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 2 nd most common cancer among women world wide Estimated 493,000 new cases 293,000 deaths annually worldwide 7 th 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 Ia 1 Ia 2 Ib 1 Ib 2 Stromal invasion < 3 mm and lateral spread < 7 mm Stromal invasion 3-5 mm and lateral spread < 7 mm lateral spread Clinically visible lesion 4 cm 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 Paraaortic Lymph Node Involvement per Stage Stage Parametrial Pelvic Para-aortic Ia 2-5% 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 Ia 1 Cervical cone Hysterectomy Stage Ia2, Ib 1 and some Ib 2 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 Ligaments Resected at level of cervix Partially resected Resection at post-pelvic insertion Uterus Removed Removed Removed Cervix Completely removed Completely removed Completely removed Extended Radical Hysterectomy Type IV - - Above plus, resection of superior vesical artery and 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 Ib 1 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 Ib 1 survival with RAH and (-) LN s 80-90% Ib 1 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 Ia 2 -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/m 2 D1 5-FU 1000mg/m 2 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 Ia 2 -Ib 2 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 follow up Overall Survival (5 year) Chang et al. J Clin Oncol, 2000. Ib-IIa Cisplatin 50mg/m 2 D1 Vincristine 1mg/m 2 D1 Bleomycin 25 mg/m 2 D1-3 q 10 days for 3 cycles 68 52 39 months 70% vs. 62%, p=0.77 Benedetti-Panici et al. J Clin Oncol, 2002. Ib 2 -III Cisplatin 80 mg/m2 D1-2 Bleomycin 15 mg/m2 D1,8 q 21 days for 2 cycles 152 144 79 months 56% vs. 44%, p=0.01 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 Ia 2 and 13 Ib 1 ) 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 Ia 2 and 52 Ib 1 ) 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 Ia 2 and small Ib 1 tumors
Radical Trachelectomy
Radical Trachelectomy Shepherd et al. BJOG, 2006. Reported on a series of 123 vaginal radical tracheletomies 2 stage Ia 2 and 121 stage Ib 1 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 1 st 5-6 weeks of external beam radiation Total dose 45 to 50 Gy Or 180 to 200 cgy each day Cisplatin 40 mg/m 2 Q week 2 nd 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 year Survival (%) Significance GOG #85 Whitney et al IIb-IVb -PALN 177 EB+BT+ Cisplatin 50 mg/m 2 (D1, 29) 5- FU 1000mg/m 2 (D2-5 & D30-33) 8.7 years 67 OS p=0.018, RR 0.74 199 EB+BT+ Hydroxyurea 80mg/kg 2 week 57 GOG #120 Rose et al IIb-IVb -PALN 176 173 EB+BT+ Cisplatin 40mg/m 2 week EB+BT+ Cisplatin 50 mg/m 2 (D1, 22) 5-FU 1000mg/m 2 (D2-5 & D23-26) Hydroxyurea 2gm/m 2 2 week 35 months 65 65 OS p=0.004, RR 0.61 OS p=0.002, RR 0.58 177 EB+BT+ Hydroxyurea 3gm/m 2 2 week 47 RTOG #9001 Morris et al Ib-IVa 195 EB+BT+ Cisplatin 75 mg/m 2 (D1) Q 3 weeks 2 5-FU 1000 mg/m 2 (D2-5) 43 months 75 OS p=0.004, RR 0.59 193 EB+BT 63 GOG #123 Keys et al Ib-IIa 183 186 EB+BT+ Cisplatin 40 mg/m 2 EB+BT+ hysterectomy week + hysterectomy 36 months 83 74 OS p=0.008, RR 0.54 GOG #109 Peters et al Ia2-IIa s/p RAH 127 EB+ Cisplatin 70 mg/m 2 (D1) Q 3 weeks 2 5-FU 1000 mg/m 2 (D2-5) 42 months 87 OS p=0.01, RR 0.49 116 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 complication is transfusion Enteric fistulas next most likely complication Mortality 5-8% Permanent colostomy, ileal conduit or continent vesicostomy and a TRAM flap/ gracilis flap needed Author Bricker 1960 Symmonds 1975 Rutledge 1977 Morley 1989 Lawhead 1989 Patients (N) 150 198 296 100 65 5-year survival rate (%) 25 33 34 61 23
Recurrent Disease (Chemotherapy) Cisplatin is the drug of choice for advanced or distally recurrent cervical cancer Dose established at 50 mg/m 2 Bonomi et al. J Clin Oncol, 1985. Compared Cisplatin at 100 mg/m 2 to 50 mg/m 2 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/m 2 vs. (N=140) Cisplatin 50 mg/m 2 and Ifosfamide 5 g/m 2 (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/m 2 vs. (N=134) Cisplatin 50 mg/m 2 and Taxol 135 mg/m 2 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/m 2 vs. (N=146) Cisplatin 50 mg/m 2 and Topotecan 0.75 mg/m 2 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 %)