Anya Litvak and William P. Tew
Epidemiology:
3rd most common CA in women worldwide & 2nd most frequent cause of CA death in women in developing countries; 12K cases w/4.2K death in the United States per y. Rates ↓ in US 2° to early detection w/pap smears; still prevalent in pts w/low socioeconomic status & poor access to medical care. Median age of dx = 48.
Etiology and Clinical Manifestations
• RF: Persistent HPV infxn: High risk in pts w/early age at coitarche, multiple sexual partners, high risk sexual partners, h/o STDs (including genital warts); ↑ parity; ↑ risk in smokers; OCP users; chronic immunosuppression (eg. HIV); low socioeconomic status (2/2 low rate of screening)
• Sx: Usu asymptomatic & found at screening. Can cause abnl vaginal bleeding (postmenopausal, intermenstrual, postcoital), pelvic pain, bowel/urinary sx, or vaginal discharge w/advanced stage
Molecular Biology
• HPV genes E6 & E7 incorporate into cervix cells & produce viral proteins capable of binding to & inactivating tumor suppressor proteins RB1 & P53. 15 subtypes of HPV considered high risk; HPV 16/18 most prevalent (70% of cervix CA cases); other high risk subtypes: 31,33,35,39,45,51,52,56,58,59,68,73,82
Screening and Prevention
• Cervical CA rate has ↓ by 70–90% in well-screened populations.
American College of Ob/Gyn recommend testing w/Pap smear or liquid-based cervical cytology (w/c ↑ Sn) starting at age 21. Reflex HPV testing performed in setting of atypical squamous cells or LSIL
• low-risk pts: q2y if <30; q3y if >30 & 3 neg annual smears
• high-risk pts (hx of CIN2/CIN3, HIV, hx of DES exposure in utero): q1y
• pts >65–70: Can consider d/cing if 3+ neg smears
• s/p hysterectomy: D/c if no h/o CIN2/CIN3. If Hx of CIN2/CIN3: D/c after 3 neg smears
Prevention
• HPV vaccination ↓ incidence of premalignant lesion development; given to girls/young women 9–26 y (ideally before HPV exposure) (Future II NEJM 2007;356(19):1915)
Workup and Staging
• W/u: If lesion seen during cervical exam: Perform cervical punch bx or endocervical curettage; for abnl Pap smear w/o visible lesion: Colposcopy for direct biopsies of squamocolumnar jxn.
• For invasive disease >stage IB: CXR, MRI, or CT of abd/pelvis. Cystoscopy & proctoscopy if clinical concern for bladder/rectal extension
• Clinical Staging: Stage 0: Carcinoma in situ Stage I: Tumor limited to the cervix Stage IA: Tumor diagnosed only by microscopy; Stage IB: Clinical visible tumor confined to the cervix; Stage IB1 < 4 cm, Stage IB2 > 4 cm(bulky) Stage II: Tumor invading beyond uterus but not to pelvic wall or lower third of vagina; Stage III: Tumor extends to pelvic wall, involves lower third of vagina, or causes hydronephrosis or nonfunctioning kidney; Stage IVa: Tumor invades mucosa of bladder/rectum; Stage IVb: Tumor extends beyond true pelvic
Management: Premalignant Lesions
• CIN1: Observe as 60% of lesions will resolve w/o intervention
• CIN II/III perform excisional procedure w/LEEP or cervical conization to r/o invasive carcinoma
Management of Stage IA Disease w/o Lymphovascular Space Invasion (LVSI)
• Surgery: Simple hysterectomy alone. Trachelectomy can be considered in pt w/Stage IA/IB disease who wish to preserve fertility
• Trachelectomy w/surveillance: Appropriate for females who want to preserve fertility as long as margins negative & <3 mm depth
Management of Stage IA Disease w/LVSI or Nonbulky Stage IA2/Stage IB1 Disease
• Surgery: Radical hysterectomy & pelvic LN dissection ± para-aortic lymph node sampling
• Adjuvant radiation: For pt at intermediate/high risk for relapse (2+ RF: Outer 1/3 cervical stromal invasion, LVSI, or tumor > 4 cm); ↑ RFS (GOG 92 Gynecol Oncol 1999;73(2):177)
• Adjuvant chemoradiation: For pt w/+LNs, + margins, or microscopic parametrial extension - CIS-based chemoradiation ↑PFS/5-y OS compared to RT alone (JCO 2000;18(8):1606)
• 1° RT ± chemotherapy: Brachytherapy + pelvic RT for nonoperable pts. Yields comparable 5-y OS to surgery
Management of Extensive Local Disease (Bulky >4 cm Stage IB2–Stage IVA)
• Chemoradiation: Preferred tx for extensive, bulky local disease; 1° whole pelvic radiation or extended field radiation (for + para-aortic LN) w/chemotherapy followed by brachytherapy. Chemotherapy options include platinum or platinum/5-FU; CIS as good as CIS combo w/less tox.
• Adjuvant hysterectomy: Benefit unclear
Management of Metastatic IVB Disease/Recurrent Disease
• Chemotherapy: CIS, carboplatin, paclitaxel, docetaxel, topotecan, vinorelbine, GEM, & ifosfamide all have activity but duration of response is generally <4 mos. CIS/topotecan combination ↑ RR, PFS, & OS compared to single-agent CIS (GOG 179 JCO 2005;23(21):4626); CIS/paclitaxel ↑ RR & PFS compared to single-agent CIS but ∼OS (JCO 2004;22(24):5021). CIS doublets (cis + paclitaxel OR vinorelbine GEM OR topotecan) = OS. However, trend in RR, PFS, & OS favors CIS + paclitaxel (JCO 2009;27(28):4649)
• Palliative radiation: Consider for symptomatic relief for pt w/extensive prior pelvic radiation
• Pelvic exenteration: Consider in selected pts who have isolated pelvic recurrence w/in previous radiation field
