Important Studies

Question 1

Surgery vs. RT

Answer 1

University of Milan, Italy “Landoni et al, Lancet, 1997
Landoni et al, J Gynecol Oncol, 2017”: Stage IB + IIA cervical cancer”→Radical hyst + LND + adjuvant RT if indicated vs. →47 Gy EBRT + LDR to 70-90 Gy (median 76)
Adjuvant EBRT to 50.4 Gy for ≥pT2b, ≤3 mm cervical stroma margin, cut-through, or N+.”

“-No difference in 5-yr OS (83%), 20-yr OS (~75%), DFS (74%), or recurrence (25%).
Median time to relapse 13.5 vs. 11.5 mos (p=0.10)

Surgery and RT have similar efficacy. RT seems preferable for larger tumors and surgery seems preferable for adenocarcinoma. Tumor diameter, histology, age, and comorbidities should be considered.

Question 2

Adjuvant hysterectomy after RT in bulky

Answer 2

GOG 71; Keys et al, Gynecol Oncol, 2003. Bulky IB disease (tumor or cervix ≥4cm) Cervix SCC Stage IB2, IIA, IIB. “→40 Gy EBRT + 40 Gy LDR
vs. →45 Gy EBRT + 30 Gy LDR + extrafascial hysterectomy”

There was no overall benefit to hysterectomy after definitive RT. On subanalysis hysterectomy seemed to be favored in larger tumors of size 4-6 cm.

Question 3

Induction chemo

Answer 3

Tata Memorial Centre, Mumbai: Gupta et al, JCO, 2018. Cervix SCC Stage IB2, IIA, IIB”→neoadjuvant carbo/taxol, radical hysterectomy, & post-op RT or chemo as indicated vs. →definitive RT + cisplatin”

“No change in OS. Worse DFS with neoadjuvant
5-yr DFS 69% neoadjuvant vs. 78%
5-yr OS 75% both arms
delayed toxicity: rectal 2.2% vs. 3.5%, bladder 1.6% vs. 3.5%, vaginal 12.0% vs. 26%”

Induction chemotherapy prior to hysterectomy provided no benefit compared to definitive chemoRT; DFS was worsened.

Question 4

Definitive CRT

Answer 4

University of Liverpool, Liverpool, UK: Green et al, Lancet, 2001”Meta-analysis of 19 trials.
→RT alone vs. →RT with concurrent chemo”

“PFS and OS improved with chemo
PFS 47% RT vs. 63% chemoRT
OS 40% vs. 52%, greatest in IB-IIB
No increase in late toxicity with RT”

GOG 85/SWOG 8695: Whitney et al, JCO, 1999
GOG 120: Rose et al, NEJM, 1999
NCIC: Pearcey et al, JCO, 2002

Question 5

Definitive CRT: EFRT vs. WPRT/chemo

Answer 5

RTOG 9001: Eifel et al, JCO, 2004. Stage IIB-IVA, or IB-IIA with tumor ≥ 5cm or + pelvic LN"→45 Gy EFRT + LDR to 85 Gy vs.  →WPRT + LDR to 85 Gy + cisplatin/5-FU".
"8-yr OS 41% vs. 67%
DFS 46% vs. 61%
LRF 35% vs. 18%
DM 35% vs. 20%
Late effects unchanged."

The addition of chemotherapy to definitive RT improves OS, LR, and DM.

Question 6

EFRT vs. pelvic RT

Answer 6

Brazil: Sapienza et al, Gynecol Oncol, 2016. Meta-analysis to evaluate EFRT. 4 studies (RTOG 7920, EORTC, Osaka University, Chang Gung University).
EFRT reduces PA failure and DM. CSM was unchanged.

RTOG 7920: Rotman et al, JAMA, 1995: EFRT has improved OS over WPRT with less DM and salvage. DFS and LRF are unchanged.

EORTC: Haei et al, Radiother Oncol, 1988: EFRT does not improve LC, DFS, or DM. There was decreased PA failure.

Question 7

Adjuvant “outback” chemo after definitive RT

Answer 7

NCI México. Duenas-Gonzales et al, JCO, 2011. Stage IIB-IVA”→EBRT 50.4 Gy + brachy 30-35 Gy with weekly cisplatin vs. →Same RT + concurrent cis/gem + ““outback”” cis/gem”. “Improved PFS with chemo

3-yr PFS 74% chemo vs. 65%
worse grade 3/4 toxicity: 87% vs. 46%
More hospitalizations 30% vs. 11%”

Concurrent cis/gem with “outback” cis/gem improved PFS compared to standard definitive RT, but toxicity was markedly increased.

Question 8

Future Adjuvant “outback” chemo after definitive RT

Answer 8

GOG 274/ANZGOG 0902/RTOG 1174 (ongoing): cervical cancer patients treated with definitive RT”WPRT+brachy with cisplatin→ →adjuvant carbo/paclitaxel vs. none”

GOG 274 will investigate further, removing gemcitabine as a component, which may contribute to the toxicity in this trial.

Question 9

Adjuvant RT after surgery

Answer 9

“Sedlis trial” GOG 92: “Sedlis et al, Gynecol Oncol, 1999, Rotman et al, IJROBP, 2006”
Stage IB, N0 s/p radical hysterectomy. Simplified criteria: at least two of >1/3 stromal invasion, LVI, ≥4cm tumor (see paper for more detailed criteria)”→WPRT 46 Gy or 50.4 Gy vs. →obs
Primary endpoint: PFS
Not powered for OS”

“10-yr LR 14% vs. 21%
10-yr PFS 78% vs. 65%
10-yr OS 80% vs. 71%, p=0.07

Update:
recurrence 8.8% (adenocarcinoma or adenosquamous) vs. 44% in obs”

Adjuvant RT improves PFS and LR in int risk IB cervical cancer.

Question 10

Adjuvant chemoRT after surgery

Answer 10

“Peters trial” GOG 109/SWOG 8797/RTOG 9112/INT 0107: Peters et al, JCO, 2000.
IA2, IB, IIA and LN+, +margin or +parametria s/p radical hysterectomy
“WPRT 49.3 Gy/ 29 fx vs. WPRT + concurrent cis/5-FU and 2x adjuvant cis/5FU”

“4-yr OS 81% vs. 71%
4-yr PFS 80% vs. 63%

“Adjuvant cisplatin improves OS and PFS in resected cervical cancer with + nodes, margin, or parametrial involvement.

Question 11

Future Further chemo after adjuvant CRT

Answer 11

RTOG 0724 (ongoing): Cervix cancer stage IA2, IB or IIA squamouss/p radical hysterectom with positive nodes, positive parametrium, positive paraaortic nodes (completely resected and PET negative after surgery)

“45-50.4 Gy + cisplatin → additional carbo/paclitaxel vs. none
VC brachy allowed”

Question 12

Nomograms for outcomes

Answer 12

Rose et al, JCO, 2015: locally advanced cervix cancer enrolled into GOG trials treated with definitive chemoRT

Question 13

PET positive nodes outcome

Answer 13

Washington University: Kidd et al, JCO, 2010. Retrospective
“-Periaortic nodes long term 4-5-yr DSS of ~20-40% (see figure)
-SCV nodes long term 4-5-yr DSS of ~10-35% (see figure)
-(Refer to paper for RFS and DSS plots for pelvic, periaortic, and SCV nodes per FIGO stage [Kaplan-Meier and HRs provided, not absolute values])

Risk of pelvic and PA nodes on PET:
Stage I: 9-51% and 0-9%
Stage IIA: 50%, 21%
Stage IIB: 54%, 17%
Stage IIIA 50%, 25%
Stage IIIB/IV 55-85%, 13-38%

Frequency of lymph node metastases was similar to historic surgical series”

Question 14

MRI guided planning

Answer 14

EMBRACE: "Mazeron et al, Radiother Oncol, 2016
Sturdza et al, Radiother Oncol, 2016
Tanderup et al, Radiother Oncol, 2016
Kirchheiner et al, Radiother Oncol, 2016
Fokdol et al, Radiother Oncol, 2016
Li-Tee et al, IJROBP, 2019
Serban et al, IJROBP, 2020"

Locally advanced cervical cancer. “Prospective multi-institutional study of MRI image guided BT to the HRCTV. Records practice patterns, characteristics, dose to tumor and OARs, toxicity. Additional retrospective exploratory analysis of this data (RetroEMBRACE) “

“Suggested dose constraints
D2cc <69.5 Gy had <10% grade 2+ toxicity
D2cc ≥75 Gy had 12.5% risk of fistula vs. 0%
D2cc <65 Gy had 2x less proctitis
Correlations also found with D0.1cc

Rectovaginal point <65 Gy EQD2
(20% have stenosis with 65 Gy, 27% with 75 Gy, and 34% with 85 Gy)

• Intersitial BT has better LC in size ≥30 cc
• Tandem and ring provides better coverage than T&O
• 5 Gy is required to compensate for each 1 week break
• IGBT had less pelvic failures compared to historical controls. IGBT failure is mainly systemic

5-yr LC 98% Stage IB, 91% IIB, 75% IIIB
overall 3-yr OS 74%, 5-yr OS 65%”

Question 15

3D planning for definitive cervix

Answer 15

French STIC. Charra-Brunaud et al, Radiother Oncol, 2012. IB-IIIB. Prospective. Brachy planning with CT vs. point A
“OS 74% with CT planning vs 65% with point A
Grade 3/4 toxicity 23% vs 3%”

Question 16

IMRT bone marrow sparing

Answer 16

INTERTECC-2: Mell et al, IJROBP, 2017. Stage IB-IVA cervical cancer. “Phase II.
IMRT to 45-50.4 Gy + weekly cisplatin x6. VC brachy as indicated.
Primary endpoint: grade ≥3 neutropenia or clinically significant GI toxicity”

• Incidence of any primary event 26.5% vs 40% expected by historical data
• Grade ≥3 neutropenia 19.3%
• Clinical significant GI toxicity 12.0%
• Daily IGRT vs no IGRT grade ≥3 neutropenia 8.6% vs 27.1%
• grade ≥3 leukopenia 25.7% with IG vs 41.7% without IGRT
• Any grade ≥3 hematologic 31.4% with IG vs 43.8% without”

IMRT with definitive chemoRT reduces acute heme and GI toxicity compared to 3DCRT historical control. IGRT reduces neutropenia.