Radiation Oncology: A Question-Based Review

Cervical Cancer

Jing Zeng and Lilie Lin

image Background

What is the annual incidence of cervical cancer in the U.S.?

~11,000 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 47 yrs in the U.S.

Name 5 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.     Multiple 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 an HGSIL result from a PAP be managed?

All pts with high-grade SIL 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 progress 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 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., 70% are squamous cell carcinomas, while ~25% are adenocarcinomas.

Name 3 histologic subtypes of adenocarcinoma of the cervix.

Subtypes of adenocarcinoma of the cervix:

1.     Mucinous

2.     Endometrioid

3.     Clear cell

4.     Serous

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.

image Workup/Staging

What should be included in the workup for a pelvic mass?

Pelvic mass workup: H&P, including a careful pelvic exam in the office, basic labs, and EUA with Bx, with cystocopy and proctoscopy for any visible lesions. Studies such as CT, PET, MRI can be obtained for Tx 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.

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 allowed in FIGO staging of cervical cancer? What common imaging modalities are not allowed?

CXR and intravenous pyelogram data are allowed in FIGO staging of cervical cancer, as are procedures such as cystoscopy, proctoscopy, and hysteroscopy. CT, PET, MRI, bone scan, lymphangiography, and laparotomy/laparascopy data are not allowed to be used for staging but can be used in Tx planning.

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. There is less agreement about its utility in detecting pelvic nodal mets.

In what group of cervical cancer pts is evaluation of the urinary tract required?

Cervical cancer pts with more than microscopic Dz require imaging of the urinary tract. This can be performed with CT, MRI, or intravenous pyelogram.

What is the FIGO (2008) staging for cervical cancer?

1.     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)

2.     Stage IB: clinically visible tumor or >IA2, with IB1 ≤4 cm, and IB2 being bulky tumors >4 cm

3.     Stage IIA: invades beyond uterus but not to pelvic wall, lower 3rd of vagina, or parametrial invasion, with IIA1 lesions ≤4 cm and IIA2 lesions >4 cm

4.     Stage IIB: invades beyond uterus and into parametria but not into pelvic wall or lower 3rd of vagina

5.     Stage IIIA: invades lower 3rd of vagina but no extension into pelvic wall

6.     Stage IIIB: invades pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney

7.     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

8.     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. AJCC stage 3 includes T3N0-1, and stage 4 includes T4NX or M1 Dz.

What factors are predictive of pelvic nodal involvement in cervical cancer?

Factors that predict for nodal involvement in cervical cancer include DOI, FIGO stage, and LVSI (10% without vs. 25% with).

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:

1.     <3 mm: <1%

2.     3–5 mm: 1%–8%

3.     6–10 mm: 15%

4.     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:

1.     Stage IA1: 1%

2.     Stage IA2: 5%

3.     Stage IB: 15%

4.     Stage II: 30%

5.     Stage III: 50%

6.     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:

1.     Stage IA: 0%

2.     Stage IB: 5%–8%

3.     Stage IIA: ~10%

4.     Stage IIB: 20%–30%

5.     Stage III: 30%

6.     Stage IVA: 40%

What are the 5-yr OS rates based on the FIGO stage?

5-yr OS based on FIGO stage:

1.     Stage I: 82%

2.     Stage II: 64%

3.     Stage III: 38%

4.     Stage IV: 14%

(Benedet et al., J Epi Biostat 1998)

image Treatment/Prognosis

What is the most important prognostic factor in cervical cancer?

Tumor stage is the most important prognostic factor in cervical cancer → LN status.

What is removed in a radical trachelectomy as Tx for cervical cancer?

In a radical trachelectomy, all cervical cancer is removed with the 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 stage IA1 as well as select cases of IA2 and small IB1 Dz.

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. Sometimes conization is also adequate for IA1, but there must be DOI <3 mm and no LVSI or dysplasia at the margin (Van Nagell 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 para−metrial and paravaginal tissue to the pelvic sidewall + pelvic LND, 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 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 et al. (Cancer 1993), pts with stage I–III cervical cancer were randomized to HDR cobalt-60 or LDR cesium-137 therapy. There was no statistically significant 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%).

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 one third to one fourth the dose to point A.

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.

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 usually ~12 Gy/hr.

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 65–75 Gy for stage IA Dz, 75–85 Gy for stage IB–IIB Dz, and 85–90 Gy for stage 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 et al. (Lancet 1997), pts with stage 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 rcv adj RT. Grade 2–3 morbidity was higher in the surgery arm (28% vs. 12%).

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, and no 2nd malignancy risk.

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 negative nodal status but have ≥2 risk features (+LVSI, >4-cm tumors, more than one third stromal invasion) may benefit from PORT.

GOG 92 (Rotman et al., IJROBP 2006) 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% → 14%, p = 0.007) and trend to OS benefit by ~10% (71% → 80%, p = 0.074).

When is adding chemo to adj RT after radical hysterectomy beneficial compared to RT alone for the surgical management of early-stage cervical cancer (IA2–IIA)?

In GOG 109 (Peters et al., JCO 2000), 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%).

What subset of pts from GOG 109 did not benefit from adding chemo to adj RT?

Monk et al. (Gyn Onc 2005) subset analysis of GOG 109 demonstrated that pts with tumors ≤2 cm and only 1 + node did not benefit from CRT compared to RT alone.

For pts with bulky (>4 cm) early-stage cervical cancer, is there an advantage to adding adj hysterectomy to definitive RT?

In GOG 71 (Keys HM et al., Gyn Onc 2003), 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).

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.

For stage IB2 cervical cancer pts, what is the advantage of preop CRT compared with preop RT alone?

In GOG 123 (Keys HM, NEJM 1999), 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.

In stage IB cervical cancer, is there a role for neoadj chemo prior to surgery?

No. Currently, there is no role for neoadj chemo. GOG 141 (Eddy GL et al., Gyn Onc 2007) 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.

EORTC 55994 is currently testing the question if 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 stage IIB–IVA, large stage 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.

What 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 (Rose et al., NEJM 1999) randomized cervical cancer pts stage 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.

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 positive pelvic nodal Dz and not receiving CRT. 2 studies have addressed this:

RTOG 79-20 (Rotman et al., JAMA 1995) randomized 337 pts with 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 slight increased toxicity with the P-A field (8% vs. 4%).

RTOG 90-01 (Morris et al., NEJM 1999Eifel P et al., JCO 2004) randomized 386 pts with locally advanced cervical cancers (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 to 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 = NSS).

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, 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.

When should Tx of inguinal nodes be considered in cervical cancer?

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 (stage III–IV).

image Toxicity

For pts with early-stage cervical cancer, name 2 advantages in terms of toxicity for pts undergoing surgery instead of RT.

For early-stage cervical cancer, advantages for choosing surgery instead of RT include better preservation of ovarian function and greater possibility of a functional vagina.

Name 3 procedure-related complications seen in cervical cancer intra-cavitary brachytherapy.

Procedure-related complications seen in cervical cancer intracavitary brachytherapy:

1.     Uterine perforation (<3%)

2.     Vaginal laceration (<1%)

3.     DVT (<1%)

Name 5 acute side effects associated with RT for cervical cancer.

Pruritis, desquamation, hemorrhoids, colitis, cystitis, vaginitis/ulceration, candidiasis, and nausea are all possible acute side effects from cervical cancer RT.

Name 5 long-term side effects associated with cervical cancer RT.

Vaginal stenosis, ureteral stricture, fistulas, SBO, and femoral head fractures all are possible long-term toxicities of cervical cancer RT.

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.