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

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

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 Paraaortic Lymph Node

Involvement per Stage

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

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?

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)

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

Neoadjuvant Chemotherapy and RAH for Bulky Cervical Disease

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 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 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

 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 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

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 %)