Describe the design and of PORTEC-1 (Post Operative Radiation Therapy in Endometrial Carcinoma).(Creutzberg CL et al., Lancet 2000; Scholten AN et al., IJROBP 2005)
- 714 pts
- Stage 1 (G1 and 1B, G2, and G3 and 1A)
- No 1B G3!
- All Histologies
- TAH/ BSO with washings with NO LND!
- High Int risk (Age >60, G3, invasion >50% 2/3 except for G3 with invasion, high risk PORTEC3)
- adj EBRT (46 Gy/23) NO BRACHY vs. observation.
- EBRT reduced LRR from
- 15.5% vs. 5.8% at 15 years
- 14% vs. 5% at 10 years
- 75% of LRs were in the vaginal vault.
- There was no difference in 10-yr OS. (85%)
- HIR has worse survival (75% vs. 50% 15 yr OS)
- Note that with central pathology review, there was a significant shift from grade 2 to grade 1.
Pelvic and P-A lymphadenectomy is recommended in which pts with endometrial cancer? Describe The ASTEC (A Study in the Treatment of Endometrial Carcinoma) trial? (ASTEC Study Group et al., Lancet 2009)
- Although controversial, LNs are commonly assessed at the time of initial surgery for endometrial cancer.
- Pelvic lymphadenectomy may not be indicated in women with Dz clinically confined to the uterus.
- N= 1,408 pts with endometrial cancer that was clinically confined to the uterus (Stage 1) to standard surgery (TAH + BSO, peritoneal washing, palpation of P-A nodes) vs. standard surgery + pelvic lymphadenectomy.
- Only HIGH risk (1B or G3) for recurrence (independent of nodal status) were further randomized to rcv pelvic RT or not.
- ~50% recieved Brachytherapy in EACH GROUP! (4Gy x 2 @ 0.5cm or LDR 15 Gy)
- 905 randomized
- Treatment compliance of EBRT 45 Gy/25 Fractions was low 82%
- nodes in low risk was 2% (2/255) vs. High-Int risk (21/244 (9%)
- Isolated pelvic or vaginal recurrence 3% difference in 5 year cumulative incidence rate (4% in EBRT to 7% in no EBRT) HR=0.53, 95% CI=0.29-0.97, p=0.038
- With adjustment for baseline characteristics and pathology details, there was no benefit to pelvic lymphadenectomy in terms of OS or RFS.
- LND toxicity: 12% none vs. 17%
- No difference in OS and DFS in Brachytherapy vs. none
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Describe the design and results of GOG 99. (Keys HM et al., Gyn Oncol 2004)
- n=392
- 1B-II s/p TAH/ BSO, +pelvic and P-A LN sampling, and peritoneal cytology
- PAP-serous/Clear cell exclusded
- Randomized to obs vs. WP RT (50.4 Gy)
- grade 2 or 3, LVI, outer one-third myometrial invasion,
- Revised to enroll only HIR: (1) age > 70 yrs with 1 risk factor (2) age > 50 yrs with 2 risk factors, and (3) any age with 3 risk factors.
- Primary end point DFS, not powered for OS
- RT improved 2 yr LR from 12% to 3%.
- The greatest benefit in LR was in HIR from 26% to 6% vs. low int risk pts from 6% to 2%.
- CIR @ 24 mos of isolated local (Vag/pelvic ) 1.6 vs. 7.4%
- There was no change in 5 yr OS, 88 vs. 74% in HIR,
- LIR 92-94%
- 5 yr LRR HIR 27% vs. 13% (HR .42)
- HIR 33% of pts 67% of recurrences
- 4 yr OS 86% NAT vs. 92% RT (NS)
- HIgher GU, GI, cutaenous, and heme side effects
- Conclusion: Limit pelvic RT to high-intermediate– risk pts.
- The major flaw of this study is that grade 2 was grouped with grade 3 even though grade 2 Dz tends to behave more similarly to grade 1.
Describe the design and results of the Aalders Norwegian study.(Aalders J et al., Ob Gyn 1980)
- 540 pts with surgical stage I rs/ p TAH/ BSO (NO LND).
- ALL GOT vaginal cuff brachytherapy (~ 40 Gy LDR at 0.5 cm or ~ 24 Gy HDR at 0.5 cm).
- Randomized to no further therapy vs. pelvic RT (40 Gy with central shielding after 20 Gy).
- Overall, the pelvic RT arm had decreased 9-yr LR (7% to 2%) but more DM (5% vs. 10%).
- There was no difference in 9-yr OS. (5yr OS ~90%)
- LVSI evaluated in last 151 patients seen in 20%
- LRR 21% in no tx vs. 0% in RT group
- On subset analysis:
- 1B and G3, pelvic RT improved 9-yr OS (72% to 82%) and improved 9-yr LR (20% to 5%) which is probably why its better.
- There was no change in DM.
- No difference in OS, LR, or DM for pts with
- LRR:Vaginal/Pelvic Grade 1-2 1B 1A G1 ~3%, 1AG3 ~4%, 1B G1-2 ~9.5%,
- Conclusions: 1BG3: Pelvic RT, LVSI, Pelvic RT, other patients just VBT
Describe the design and results of PORTEC-2.(Nout RA et al., Lancet 2010)
427 pts
HIR definition
- Age > 60 yrs + 1A G3l (old 1B G3)
- Age > 60, 1B G1-2
- stage 2A disease, any age (apart from grade 3 with greater than 50% myometrial invasion).
All pts were s/ p TAH/ BSO without pelvic LND and were randomized to EBRT (46 Gy) vs. vaginal brachytherapy alone (HDR 21 Gy in 3 fx or LDR 30 Gy).
- At median follow-up at 3.8 yrs, vaginal brachytherapy was similar to EBRT with respect to 5-yr outcomes: vaginal relapse (1.8% vs. 1.6%), isolated pelvic relapse (3.8% vs. 0.5% SS), LRR (5.1% vs. 2.1%), or OS (85% vs. 80%).
- However, there were significantly higher rates of acute grades 1– 2 GI toxicity in the EBRT group. RT VBT 13% vs EBRT 54%
- The authors concluded that vaginal brachytherapy should be standard in intermediate-high– risk endometrial cancer.
Describe results from Cochrane Metaanalysis PMID 17803718
5 randomized trials.
- Low-risk disease (IA, IBG1-2): EBRT worsens survival (OR for death without RT 0.71, SS)
- Intermediate-risk disease (IBG3, ICG1-2): EBRT doesn’t alter survival (OR 0.97, NS)
- High-risk disease (ICG3): EBRT offers DFS benefit (OR 1.76, SS), and benefits 1/10 women
- Conclusion: Adjuvant EBRT should not be used for IA, IB, or IC G1-2 disease. There is a 10% survival advantage for IC G3 patients
Describe Study and design of PORTEC 4
- HIR endometrial Carcinoma
- VBT (3x 7 Gy at 5mm vs. 3X5 Gy at 5mm vs. No treatment)
- Inclusion Criteria Endometrioid endometrial CA, FIGO I, with one of the following combinations of substage, age, and grade:
- a. Stage IA, any age, grade 3 NO (LVSI)
- b. Stage IB, age 60 years or older and grade 1 or 2 c. Stage IB, any age, grade 1 or 2 with documented LVSI
SEER; 2012 (UNC) (1988-2006) PMID 21640502 – “The influence of radiation modality and lymph node dissection on survival in early-stage endometrial cancer.” (Chino JP, Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1872-9.)
- 56,360 pts with Stage IA or IB (using FIGO 2009 staging), negative lymph nodes if sampled.
- 70% were low risk, 26% intermediate, and 3% high.
- 42% underwent lymph node dissection. 17% had RT: 9.4% WPRT alone, 4.6% VB alone, and a combination in 3.7%.
- RT was used less frequently over the later years of the study, decreasing from 25% in 1988 to 16% in 2006. (The drop was from a decrease in the use of WPRT. The use of VB alone and combination EBRT+VB remained stable.) The use of LND increased: 16.2% to 59.5%.
- In low-risk disease, LND was associated with higher survival; RT was not. In intermediate-risk, both LND and RT were associated with higher survival; there were no differences between RT modalities. In high risk, both LND and RT were associated with increased survival; VB alone was inferior to WPRT if LND was not performed.
- Conclusion: “Both WPRT and VB alone are associated with increased survival in the intermediate-risk group. In the high-risk group, in the absence of LND, only WPRT is associated with increased survival. LND was also associated with increased survival.”
- The high-risk group was defined as including those with both G3 and IB disease—corresponding to those determined to be high risk in the PORTEC group. The intermediate-risk group was defined using GOG 99 criteria for “high-intermediate risk”: (1) Grade 2–3 disease or IB disease if ≥70 years of age, or (2) Grade 2 and IB disease if ≥50 years of age. All those not meeting the above criteria were defined as low risk.
SEER 2006 “Frequency and effect of adjuvant radiation therapy among women with stage I endometrial adenocarcinoma.” (Lee CM, JAMA. 2006 Jan 25;295(4):389-97.)
- Population-based. 21,249 patients with Stage IA-IC on TAH/BSO and pathologic staging, N0 endometrial adenocarcinoma. Adjuvant RT in 19% (62% EBRT, 18% BT, 26% EBRT+BT). Median F/U 3.8 years
- Outcome: 4-year OS 86% (3% dead due to endometrial CA, 10% dead due to other causes)
- Adjuvant RT improved OS in Stage IC G1 (SS) and IC G3-4 (SS)
- Conclusion: Statistically significant improvement in survival in Stage IC disease
Describe the design and results of GOG 122.(Randall ME et al., JCO 2006)
- 388 pts with endometrial tumors invading beyond the uterus (all histologies) underwent TAH/ BSO and surgical staging with
- P-A LNs were allowed, but mets to the chest or supraclavicular nodes were not allowed. 25% Stage IV
- Pts were randomized to whole abdomen irradiation (30 Gy AP/ PA + 15 Gy boost to pelvic +/– P-A LNs) vs. chemo (doxorubicin/ cisplatin q3wks × 8 cycles).
- At 5 yrs, chemo had improved stage-adjusted OS (55% vs. 42%) and PFS (38% vs. 50%). Chemo had increased grades 3– 4 heme toxicity (88% vs. 14%) and increased GI, cardiac, and neurologic toxicity. Note: Results were questioned b/ c although this was a randomized trial, the analysis was based on stage-adjusted results that may not be justified.
RTOG 9708 (Greven et al. Gyn Onc 2006)
- Phase II N=46
- IC G2-3, Stage II-III Pelvic confined only)
- Concurrent Cisplatin 50mg/m2 d 1,28 with RT followed by adjuvant cisplatin 50mg/m2 + paclitael 175mg/m2 4 cycles
- 4 yr LRR 4%, distant 19%
- 4 yr DFS 81%, OS 85% (Stage III 77, 72% resectively)
- NO RECURRENCES in stage 1C, IIA, IIB
- RTOG 9901 was Phase III closed due to lack of accural
- s/p TAH- BSO +/- Nodal surgery
Describe the design and results of the Nordic Society of Gynaecological Oncology (NSGO) 9501-EORTC 55991 trial that evaluated adj RT ± chemo in high-risk endometrial cancer. MaNGO ILIADE-III
The NSGO-EORTC trial
- 383 accrued endometrial cancer pts
- Stages I– II, positive peritoneal fluid cytology or positive pelvic LNs. Most had ≥ 2 risk factors: grade 3, deep myometrial invasion, or DNA nondiploidy. Pts with serous, clear cell, or anaplastic carcinomas were eligible regardless of risk factors.
- Pts were randomized to adjuvant RT (45/25 PA field as needed to L1/L2, VBT if cervical stomal involvement) vs. sequential RT + chemo ( Doxorubicin 60mg/m2 and cisplatin 50mg /m2 q3w x 3 cycles various regimens allowed). RT was pelvic EBRT (44 Gy) +/– vaginal brachytherapy.
- Primary end point PFS
- HR 0.63 PFS (79 RTCT vs 72% RT) at 5 years OS (82% vs. 75% HR 0.7 p =0.07) CSS 0.55 (p=0.01)
- no benefit for clear cell, pap serous
- signifcant for endometroid
Describe the design and results of the Japanese GOG (JGOG) 2033.(Susumu N et al., Gyn Oncol 2007)
- 385 pts with more than one-half myometrial invasion, including pts with stages II– III Dz.
- All were s/ p TAH/ BSO and surgical staging
- 40– 50 Gy EBRT AP/ PA vs. ≥ 3 cycles of chemo (cyclophosphamide/ doxorubicin/ cisplatin).
- At 5 yrs, there was no difference in PFS, OS, or toxicity.
- An unplanned subset analysis defined high-intermediate risk:
- Stage I and age > 70 yrs or grade 3 Dz
- Stage II or + cytology
- In this subset, chemo improved PFS (83.8% vs. 66.2%).
- The authors concluded that adj chemo is a reasonable alternative to RT in intermediate-risk endometrial cancer.
Describe the design and results of the Finnish randomized trial comparing adj EBRT vs. interdigitated CRT in endometrial cancer.
The Finland trial included 156 endometrial cancer pts with (1) less than one-half myometrial invasion and grade 3 or (2) one-half or more myometrial invasion or extrauterine extension up to stage IIIA and any grade.All were s/ p TAH/ BSO (with pelvic LAD in 80%) and randomized to split-course pelvic EBRT (28 Gy × 2 with a 3-wk break) vs. interdigitated CRT (28 Gy → chemo → 28 Gy → chemo, where chemo used was cisplatin/ epirubicin/ cyclophosphamide). There was no difference in 5-yr DFS, LR, or DM. Note the atypical Tx paradigms including split-course therapy. (Kuoppala T et al., Gyn Oncol 2008)
Describe the design and results of GOG 94— the study of UPSC and CCC.
GOG 94 was a phase I– II trial enrolling 21 pts with UPSC or CCC of the uterus s/ p TAH/ BSO, pelvic/ P-A nodal sampling, and peritoneal washing. Pts were treated with whole abdomen irradiation (30 Gy/ 20 fx) and pelvic boost (19.8 Gy/ 11 fx). At 5 yrs, > 50% failures were within the RT field, and 5-yr PFS was 38% for UPSC and 54% for CCC. The authors concluded that chemo likely is necessary for these radioresistant histologies. (Sutton G et al., Gyn Oncol 2006)
SEER data for RT vs. no RT for Stage III node positive cancer
Schmid et al. Gynecol Oncol 2009
- Schmid et al (Gyn Onc, 2009) reviewed the SEER data base from 1988 – 2001
- 5-year disease specific survival (DSS) with RT 67.9% vs 53.4% without RT (p
- Single lymph node DSS 74.3 vs. 54.4 % (p
- Endometroid 73.7 vs 61.9% (p=0.007)
- Clear Cell 77.1 vs. 39.2% (p=0.046)
- Papillary Serous 44 vs. 45.5 % (p=0.48)
- Sarcoma 44.9 vs 46.3 % (p=0.51)
- The data remained significant on multivariate analysis
Describe Trial of PORTEC 3
- Randomized trial of combined chemotherapy and radiotherapy for high risk endometrial CA
- Endometrial carcinoma
- stage IA(old 1B) grade 3 + LVSI
- stage 1B (old IC) or IIA Grade 3
- IIB
- IIIA or IIIC (IIIA only if grade 3)
- Stage 1A-III with serous or clear cell
- Randomized post op pts to Pelvic RT (48.6 Gy) vs. RT + Concurrent cisplatin 50mg/m2 with adjuvant Carbo AUC5 and paclitaxel x 4 cycles with brachy boost if cervical invasion
GOG 249
- Randomized 601 patients
- High risk Stage I-IIA patients, Stage I-II serous or clear cell (Grade 2/3, LVSI, 1B) >70+1 risk factor, >50 with 2, >18 with 3
- Pelvic RT vs. VB+ Paclitaxel 175mg/m2 +Carboplatin AUC 6 q 3 weeks x 3 cycles
- Prelim results McMeekin 2014
- Vag recurrence 5 RT vs. 2% VBT+C
- Pelvic Recurrence 2 vs 19%
- Distant failure 32% vs. 24%
- RFS 82% vs. 84%
- OS 93 % vs. 92%
- didn’t demonstrate superiority of VBT/C to PRT
GOG 258
- Phase III
- Adjuvant CRT with Cisplatin and Tumor volume directed RT followed by adjuvant carboplatin and paclitaxel vs. carboplatin and paclitaxel alone
- Stage III or IV A
- Primary outcome RFS
