Cervical Cancer
BACKGROUND
What is the annual incidence of cervical cancer in the U.S.?
~12,000 cases/yr of cervical cancer in the U.S.
What is the mean age of presentation for cervical cancer?
The mean age of presentation for cervical cancer is in the 40s in the U.S.
List the 7 lifestyle factors associated with an increased risk of cervical cancer.
Lifestyle factors associated with increased risk of cervical cancer:
1. Early onset of sexual activity
2. Larger number of sexual partners
3. Exposure to high-risk partners
4. Hx of STD
5. Smoking
6. High parity
7. Prolonged use of oral contraceptives
HPV is detectable in what % of cervical cancer?
HPV is detectable in >99% of cervical cancer.
Roughly what % reduction in mortality has been achieved with PAP screening for cervical cancer?
There has been an ~70% reduction in cervical cancer mortality with PAP screening.
What does ASCUS stand for (on a PAP result), and how should it be managed?
ASCUS stands for Atypical Squamous Cells of Unknown Significance. About two-thirds can resolve spontaneously. Pts can undergo repeat PAP in 6 mos and then colposcopy if abnl.
How should LGSIL seen on PAP be managed?
LGSIL resolves spontaneously ∼40% of the time; therefore, like with ASCUS, pts can undergo repeat PAP in 6 mos with colposcopy if abnl.
How should a HGSIL result from a PAP be managed?
All pts with HGSIL should undergo colposcopy with Bx. One-third of these pts can still resolve spontaneously, but waiting without further investigation is not recommended due to concern for progression.
What % of HGSIL progresses to invasive cancers?
~22% of HGSIL progress to invasive cancer. This is in contrast to ASCUS (<1%) and LGSIL (∼5%).
What % of cervical cancers are caused by HPV-16 and -18?
>70% of cervical cancers are caused by HPV-16 and -18.
What HPV subtypes cause the most cases of benign warts?
HPV subtypes 6 and 11 cause most cases of benign warts.
In the U.S., what % of cervical cancers are squamous cell carcinomas vs. adenocarcinomas?
With regard to cervical cancers in the U.S., 80% are squamous cell carcinomas, while ~20% are adenocarcinomas.
List 5 histologic subtypes of adenocarcinoma of the cervix.
Subtypes of adenocarcinoma of the cervix:
1. Mucinous
2. Adenosquamous
3. Endometrioid
4. Clear cell
5. Glassy cell
Name 3 common presenting Sx of cervical cancer.
Common presenting Sx of cervical cancer:
1. Abnl vaginal bleeding
2. Postcoital bleeding
3. Abnl vaginal discharge
What specific area of the cervix is the most common point of origin for cervical cancer?
The transformation zone is the most common point of origin for cervical cancer. It is a dynamic area between the original and present squamocolumnar junction.
WORKUP/STAGING
What should be included in the workup for a cervical mass?
Pelvic mass workup: H&P, including a careful pelvic exam in the office, basic labs, and EUA with Bx, with cystoscopy and proctoscopy (if concern for invasion) for any visible lesions. Imaging studies such as CT, PET, and MRI can be obtained for treatment decision making and planning purposes (but do not enter FIGO staging of the pt).
What are the areas at risk for local extension of cervical cancer?
Cervical cancer can spread locally to the corpus, parametria, and vagina. These should be carefully assessed during a physical exam. Tumor size and parametrial involvement are best assessed by rectovaginal exam. Cervical tumors can also spread to bladder anteriorly or rectum posteriorly, but this is rare in North America.
Name 3 routes of lymphatic drainage from the cervix.
Routes of lymphatic drainage from the cervix:
1. Lat to the external iliac nodes
2. Post into common iliac and lat sacral nodes
3. Post-lat into internal iliac nodes
What imaging studies are included in FIGO staging of cervical cancer? What common imaging modalities are not allowed?
CXR, barium enema, and intravenous pyelogram data are included in FIGO staging of cervical cancer, as are procedures such as cystoscopy, proctoscopy, and hysteroscopy. CT, PET, MRI, bone scan, lymphangiography, and laparotomy/laparoscopy data are not allowed to be used for staging but can be used for decisions regarding management.
What is the utility of PET scans in cervical cancer?
PET is generally fairly sensitive (85%–90%) and specific (95%–100%) for detection of para-aortic (P-A) nodes in pts with locally advanced cervical cancer.
In what group of cervical cancer pts is evaluation of the urinary tract required?
Cervical cancer pts with more than stage IB1 disease require imaging of the urinary tract. This can be performed with CT, MRI, or intravenous pyelogram.
What is the FIGO (2010) staging for cervical cancer?
Stage IA: microscopic Dz, with ≤5 mm DOI and ≤7 mm horizontal spread. It is further delineated into IA1 (tumors ≤3 mm depth and ≤7 mm wide) and IA2 (tumors >3 mm but ≤5 mm deep and ≤7 mm wide)
Stage IB: clinically visible tumor or >IA2, with IB1 ≤4 cm, and IB2 being bulky tumors >4 cm
Stage IIA: invades beyond uterus/cervix; involves the upper two-thirds of the vagina without parametrial invasion with IIA1 lesions ≤4 cm and IIA2 lesions >4 cm
Stage IIB: invades beyond uterus/cervix and into parametria but not into pelvic wall or lower 3rd of vagina
Stage IIIA: invades lower 3rd of vagina but no extension into pelvic wall
Stage IIIB: invades pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney
Stage IVA: invades beyond true pelvis or mucosa of bladder or rectum (must be Bx proven); bullous edema of bladder or rectum does not count
Stage IVB: DMs
How does the AJCC (TNM) staging system for cervical cancer compare with the FIGO system?
In AJCC cervical cancer staging, the T stage corresponds to the FIGO stage, except for FIGO stage IVB. Node+ patients are AJCC stage IIIB. Stage 0 exists in the AJCC but not in the FIGO system.
What factors are predictive of pelvic nodal involvement in cervical cancer?
Factors that predict for nodal involvement in cervical cancer include DOI, FIGO stage, tumor size, and LVSI (10% without vs. 25% with). It is controversial whether histologic subtype is an independent predictor for nodal involvement, although some studies show adenocarcinomas having higher rates of distant metastasis.
Estimate the risk of pelvic LN involvement based on the following DOIs of a cervical cancer: <3 mm, 3–5 mm, 6–10 mm, and 10–20 mm.
Risk of pelvic nodal involvement by DOI:
≤3 mm: <1%
3–5 mm: 1%–8%
6–10 mm: 15%
10–20 mm: 25%
Estimate the risk of pelvic LN involvement based on the FIGO stage of cervical cancer.
Pelvic LN+ rates for cervical cancer based on the FIGO stage:
Stage IA1: 1%
Stage IA2: 5%
Stage IB: 15%
Stage II: 30%
Stage III: 50%
Stage IVA: 60%
Estimate the risk of P-A nodal involvement based on the FIGO stage of cervical cancer.
P-A LN+ rates for cervical cancer based on the FIGO stage:
Stage IA: 0%
Stage IB: 5%–8%
Stage IIA: ∼10%
Stage IIB: ∼15%
Stage III: 30%
Stage IVA: 40%
What are the 5-yr OS rates based on the FIGO stage?
5-yr OS based on FIGO stage:
Stage IA: 93%
Stage IB: 75%–80%
Stage IIA: 80%
Stage IIB: 65%–70%
Stage IIIA: 35%
Stage IIIB: 35%–40%
Stage IVA: 10%
Stage IVB: 0%
(AJCC 7th edition, 2011)
TREATMENT/PROGNOSIS
What is the most important prognostic factor in cervical cancer?
Tumor stage is the most important prognostic factor in cervical cancer since FIGO staging is based on prognostic factors. Per stage, extent of nodal involvement is the next most important factor.
What is removed in a radical trachelectomy as Tx for cervical cancer?
In a radical trachelectomy, all cervical cancer is removed with a margin, but the internal os is left behind and stitched closed, with a small meatus for menses to escape. This procedure allows future pregnancy, delivered via a C-section. This procedure should be reserved for women desiring fertility preservation and with stage IA1 as well as select cases of IA2 and small IB1 and tumors <2.0 cm in size.
How should pts with preinvasive cervical cancer (HGSIL or CIN III) be managed?
Pts with preinvasive cervical cancer should be managed with colposcopy → conization, LEEP, laser, cryotherapy, or simple hysterectomy.
In which subset of cervical cancer pts is simple hysterectomy adequate as definitive management?
Pts with IA1 Dz can be treated with simple abdominal hysterectomy. A cone should be done 1st to ensure that there are no foci of invasion beyond 3 mm identified. Sometimes, conization is also adequate for IA1, but there must be DOI <3 mm and no LVSI or dysplasia at the margin. (Van Nagell J et al., Am J Obstet Gynecol 1983) All other pts (≥IA2) should get radical hysterectomy with pelvic LND.
What is the difference between a class II and class III radical hysterectomy (Piver-Rutledge-Smith classification)?
In a class II modified radical hysterectomy (Piver-Rutledge-Smith classification), there is removal of the uterus, ureters are unroofed to remove parametrial and paracervical tissue medial to the ureters and 1–2 cm of vaginal cuff, and the uterine artery is ligated at the ureter. In a class III surgery, there is removal of parametrial and paravaginal tissue to the pelvic sidewall, ligation of the uterine artery at the ureter, and removal of the upper half to two-thirds of the vagina.
What stage of cervical cancer can be treated with brachytherapy alone?
Stage IA cervical cancer can be treated with brachytherapy alone with LDR 65–75 Gy or HDR 7 Gy × 5–6 fx, with LC of 97%. (Grisby P et al., IJROBP 1992)
When treating cervical cancer pts with brachytherapy, is there a Dz control or toxicity difference between LDR and HDR?
This is uncertain. In Teshima T et al., pts with stages I–III cervical cancer were randomized to HDR cobalt-60 or LDR cesium-137 therapy. There was no SS difference in 5-yr CSS between the 2 groups (stage I, 85%–93%; stage II, 73%–78%; stage III, 47%–53%). Moderate to severe complications were higher in HDR (10% vs. 4%). (Cancer 1993)
Where is point A, and what should it correspond to anatomically?
Point A is 2 cm above the external cervical os and 2 cm lat to the central canal/tandem. This should correspond to the paracervical triangle, where the uterine vessels cross the ureter.
Where is point B, and what should it correspond to anatomically? How does the dose to point B typically relate to the dose to point A?
Point B is 5 cm lat from the midline at the same level as point A (2 cm above the external cervical os). It is supposed to represent the obturator nodes. The dose to point B is usually <20% of the dose to point A using current ring and tandem systems.
Before CT-based planning, how were the bladder, rectum, and vaginal points defined for cervical cancer brachytherapy?
Before CT-based planning, the bladder point was 5 mm behind the post surface of the Foley balloon on a lat x-ray filled with 7 cc radiopaque fluid and pulled down against the urethra. The rectum point was 5 mm behind the post vaginal wall between the ovoids at the inf point of the last intrauterine tandem source or mid vaginal source. The vaginal point was the lat edge of the ovoids on AP film and mid ovoid on lat film. In the present age of CT planning, an alternative is to contour the organs and calculate the max dose to the organ using 3D planning.
What are the dose limits to the bladder, rectum, and vaginal points in cervical cancer brachytherapy?
In cervical cancer brachytherapy, typically the max allowed dose to the rectal point is 75 Gy, the max bladder point dose is 80 Gy, and the max vaginal dose is 120 Gy. With 3D planning, dose limit to 2cc of bladder is £90 Gy equivalent 2Gy dose (EQD2) (normalized therapy dose), rectum dose to 2cc (D2cc) £75 Gy EQD2. (Viswanathan A et al., Brachy 2012)
What RT dose can cause ovarian failure? What about sterility?
Ovarian failure can occur with 5–10 Gy of RT. Sterility can occur after 2–3 Gy.
What are the typical LDR and HDR in cervical cancer Tx?
In cervical cancer brachytherapy, LDR is usually 0.4–0.8 Gy/hr, while HDR is much higher, at least 12 Gy/hr. Typically, 1 treatment of 5.5–6.0 Gy takes approximately 5–10 min to deliver.
What should be the dose to point A in RT for cervical cancer (sum of EBRT + brachytherapy)? Does it depend on the stage of Dz?
In cervical cancer radiotherapy, the cumulative dose to point A should be at least 75 Gy for stage IA Dz, 80–85 Gy for stages IB–IIB Dz, and 85–90 Gy for stages III–IVA Dz, so staging is a factor in determining the dose.
What is the role for definitive surgery vs. definitive RT for the management of early stage (IB–IIA) cervical cancers? What study tested these 2 modalities?
In Landoni F et al., pts with stages IB and IIA cervical carcinoma were randomized to surgery (class III) vs. RT for definitive therapy. Adj RT was allowed for the surgery group based on preset criteria. 5-yr OS and DFS were equal (83% and 74%, respectively, for both groups). 64% of surgery pts rcvd adj RT. Grades 2–3 morbidity was higher in the surgery arm (28% vs. 12%). (Lancet 1997)
What are the benefits of surgery over RT for the Tx of early-stage cervical cancers?
Benefits of surgery over RT include shorter Tx time, preservation of ovarian function, possibly better sexual functioning after Tx, no 2nd malignancy risk, avoidance of long-term RT sequelae, and psychologically easier for many patients to understand. Surgery can also better identify the accurate anatomic extent of disease.
For pts with early-stage cervical cancer treated with radical or modified radical hysterectomy, what are 3 major indications for adj therapy?
For pts with early-stage cervical cancer treated with radical or modified radical hysterectomy, major indications for adj therapy include +/close margin, LN mets, and microscopic parametrial invasion. Other indications include tumor >4 cm, deep stromal invasion, or LVI.
What adverse features after surgery are indications for adj RT alone without chemo?
Cervical cancer pts after radical hysterectomy to –margins and –nodal status but have ≥2 risk features (+LVSI, >4-cm tumors, more than one-third stromal invasion) may benefit from PORT.
The Gynecologic Oncology Group’s study GOG 92 enrolled 277 stage IB cervical cancer pts who underwent surgery and had –nodes but >1 adverse feature: more than one-third stromal invasion, LVI, or tumor >4 cm. Compared to observation, there was a pelvic RT (46–50.4 Gy) RR of recurrence by 46% (21% vs. 14%, p = 0.007) and trend to OS benefit by ∼10% (71% vs. 80%, p = 0.074). (Rotman M et al., IJROBP 2006)
When is adding chemo to adj RT after radical hysterectomy beneficial compared with RT alone for the surgical management of early-stage cervical cancer (IA2–IIA)?
In GOG 109, high-risk pts (with at least 1 of the following features: +margin, +nodes, or microscopic parametrial invasion) with stage IA2, IB, and IIA cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy were randomized to standard pelvic field RT (49.3 Gy) vs. RT + cisplatin/5-FU for 4 cycles. CRT was superior in both 4-yr OS (81% vs. 71%) and 4-yr PFS (80% vs. 63%). (Peters W et al., JCO 2000)
What subset of pts from GOG 109 did not benefit from adding chemo to adj RT?
The subset analysis of GOG 109 demonstrated that pts with tumors £2 cm and only 1 +node did not benefit from CRT compared with RT alone. (Monk B et al., Gyn Oncol 2005)
For pts with bulky (>4 cm) early-stage cervical cancer, is there an advantage to adding adj hysterectomy to definitive RT?
In GOG 71, pts with tumors >4 cm were randomized to RT alone vs. RT + adj hysterectomy. RT consisted of EBRT + brachytherapy (80 Gy to point A for the RT-alone group, and 75 Gy to point A for the surgery group). At median 9.6-yr follow-up, there was no difference in OS or severe toxicity. There was a trend to improved LR (26% vs. 14%, p = 0.08). (Keys HM et al., Gyn Oncol 2003)
An option is to give upfront CRT and assess for response at 2 mos. If residual Dz is evident, then salvage surgery can be considered. A downside to adjuvant hysterectomy is the potential for complications due to the high-dose radiation delivered to the area, including a relatively high dose to the posterior bladder wall.
For stage IB2 cervical cancer pts, what is the advantage of preop CRT compared with preop RT alone?
In GOG 123, stage IB2 cervical cancer pts were randomized to preop RT vs. CRT → adj simple hysterectomy. RT was whole pelvis (WP) + brachytherapy to a point A dose of 75 Gy. CRT added weekly cisplatin 40 mg/m2. CRT was superior in 3-yr pCR (52% vs. 41%), OS (83% vs. 74%), and pCR (52% vs. 41%). Note: Adj and immediate hysterectomy was included in this trial prior to the results of GOG 71 being available. (Keys HM, NEJM 1999)
In stage IB cervical cancer, is there a role for neoadj chemo prior to surgery?
Controversial. GOG 141 looked at stage IB2 pts randomized to radical hysterectomy with nodal dissection +/– neoadj vincristine/cisplatin × 3 cycles. The study closed early, but there was comparable LC and OS in both groups, and PORT was needed in 45%–52% of pts. (Eddy GL et al., Gyn Oncol 2007)
A phase III trial from Italy looked at neoadj chemo + surgery vs. radiation alone for stages IB2 to III patients and found superior OS and PFS in the chemo + surgery arm. Benefit was significant only for stages IB2 to IIB group (Benedetti-Panici P et al., JCO 2002)
EORTC 55994 is currently testing the question whether preop CRT is better than preop chemo alone.
In locally advanced cervical cancer, what is the OS advantage of definitive CRT over RT alone?
The benefit of CRT over RT alone in locally advanced cervical cancer was evaluated in RTOG 90-01. (Eifel P et al., JCO 2004) This study randomized stages IIB–IVA, large stages IB–IIA (>5 cm), or LN+ pts and randomized to RT to the pelvis and P-A nodes vs. pelvis RT + 3 cycles of cisplatin/5-FU. Both arms had brachytherapy with a point A dose of 85 Gy. 8-yr OS was 67% vs. 41%, benefiting the CRT.
Which chemo agents are most effective in CRT for cervical cancer?
Weekly cisplatin at 40 mg/m2 is the current standard to be given with definitive RT. GOG 120 randomized cervical cancer pts stages IIB–IVA to RT + 3 different chemo arms. RT was WP + brachytherapy (to 81 Gy at point A). Chemo was weekly cisplatin 40 mg/m2, or hydroxyurea, or cisplatin/5-FU/hydroxyurea. Cisplatin arms had better 4-yr OS (65% vs. 47%) and reduced recurrence (34%–35% vs. 54%). Toxicity was less with cisplatin alone or hydroxyurea alone. The benefit of adding 5-FU is unknown b/c of the confounding effect of hydroxyurea. (Rose P et al., NEJM 1999)
To what subset of pts is adding P-A fields to the pelvic field beneficial in the definitive Tx of cervical cancer?
There are 2 indications where the P-A field should be added to the definitive management of cervical cancer pts: (1) pts with +P-A Dz and (2) pts with +pelvic nodal Dz and not receiving CRT. 2 studies have addressed this:
RTOG 79-20 randomized 337 pts with stage IIB Dz without clinical or radiographic evidence of P-A Dz to the WP (45 Gy) alone vs. WP + P-A field (extended-field radiation therapy [EFRT]) (45 Gy). No chemo was given. Adding the P-A field improved 10-yr OS (55% vs. 44%) without improvement in LC or DM. However, there was slightly increased toxicity with the P-A field (8% vs. 4%). (Rotman M et al., JAMA 1995)
RTOG 90-01 randomized 386 pts with locally advanced cervical cancers (stages IIB–IVA or IB–IIA with ≥5 cm) or with a +pelvic LN (no P-A nodal Dz) to WP RT + chemo vs. WP + P-A field alone (EFRT). All pts were treated with post-EBRT brachytherapy of 85 Gy to point A. Chemo was cisplatin 75 mg/m2 + 5-FU 1,000 mg/day × 4 days per 21-day cycle for 3 cycles. Pelvic CRT was superior to EFRT in 8-yr OS (67% vs. 41%), DFS (61% vs. 46%), LRF (18% vs. 35%), and DM (20% vs. 35%). There was a slight increase in P-A nodal failure in the CRT arm (8% vs. 4%, p = N SS). (Morris M et al., NEJM 1999; Eifel P et al., JCO 2004)
Describe the borders of typical AP and lat fields in cervical cancer Tx.
In cervical cancer therapy, the typical borders of an AP field are sup to L4-5 or L5/S1, inf to 3 cm below the most inf vaginal involvement or inf obturator foramen, and lat 2 cm from the pelvic rim. Lat beams would have the same sup and inf extent, with the ant edge to 1 cm ant of the pubic symphysis and post edge to include the entire sacrum. For common iliac nodal involvement, extend the field to cover up to L2. For P-A nodal involvement, extend the field to the top of T12. The borders can be tailored for early-stage vs. more advanced Dz. In the CT planning era, the alternative is to contour the organs and nodes of interest to ensure adequate coverage.
What is a typical EBRT prescription for cervical cancer?
Typically, cervical cancer pts treated with EBRT rcv RT to the WP to 45 Gy in 1.8 Gy/fx. Sidewall boosts usually go to 50–54 Gy. Persistent or bulky parametrial tumors usually rcv 60 Gy. P-A nodes go to 45 Gy if treated. Bulky nodes go to 60 Gy with 3D-CRT or IMRT.
What should be the total dose to point A and point B in patients with stage IB2 or higher disease? When should Tx of inguinal nodes be considered in cervical cancer?
For most patients with stage IB2 or higher disease, point A dose should be at least 80 Gy and point B dose should be at least 55 Gy. In cervical cancer, Tx of inguinal nodes should be considered if Dz involves the lower 3rd of the vagina.
Does overall Tx time in cervical cancer impact outcome? Ideally, how long should the RT Tx take?
Yes. Prolonged overall RT Tx time in cervical cancer is associated with poorer outcomes. Ideally, EBRT and brachytherapy should be completed within 7 wks. The effect is more notable in more advanced-stage pts (stages III–IV).
TOXICITY
List 3 procedure-related complications seen in cervical cancer intracavitary brachytherapy.
Procedure-related complications seen in cervical cancer intracavitary brachytherapy:
1. Uterine perforation (<3%)
2. Vaginal laceration (<1%)
3. DVT (<1%)
Name the most common acute side effects associated with RT for cervical cancer.
Skin irritation, fatigue, hemorrhoids, colitis-diarrhea, cystitis-frequency/dysuria, and nausea are all possible acute side effects from cervical cancer RT.
Name the common long-term side effects associated with cervical cancer RT.
Common long-term side effects of cervical cancer radiation include permanent alteration in bowel habit, menopause in the premenopausal age group, chronic cystitis with frequency, and vaginal stenosis with dyspareunia and postcoital bleeding. The major severe long-term toxicities are most commonly bowel related: rectosigmoid stenosis, requiring possible colostomy, and major rectal bleeding. Hematuria, ureteral stricture, fistula, SBO, and hip fracture or sacral insufficiency fracture can also occur.
What should pts do regularly to prevent vaginal stenosis after receiving RT for cervical cancer?
Routine use of a vaginal dilator is essential to preventing vaginal stenosis in pts who have undergone RT for cervical cancer.
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