Studies

Question 1

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? Landoni et al 1997

Answer 1

• 343 patients 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)

Question 2

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

Answer 2

Benefits of surgery over RT include

1. shorter Tx time,
2. preservation of ovarian function,
3. possibly better sexual functioning after Tx,
4. no 2nd malignancy risk,
5. avoidance of long-term RT sequelae, and
6. psychologically easier for many patients to understand.
7. Surgery can also better identify the accurate anatomic extent of disease.

Question 3

For pts with early-stage cervical cancer treated with radical or modified radical hysterectomy, what are 3 major indications for adj therapy?

Answer 3

• For pts with early-stage cervical cancer treated with radical or modified radical hysterectomy, major indications for adj therapy include

Radiation:

1. Tumor >4cm
2. Deep stromal invasion
3. LVI

CRT

1. Peters
2. Postop
3. Positive margin/close margin
4. Positive Pelvic lymph nodes
5. Parametrial invasion

Question 4

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

Describe GOG 92 (Sedlis

Rotman M et al., IJROBP 2006)

Answer 4

• Cervical cancer pts after radical hysterectomy to –margins and –nodal status no parametrial involvement but have ≥ 2 risk features
• ( Sedlis criteria: + LVSI, > 4-cm tumors, more than one-third stromal invasion) may benefit from PORT.

GOG 92

• 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)

Question 5

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)?

GOG 109 Peters W et al. JCO 2000

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

Answer 5

GOG 109

• 243 patients stage IA2, IB, and IIA cervical cancer
• high-risk pts (with at least 1 of the following features: + margin, + nodes, or microscopic parametrial invasion)
• s/p radical hysterectomy and pelvic lymphadenectomy
• Randomized 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)

Subset analysis of GOG 109 (Monk B et al. Gyn Onc 2005)

• pts with tumors < 2 cm and only 1 + node did not benefit from CRT compared with RT alone.
• 1 LN is positive (79% versus 83% OS at 5 years) or if tumor was ≤2 cm (77% versus 82%).

Question 6

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

GOG 71

Answer 6

• GOG 71
• 282 patients with 1B2 tumors >4cm
• randomized to RT vs. RT + adjuvant Hysterectomy
• RT EBRT + Brachy (80 to Point A RT alone vs. 75 Gy surgery)
• 9.6 yrs no difference in OS or severe toxicity
• Trend towards 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. 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.

Question 7

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

GOG 123 (Keys et al. NJEM 1999)

Answer 7

• GOG 123
• 1B2 cervical cancer randomized to preop RT vs. Preop CRT (cis 40mg/m2)–> adj hyst
• RT whole pelvis + Brachy point a 75 Gy
• CRT superior 3yr pCR (52 vs. 41%), OS 83 vs. 74%
• Note: Adj and immediate hysterectomy was included in this trial prior to the results of GOG 71 being available. Edition.

Question 8

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

Answer 8

• 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.

Question 9

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

RTOG 90-01. (Eifel P et al., JCO 2004)

Answer 9

• RTOG 90-01
• 386 patients
• Locally advanced cervical CA:
  
  • Stages IIB– IVA, large stages IB– IIA (> 5 cm), or LN + pts
  • NO PA NODAL DISEASE
• Randomized to RT to the pelvis and P-A nodes vs. pelvis RT NO PA NODAL DISEASE + 3 cycles of cisplatin (75mg/m2) 5 FU (1000mg/mgd x 4 days per 21 cycle).
• Both arms had brachytherapy with a point A dose of 85 Gy.
• 8-yr OS was 67% vs. 41%, benefiting the CRT, DFS 61 vs. 46, LFR 18 vs 35, DM 20 vs. 35
• Slight increase in PA nodal failure in CRT arm (8 % vs. 4% NS)

Question 10

Which chemo agents are most effective in CRT for cervical cancer?

GOG 120 (Rose P et al., NEJM 1999)

Answer 10

• Weekly Cisplatin 40mg/m2 standard
• GOG 120
  
  • IIB-IV A to RT +3 different chemo arms
  • RT was WP + Brachy 81Gy to point A
  • Chemo: Cisplatin 40mg/m2, hydroxyurea, or cisplatin/5FU/hydroxyurea
  • Cisplatin had better 4 yr OS (65 vs. 47%) and reduced recurrence (34-35% vs. 54%)
  • Toxicity was less with cisplatin alone or hydroxyurea alone
  • Benefit of 5FU unknown due to confounding effect of hydroxyurea

Question 11

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

Specifically regarding RTOG 79-20 and RTOG 90-01?

Answer 11

1. +PA nodal disease
2. • pelvic nodal disease but NO Chemoradiation (see RTOG 90-01) failure was 8 vs. 4% in CRT arm non significant

• RTOG 79-20
  
  • 337 pts with Stage IIB disease w/o evidence of clinical or xray evidence of PA disease
  • Randomized to 45 Gy WP vs. WP + PA field (EFRT)
  • NO CHEMO
  • improved 10 yr OS 55 vs. 44%
  • no improvement in LC or DM
  • slightly increased toxicity in PA field 8% vs. 4%