laparotomy, one for a cystotomy  Median blood loss 250 ml (range, 50-700 ml)  Median OR time 205 minutes (range, 150-430 minutes)  Median hospital stay 2.9 day (range, 1-7 days) Radical Laparoscopic Hysterectomy  Results  9 patients (11%) had positive lymph nodes  10 patients (13%) had complications (cystotomy ×3, UV fistula, DVT, urosepsis, vaginal cuff abscess, abdominal wall hematoma and lymphocyst ×2)  Mean follow up 68 months  8 patients (10%) have had a recurrence  3 pelvic sidewall  1 external iliac artery distal to the deep C.I.  1 vaginal apex  1 liver  1 pulmonary  1 suprarenal LN  5 patients have died, 93% 5 year survival rate  3 recurrent disease  1 CAD  1 sepsis and bowel obstruction, 1 months out from surgery Radical Laparoscopic Hysterectomy

 Steed et al. Gynecol Oncol, 2004.  Compared 71 cases of laparoscopic assisted radical vaginal hysterectomy (LAVRH) to 205 cases of RAH.  Retrospective analysis  No differences in tumor size, histology, grade, depth of invasion, lymph node metastases or surgical margins  No conversions to laparotomy Radical Laparoscopic Hysterectomy

 Results (LAVRH vs. RAH)  EBL: 300 ml vs. 500 ml (p<0.001)  OR time: 3.5 hrs vs. 2.5 hrs (p<0.001)  Intraoperative complications 13% vs. 4% (p<0.03)  LAVRH: cystotomy ×7, ureteral injury and bowel perforation  Hospital stay: 1 day vs. 5 days (p<0.001)  Median follow up: 17 months vs. 21 months  Recurrences: 4 vs. 13 patients (NS)  2 year survival: 94% vs. 94% (NS) Radical Laparoscopic Hysterectomy Summary

 Total laparoscopic and laparoscopic assisted radical hysterectomy can be safely employed to treat early stage cervical carcinoma  Not gold standard therapy  Longer OR time and more complications with laparoscopy  Benefit: shorter hospital stay and blood loss  Survival and recurrence rates are comparable  Need a phase III trial between RAH vs. total laparoscopic RAH Radical Comics Radical Trachelectomy

 Conservative (relatively) therapy designed to preserve the uterus for child bearing while removing the cervical carcinoma  Preserves uterine arteries  Cervix and parametrium are resected along with pelvic lymph nodes

 Ideally suited for Ia2 and small Ib1 tumors Radical Trachelectomy Radical Trachelectomy

 Shepherd et al. BJOG, 2006.  Reported on a series of 123 vaginal radical tracheletomies

 2 stage Ia2 and 121 stage Ib1  Mean age 30 (range, 21-45 years)  11 women (8%) underwent definitive RAH (2) or Chemo/XRT (9) for positive lymph nodes and close margins  6 intraoperative complications: cystotomy and pelvic hemorrhage ×4 and uterine perforation  Mean follow up 45 months Radical Trachelectomy

 Results  3/112 recurrences (3%) for vaginal radical trachelectomy (2 DOD)  63 women attempted pregnancy  55 pregnancies in 26 women  28 live births in 19 women  5-year pregnancy rate is 53%  All but 2 women delivered by classical C/S  7/28 infants were preterm < 32 weeks gestation Radical Trachelectomy Summary

 Acceptable method for treating early cervical carcinoma  Moderate success rate for pregnancy  Few centers perform this surgery  Counsel patient she will likely have preterm labor and a C/S Treatment for Stage II-IVa

 Stages II-IVb receive radiation (XRT) and chemotherapy  XRT given in two phases

 1st 5-6 weeks of external beam radiation  Total dose 45 to 50 Gy  Or 180 to 200 cGy each day  Cisplatin 40 mg/m2 Q week

 2nd Brachytherapy  HDR or LDR  Positions a radioactive implant adjacent to the carcinoma Radical Radiation XRT

 Field size  16 by 16 cm field  Superior border- L4-L5 interspace  Lateral border- 2 cm lateral to bony pelvis  Inferior border- inferior border of the obturator foramen  Field covers external and internal iliac LN groups XRT

 Brachytherapy  Low dose rate (LDR)- 40-200 cGy/hour  High dose rate (HDR)- >1200 cGy/hour  Generally, higher dose rates increase late reactions: fistulas  Benefit- less acute reactions and better compliance  LDR 36 hours vs. HDR 4 hours XRT

 Brachytherapy  HDR delivers 5 fractions of 6 Gy or 30 Gy total dose  No significant difference between survival rate of LDR and HDR  No randomized trials in the US have compared HDR to LDR  Many studies show a trend (but NS) for better survival rates with LDR Chemoradiation

Study Stage N Treatment Follow up Median 3 Significance year Survival (%) GOG #85 IIb-IVb 177 EB+BT+ Cisplatin 50 mg/m2 (D1, 29) 8.7 years 67 OS p=0.018, RR 0.74 Whitney et al -PALN 5- FU 1000mg/m2 (D2-5 & D30-33)

199 EB+BT+ Hydroxyurea 80mg/kg 2× week 57

GOG #120 IIb-IVb 176 EB+BT+ Cisplatin 40mg/m2 week 35 months 65 OS p=0.004, RR 0.61 Rose et al -PALN 173 EB+BT+ Cisplatin 50 mg/m2 (D1, 22) 65 OS p=0.002, RR 0.58 5-FU 1000mg/m2 (D2-5 & D23-26) Hydroxyurea 2gm/m2 2× week

177 EB+BT+ Hydroxyurea 3gm/m2 2× week 47 RTOG #9001 Ib-IVa 195 EB+BT+ Cisplatin 75 mg/m2 (D1) Q 3 weeks ×2 43 months 75 OS p=0.004, RR 0.59 Morris et al 5-FU 1000 mg/m2 (D2-5)

193 EB+BT 63 GOG #123 Ib-IIa 183 EB+BT+ Cisplatin 40 mg/m2 week + hysterectomy 36 months 83 OS p=0.008, RR 0.54 Keys et al 186 EB+BT+ hysterectomy 74

GOG #109 Ia2-IIa 127 EB+ Cisplatin 70 mg/m2 (D1) Q 3 weeks ×2 42 months 87 OS p=0.01, RR 0.49 Peters et al s/p 5-FU 1000 mg/m2 (D2-5) RAH 116 EB 77 Advanced Disease (Stage IVb)

 Current trend is chemotherapy  Advanced (stage IVb) receive palliative XRT and chemotherapy  Chemotherapy of choice is Cisplatin- response rate of ~ 30%  GOG # 204 treats stage IV cervical cancer with combinations of Cisplatin and:  Vinerolbine  Gemzar  Topotecan  Taxol Recurrent Disease

 Possible treatments  XRT  Surgery  Chemotherapy Recurrent Disease (XRT)

 Local recurrence to the vagina and pelvis can be salvaged with XRT  Tissues do not have the same tolerance to XRT, therefore severe late effects observed  Best employed for patients with a long disease-free interval  Mainstay: interstitial or intracavitary XRT  Small number of patients reported in the literature Recurrent Disease (XRT)

 Puthawala et al. Cancer, 1982.  Interstitial implants  7/10 patients experienced tumor control  30% had mild proctitis, cystitis  10% severe complication rate (RV, VV, EV fistulas)

 Randall et al. Gynecol Oncol, 1993.  Interstitial implants (30-50 Gy) and LDR implants  13 patients treated, median follow up 59 months  69% CR and 46% NED after 2 years  Squamous histology, small tumor volume and proximal vaginal recurrences did better  1 patient had a RV fistula Recurrent Disease (XRT)

 Wang et al. Am J Obstet Gynecol, 1999.  73 patients  20-40 Gy given using LDR and HDR  40% 5 year survival rate  Favorable prognosis for tumors <4 cm and proximal vaginal involvement  12% fistula rate Recurrent Disease (Surgery)

 Exenteration traditionally used for central recurrences  Modern Chemo/XRT leads to few isolated central recurrences  Exenteration includes removal of the uterus, cervix, tubes, ovaries, and parametria PLUS:  Bladder (Anterior exenteration)  Rectum/Sigmoid (Posterior exenteration)  Both (Complete exenteration) Recurrent Disease (Surgery)

 Pre operative assessment

 Clinical exam: fixed pelvic lesion, weight loss, hydronephrosis, leg edema and hip pain. These findings are not suitable for the exenterative surgery

 CT scan ± PET scan for pelvic and para-aortic lymphadenopathy, ascites and pelvic masses

 Shingleton et al. Obstet Gynecol, 1989.

 Defined risk groups for exenteration candidates . Time from initial therapy to recurrence . Size of recurrence . Preoperative pelvic sidewall fixation

 Patients with recurrence <1 year, tumors > 3 cm and pelvic sidewall fixation all died of complications or carcinoma within 18 months of exenteration Recurrent Disease (Surgery) Exenteration facts  Morbidity rate 15%  Most common Author Patients (N) 5-year survival complication is rate (%) transfusion Bricker 1960 150 25  Enteric fistulas next most Symmonds 198 33 likely complication 1975 Rutledge 1977 296 34  Mortality 5-8%  Permanent colostomy, Morley 1989 100 61 ileal conduit or continent Lawhead 1989 65 23 vesicostomy and a TRAM flap/ gracilis flap needed Recurrent Disease (Chemotherapy)

 Cisplatin is the drug of choice for advanced or distally recurrent cervical cancer  Dose established at 50 mg/m2  Bonomi et al. J Clin Oncol, 1985.  Compared Cisplatin at 100 mg/m2 to 50 mg/m2  No difference in response rate, progression free interval and survival  Studies today focusing on using Cisplatin with another agent Recurrent Disease (Chemotherapy)

 Omura et al. J Clin Oncol, 1997. GOG 110.  Compared:  Cisplatin 50 mg/m2 vs. (N=140)  Cisplatin 50 mg/m2 and Ifosfamide 5 g/m2 (24 hr infusion) every 21 days (N=151)  Stage IVb, persistent or recurrent cervical carcinomas Recurrent Disease (Chemotherapy)

 Results  C/Ifos had a higher response rate (31% vs. 18%, p=0.004)  C/Ifos had a longer progression-free survival (4.6 vs. 3.2 months, p=0.003)  No difference in overall survival  C/Ifos had greater neutropenia, renal toxicity, peripheral neuropathy and CNS toxicity Recurrent Disease (Chemotherapy)

 Moore et al. J Clin Oncol, 2004. GOG 169.  Compared:  Cisplatin 50 mg/m2 vs. (N=134)  Cisplatin 50 mg/m2 and Taxol 135 mg/m2 every 21 days (N=130)  Stage IVb, persistent or recurrent cervical carcinomas Recurrent Disease (Chemotherapy)

 Results  C/Taxol had a higher response rate (36% vs. 19%, p=0.002)  C/Taxol had a longer progression-free survival (4.8 vs. 2.4 months, p<0.001)  No difference in overall survival  C/Taxol had greater Grade 3 and 4 neutropenia and anemia Recurrent Disease (Chemotherapy)

 Long et al. J Clin Oncol, 2005. GOG 179.  Compared:  Cisplatin 50 mg/m2 vs. (N=146)  Cisplatin 50 mg/m2 and Topotecan 0.75 mg/m2 D1-3 every 21 days (N=147)  Stage IVb, persistent or recurrent cervical carcinomas Recurrent Disease (Chemotherapy)

 Results  C/Topo had a higher response rate (27% vs. 13%, p=0.004)  C/Topo had a longer progression-free survival (4.6 vs. 2.9 months, p=0.014)  C/Topo had a greater overall survival (9.4 vs. 6.5 months, p=0.017)  C/Topo had greater Grade 3 and 4 hematologic toxicity (70% vs. 1.4 %)