Treatment/Prognosis

Question 1

What is the most important prognostic factor in cervical cancer?

Answer 1

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.

Question 2

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

Answer 2

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 (performed at select centers) 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.

Question 3

How should pts with preinvasive cervical cancer (HGSIL or CIN III) be managed?

Answer 3

Pts with preinvasive cervical cancer should be managed with colposcopy → conization, LEEP, laser, cryotherapy, or simple hysterectomy.

Question 4

In which subset of cervical cancer pts is simple hysterectomy adequate as definitive management?

Answer 4

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.

Question 5

What is the difference b/t a class I–III radical hysterectomy (Piver–Rutledge–Smith classification)?

Answer 5

In a class I (aka: total abdominal, simple, or extrafascial hysterectomy), the uterus is removed with little or no removal of vaginal tissue, cardinal ligament, or uterosacral ligament. In a class II (modified radical hysterectomy) 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 Sg (radical hysterectomy), 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.

Question 6

What stage of cervical cancer can be treated with brachytherapy alone?

Answer 6

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)

Question 7

When treating cervical cancer pts with brachytherapy, is there a Dz control or toxicity difference b/t LDR and HDR?

Answer 7

This is uncertain. In Teshima T et al. pts with stages I–III cervical cancer were randomized to HDR Co-60 or LDR cesium-137 therapy. There was no SS difference in 5-yr CSS b/t 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)

Question 8

Where are points A and B, and what should it correspond to anatomically?

Answer 8

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.

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 a tandem and ovoid system.

Question 9

Before CT-based planning, how were the bladder, rectum, and vaginal points defined for cervical cancer brachytherapy?

Answer 9

Before CT-based planning, the bladder point was the post surface of the Foley balloon at midplane of ovoids 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 b/t 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.

Question 10

What are the dose limits to the bladder, rectum, and vaginal points in cervical cancer brachytherapy for 2D and 3D planning?

Answer 10

In cervical cancer brachytherapy, 2D International Commission on Radiation Units (ICRU) doses are max point doses. Typically in 2D planning the max allowed dose to the rectal point dose is <72 Gy, the max bladder point dose is <80 Gy, and the max vaginal point dose is <120 Gy.

With 3D planning, limits are volume based and quantified as D2cc which is defined as the min dose within the 2-cc volume of greatest dose. The bladder limit is D2cc <90 Gy equivalent 2 Gy dose (EQD2), rectum and sigmoid limit is D2cc <75 Gy EQD2. (Viswanathan A et al., Brachy 2012)

Question 11

What RT dose can cause ovarian failure? What about sterility?

Answer 11

Ovarian failure can occur with 5–10 Gy of RT. Sterility can occur after 2–3 Gy.

Question 12

What are the typical LDR and HDR in cervical cancer Tx?

Answer 12

In cervical cancer brachytherapy, LDR range is 40–200 cGy/hr, while HDR is much higher >12 Gy/hr. Typically, 1 HDR Tx of 5.5–6.0 Gy takes appx 5–10 min to deliver.

Question 13

What is the role for definitive Sg vs. definitive RT for the management of early stage (IB–IIA) cervical cancers? What study tested these 2 modalities?

Answer 13

In Landoni F et al. pts with stages IB and IIA cervical carcinoma were randomized to Sg (class III) vs. RT (without chemo) for definitive therapy. Adj RT was allowed for the Sg group based on preset criteria. 5-yr OS and DFS were equal (83% and 74%, respectively, for both groups). 64% of Sg pts rcvd adj RT. Grades 2–3 morbidity was higher in the Sg arm (28% vs. 12%). Pts with adenocarcinoma of the cervix were found to have a survival benefit with hysterectomy. (Lancet 1997)

Question 14

What are the benefits of Sg over RT for the Tx of early-stage cervical cancers?

Answer 14

Benefits of Sg 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 pts to understand. Sg can also better identify the accurate anatomic extent of Dz.

Question 15

What adverse features after Sg are indications for adj RT alone without chemo?

Answer 15

Pts with cervical cancer s/p hysterectomy with –margins and –nodal status but have ≥2 risk features (+LVSI, >4-cm tumors, more than one-third stromal invasion) benefit from adj RT.

The Gynecologic Oncology Group’s study GOG 92 enrolled 277 stage IB cervical cancer pts who underwent Sg 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)

Question 16

What adverse features after Sg are indications for adj chemo–RT?

Answer 16

In GOG 109, high-risk pts (with at least 1 of the following features: +margin, +nodes, or microscopic parametrial invasion) with initially staged 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 sup in both 4-yr OS (81% vs. 71%) and 4-yr PFS (80% vs. 63%). (Peters W et al., JCO 2000)

Question 17

What subset of pts from GOG 109 can be managed with adj RT alone?

Answer 17

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)

Question 18

What trial is currently evaluating adj RT vs. CRT after hysterectomy and LND in pts with intermediate-risk stage I–IIA cervical cancer?

Answer 18

GOG 263 compares adj RT vs. CRT in intermediate-risk pts s/p hysterectomy defined as:

LVSI and deep 3rd cervical stromal invasion
LVSI and middle 3rd invasion and tumor ≥2 cm
LVSI and superficial 3rd invasion and tumor ≥5 cm or
No LVSI with middle or deep 3rd invasion and tumor ≥4 cm.

Question 19

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

Answer 19

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 Sg group). At median 9.6-yr f/u, 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 treat with CRT and assess for response at 2 mos. If residual Dz is evident, then salvage Sg can be considered. A downside to adj hysterectomy is the potential for complications d/t the high-dose radiation delivered to the area, including a relatively high dose to the post bladder wall.

Question 20

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

Answer 20

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 sup 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)

Question 21

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

Answer 21

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 + Sg vs. RT alone for stages IB2 to III pts and found sup OS and PFS in the chemo + Sg arm. Benefit was significant only for stages IB2 to IIB group. (Benedetti-Panici P et al., JCO 2002)

EORTC 55994 closed prematurely as interim analysis revealed inf OS in the with neoadj chemo arm compared to Sg without chemo. (Katsumata Br J, Cancer 2013)

Question 22

In locally advanced cervical cancer, what is the OS advantage of definitive CRT over RT alone?

Answer 22

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. 5 RCT’s show OS benefit with addition of chemo. (NCI press office, 1999)

Question 23

Which chemo agent is most commonly used during CRT for cervical cancer?

Answer 23

Weekly cisplatin at 40 mg/m2 is the current standard to be given with definitive RT. RTOG 90-01 also utilized cisplatin, but at a dose of 75 mg/m2 q3wks.

Question 24

To what subset of pts is adding P-A fields to the pelvic field beneficial in the definitive Tx of cervical cancer?

Answer 24

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 (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 sup 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). (Morris M et al., NEJM 1999; Eifel P et al., JCO 2004)

Question 25

Describe the borders of typical AP and lat fields in cervical cancer Tx.

Answer 25

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 with coverage of entire uterus 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 with ∼70% AP/PA 30% lat field weighting if using 3D. 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.

Question 26

Is there benefit in using IMRT to treat intact cervical cancer?

Answer 26

Potentially; a single arm study (Intertecc-2 trial) revealed IMRT reduced acute hematologic and GI toxicity compared to historical 3D outcomes. (Mell L et al., IJROBP 2016)

Question 27

What is a typical EBRT Rx for cervical cancer?

Answer 27

Typically, cervical cancer pts treated with EBRT rcv RT to the WP to 45 Gy in 1.8 Gy/fx. Sidewall boosts to 50–54 Gy. Persistent or bulky parametrial tumors usually rcv 60 Gy. P-A nodes to 45 Gy if treated electively and sequential boost to 54–65 Gy if positive with 3D-CRT or IMRT.

Question 28

What should be the total Rx dose to the high-risk (HR) CTV for cervical cancer (sum of EBRT + brachytherapy)? Who needs a sidewall boost?

Answer 28

In cervical cancer radiotherapy, the planning aim for the cumulative EQD2 to the HR-CTV (defined as the GTV + the entire cervix + presumed extracervical tumor extension) D90 >85 Gy. T2 MRI after EB can be used to identify residual GTV (EMBRACE study). Pts with residual side wall or parametrial Dz after EB should rcv a boost in the form of EB or interstitial brachytherapy.

Question 29

Is SBRT boost for cervical cancer equivalent to brachytherapy?

Answer 29

The use of SBRT or other EB modalities has not proven to be sup or equivalent to brachytherapy. The use of brachytherapy should be utilized to achieve an EQD2 dose of D90 >80 Gy as it has a greater OS vs. SBRT/IMRT boost. (Gill et al., IJROBP 2014) Further, image-guided brachytherapy improves OS and reduces grade 3–4 toxicity vs. standard brachy in prospective STIC trial. (Charra-Brunaud et al., Radiother Oncol 2012)

Question 30

Does overall Tx time in cervical cancer impact outcome? Ideally, how long should the RT Tx take?

Answer 30

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).

Question 31

Per GOG 240, the addition of what agent improves outcomes for pts with recurrent, persistent, or metastatic cervical cancer?

Answer 31

Addition of bevacizumab to either topotecan-paclitaxel or cisplatin-paclitaxel resulted in an OS benefit extending MS from 13.3 mos to 17 mos. (Tewari KS et al., Lancet 2017)