# Radiation Oncology/Endometrium/Early Stage

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Early Stage Endometrial Cancer (Stage I-II)

## Preop BT vs EBRT

* St. Louis/Peoria, Illinois (1968-1975) -- Intrauterine BT vs EBRT
** Randomized. 105 patients, adenocarcinoma, FIGO clinical Stage I. Arm 1) Single implant Cs-137 with Heyman capsules and/or T&O 6000-6500 mg-hrs vs Arm 2) EBRT 40/20
** 1984 PMID 6360334 -- "Preoperative radiation therapy in Stage I endometrial adenocarcinoma. II. Final report of a clinical trial." (Weigensberg IJ, Cancer. 1984 Jan 15;53(2):242-7.)
*** Outcome: pCR at surgery BT 49% vs 30%; pelvic failure 4% vs 13%; 5-year DFS BT 80% vs EBRT 70%; 10-year DFS 67% vs 59%. Half recurrences in pelvis
*** Toxicity: BT 46% vs EBRT 24%
*** Conclusion: Intracavitary radiation is superior to EBRT

## Pre-op RT vs. Adjuvant RT

* GOG 16
** Randomized. Clinical Stage I, Grade 1-3. Closed early due to non-accrual.

## Adjuvant RT

* 4 randomized trials published thus far
** The Norwegian trial randomized patients with surgical Stage I (but no lymph node dissection) and brachytherapy to +/- EBRT. There was local control overall, but survival benefit only for Stage IC G3
** The PORTEC trial randomized patients with intermediate-risk Stage I (specifically no IC G3; no lymph node dissection) to +/- EBRT. There was local control benefit, but no survival benefit
** The GOG 99 trial randomized patients with Stage IB-IC or occult IIA-IIB (selective LND) to +/- EBRT. There was local control benefit, but no survival benefit
** Data from ASTEC/CTG EN.5 trials randomizing patients with IC-IIA or IA-IIAG3 or serous papillary/clear cell (PLND done per institution) to +/- EBRT. Approximately 50% of patients in observation arm received vaginal brachytherapy. There was no OS or DFS benefit, and higher toxicity
** Due to low number of events, none of the trials were really powered to show overall survival benefit. Endpoint for GOG 99 was DFS
** Cochrane meta-analysis didn't find benefit for EBRT in IA-ICG2, but found 10% survival benefit in ICG3
* SEER Registry population-based analysis revealed statistically significant benefit for survival with adjuvant radiation in Stage IC patients, but not IA-B
* A Japanese randomized trial comparing pelvic RT vs. chemotherapy in patients with >50% myometrial invasion (Stage IC-IV) found no overall difference in PFS or OS, and on subset found benefit in high risk patients in favor of chemotherapy
* PORTEC 2 has been published (see below) comparing EBRT vs BT (but excluding ICG3). BT had slightly higher pelvic failure rate (NS), but no impact on OS, and was felt to be the standard of care for these patients

### Randomized

Meta-analysis
* Cochrane; 2007 PMID 17803718 -- "Survival and recurrent disease after postoperative radiotherapy for early endometrial cancer: systematic review and meta-analysis." (Johnson N, et al. BJOG. 2007 Nov;114(11):1313-20. Epub 2007 Sep 5.)
** Cochrane methodology. 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
Randomized
* PORTEC 2 (2002-2006) -- Pelvic EBRT 46/23 vs. vaginal BT
** Randomized. 427 patients, intermediate-high risk endometrial CA. Eligible if: (1) age greater than 60 years and stage 1C grade 1 or 2 disease, or stage 1B grade 3 disease; and (2) stage 2A disease, any age (apart from grade 3 with greater than 50% myometrial invasion). TAH/BSO, PLND not allowed. Excluded papillary serous and clear cell. Arm 1) EBRT 46/23 vs. Arm 2) HDR 21/3 or LDR 30/1. Primary endpoint vaginal relapse.
** 2008 ASCO Abstract -- "Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial." (Nout RA, et al. J Clin Oncol. 2008 May 20;26(15_suppl):LBA5503.) Median F/U 2.8 years
*** Outcome: 3-year vaginal relapse EBRT 2.0% vs. VBT 0.9% (NS), pelvic relapse 0.7% vs. 3.6% (SS), OS 90% vs. 91% (NS)
*** Toxicity: Significantly higher rate of diarrhea, persisted >2 years in EBRT group
*** Conclusion: Vaginal BT effective in preventing vaginal recurrences, with slightly higher pelvic failure rate, but no impact on RFS or OS. Quality of life better, so should be considered standard for these patients
*** Comment: Oncolink at UPenn
** QoL; 2009 PMID 19546404 -- "Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial." (Nout RA, et al. J Clin Oncol. 2009 Jul 20;27(21):3547-56. Epub 2009 Jun 22.)
*** QoL evaluated by EORTC QoL-C30, PR-25, and OV-28 questionnaires. 348 patients (81%) evaluable for QoL. Median F/U 2 years
*** Outcome: VBT better social functioning (SS), and significantly improved diarrhea, fecal leakage, need to stay close to the toilet, and limitation of daily activities due to bowel symptoms (SS). No difference in sexual functioning (~40%)
*** Conclusion: EBRT patients significantly worse diarrhea and bowel symptoms, and worse social functioning
** 2010 PMID 20206777 -- "Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial." (Nout RA, et al. Lancet. 2010 Mar 6;375(9717):816-23.) Median F/U 3.75 years
*** Outcome: 5-year vaginal recurrence VBT 1.8% vs EBRT 1.6% (NS); 5-year loco-regional relapse 5.1% vs 2.1% (NS); isolated pelvic recurrence 1.5% vs 0.5% (NS); DM 8.3% vs 5.7% (NS). 5-year OS 85% vs 80% (NS).
*** Toxicity: Acute G1-2 at completion of RT VBT 13% vs EBRT 54%
*** Conclusion: VBT is effective, with fewer toxic effects
*** Editorial (PMID 20206759): Agree that VBT should be the standard of care for these patients
** Long-term QoL, 2015 PMID 26530748 -- "Long-term impact of endometrial cancer diagnosis and treatment on health-related quality of life and cancer survivorship: results from the randomized PORTEC-2 trial." de Boer SM, et al. Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):797-809.
*** QoL evaluated by EORTC QoL-C30 and Impact Of Cancer (IOC) version 2 questionnaires at 7 and 10 years. 202 out of 265 patients (76%) evaluable at 7 years, and 80 out of 119 (67%) at 10 years.
*** Outcome: Persistence of higher bowel symptoms in EBRT arm -- fecal leakage 10.6% vs 1.8% (SS), diarrhea 8.4% vs 0.9% (SS), limitations due to bowel symptoms 10.5% vs 1.8% (SS), and bowel urgency 23.3% vs 6.6% (SS). Trend for more urinary urgency (39.3% vs 25.5%, p=0.05). Sexual activity not differ.
*** Conclusion: EBRT had long-lasting impact on bowel symptoms.
** 10-year, 2018 PMID 30356126 -- "Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy." Wortman BG, et al. Br J Cancer. 2018 Oct;119(9):1067-74. Median F/U 116 months (9.6 years).
*** Outcome: 10-year vaginal recurrence VBT 3.4% vs EBRT 2.4% (NS). Pelvic recurrence VBT 6.3% vs EBRT 0.9% (SS), but mostly combined with distant metastasis. Isolated pelvic recurrence 2.5% vs 0.5% (NS); distant metastasis 10.4% vs 8.9% (NS). 10-year OS 69.5% vs 67.6% (NS). L1CAM, p53-mutant, and substantial LVSI were risk for PR and DM.
*** Conclusion: VBT is standard adjuvant for high-intermediate risk. EBRT had better pelvic control in unfavorable risk.
* MRC ASTEC and NCIC CTG EN.5 (1996-2005) -- EBRT vs Observation
** Two randomized trials merged in 1998 to pool results and facilitate data monitoring. 906 Stage I-IIA endometrial CA patients, with intermediate or high risk features (one or more of the following: IA-IB Grade 3, IC Grade 1-3, serous papillary or clear cell type, FIGO stage IIa). PLND not required; women with positive pelvic LN eligible for ASTEC but not EN.5. Para-aortic LN+ excluded. Peritoneal washings could be negative, positive, or not done. Arm 1) EBRT 40-46 Gy daily vs. Arm 2) observation. BT allowed by institutional preference (ASTEC HDR 8/2 or LDR 15/1, EN.5 per institution), BT given in 51% of observation arm vs. 5% of EBRT arm
** Patient characteristics: 30% PLND; 84% endometrioid; IA 3%, IB 20%, IC 77%; Grade 1 26%, Grade 2 42%, Grade 3 31%. Brachy given to 52% patients in both arms
** 2007 ASCO Abstract -- "Adjuvant external beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN.5 trial." (Orton J, et al. J Clin Oncol. 2007 Jun 20;25(18_suppl):5504.) Median F/U 3.8 years
*** 5-year outcome: OS 84% both groups (NS), DSS 89% (NS); small difference in isolated vaginal/pelvic recurrence with brachytherapy
*** Morbidity: EBRT 56% vs. no EBRT 24%; Grade 3+ toxicity rare
*** Conclusion: EBRT alone not indicated due to no benefit on OS/DFS, but higher toxicity
** RT; 2009 PMID 19070891 -- "Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis." (ASTEC/EN.5 Study Group, Lancet. 2009 Jan 10;373(9658):137-46. Epub 2008 Dec 16.) Median F/U 4.8 years
*** Outcome: 5-year OS OBS 84% vs EBRT 84% (NS), DSS 90% vs 89% (NS), Recurrence 15% vs. 15%, Isolated vaginal or pelvic recurrence OBS 6% vs. EBRT 3% (SS)
*** Subset analysis: No difference in intermediate risk, high risk, no PLND, and PLND for both OS and DSS
*** Toxicity: Any acute toxicity OBS 27% vs. EBRT 57%, Grade 3 <1% vs. 3%; Any late toxicity 45% vs. 61%, any Grade 3-4 3% vs. 8%
*** Updated Meta-analysis (GOG99, PORTEC1, ASTEC/EN.5): HR 1.04 for benefit of RT (0.84-1.29, NS)
*** Conclusion: Adjuvant EBRT cannot be recommended as part of routine treatment for women with intermediate/high risk early stage endometrial CA. There is no benefit on OS or DFSS, and absolute benefit for isolated local recurrence is small and not without toxicity
** ASTEC PLND; 2009 PMID 19070889 -- "Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study." (Kitchener H, Lancet. 2009 Jan 10;373(9658):125-36. Epub 2008 Dec 16.)
*** Please see the Lymphadenectomy section
** Comment; 2010 PMID 19897230 -- "ASTEC lymphadenectomy and radiation therapy studies: are conclusions valid?" (Creasman WT, Gynecol Oncol. 2010 Mar;116(3):293-4. Epub 2009 Nov 7.)
*** Two different questions, but due to overlap don't answer either one
* PORTEC 1 (The Netherlands) (1990-1997)
** Randomized. 715 patients with Stage IB (G2-3) or IC (G1-2), specifically no IC G3. TAH/BSO with washings, not allowed to have lymphadenectomy. Allowed adenocarcinoma and variants (including papillary serous and clear cell).
** Randomized to postoperative EBRT 46 Gy vs no further therapy. Fields: superior border at L5/S1.
** 5-years, 2000 PMID 10791524 — "Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma." Creutzberg CL et al. Lancet. 2000 Apr 22;355(9213):1404-11. Median F/U 4.3 years
*** 5-year outcome: LRF: 4% vs 14% (SS); 73% of recurrences in vagina. DM unaffected (7%). OS same (80% vs 84%, NS) with ~50% deaths due to other causes
*** Salvage: Most LR salvaged, which may explain why the survival is similar in both arms despite a difference in LR. 3-year OS after vaginal relapse 69% vs. 13% for pelvic or DM.
*** Toxicity: RT 25% vs. 6% (SS); excess of secondary cancers of the GI tract, which is associated with endometrial cancer.
*** Prognostic: Age < 60 was good prognostic, IBG2 also had low LRR of < 5%; suggesting omission of RT in these subgroups. Age ≥ 60 with ICG1-2 or IBG3 had more LRR in control group (5% vs 18%, p-value not reported), but similar DM and EC death.
*** Conclusion: EBRT reduces LR but has no impact on survival. Don't recommend if <60 or if IB G2
** Side effects, 2001 PMID 11728684 -- "The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial." (Creutzberg CL, Int J Radiat Oncol Biol Phys. 2001 Dec 1;51(5):1246-55.) Median F/U 5 years
*** Late complications: RT 26% vs. control 4% (SS). Most grade I (65%). Grade 3-4 complications 3% vs. 0%
*** By site: GI 20% (3% severe); GU 8% (no severe); bone 2% (no severe); vagina 1% (no severe)
*** Time course: ~50% Grade 1-2 resolved over time (2-3 years), but not in Grade 3-4 complications
*** Technique: 4F box lower risk; 4F 21% vs. AP/PA 30% vs. 3F 36% (p=0.06)
*** Conclusion: Severe complications 3%, mild complications 20%. RT use requires careful consideration, since no survival benefit
*** Comment: Reporting done differently between the 2 arms, special form for acute RT toxicity. Also, surgeons don't report large midline scar as a complication while transient erythema is one
** Vaginal Relapse / Salvage, 2003 PMID 12713981 — "Survival after relapse in patients with endometrial cancer: results from a randomized trial." (Creutzberg CL et al. Gynecol Oncol. 2003 May;89(2):201-9.) Median F/U 6.1 years
*** See also at: Radiation Oncology/Endometrium/Recurrence
*** 8-year outcome: LRF: RT 4% vs. control 15% (SS), majority failures after surgery only in vagina; DM 10% vs. 6% (NS); OS RT 71% vs. control 77% (NS)
*** 39 pts with isolated vaginal relapse; 31 of these treated with curative intent (usually RT+brachy). CR obtained in 31 of 35 (89%), with long term control in 24 of 31 (77%). Total long term control rate is thus 24/35 (68%).
*** Survival after 1st relapse at 3 yrs: 51% (control group) vs 19% (RT).
*** Survival after vaginal relapse 73%, after pelvic relapse 8%, after DM relapse 14%.
*** Vaginal salvage: 5-year OS: control group better 65% vs. RT group 43% (SS).
*** Conclusion: Limit pelvic RT to pts with ≥ 15% risk of recurrence
** Stage IC G3, 2004 PMID 15051771 — "Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial." Creutzberg CL et al. J Clin Oncol. 2004 Apr 1;22(7):1234-41.
*** Analysis of 99 IC G3 registered but ineligible patients, treated per same protocol. Median F/U 6.9 years
*** 5-year outcome: OS: IB-C G1-2 83-85%, IB G3 74%, IC G3 58%; DM rate 3-8%, 20%, and 31%
*** Conclusion: IC G3 at high risk of DM and cancer-related death
** 10-years, 2005 PMID 15927414 -- "Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review." (Scholten AN, Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):834-8.)
*** Central pathology review for 569 patients (80%). Poor reproducibility for G1 vs. G2
*** 10-year outcome: LR: 5% vs. 14% (SS); OS 66% vs. 73% (p=0.09), cancer-related deaths 11% vs. 9% (NS)
*** Poor prognosis for LR: at least 2 of Age ≥ 60, Stage IC (≥ 50% invasion), and Grade 3. 10-year LRR of this group 4% (RT) vs 23% (no RT) (p-value not reported).
*** Conclusion: In view of significant LR control benefit, RT indicated if high-risk features.
** Comment: Since ~50% deaths due to competing causes, overall survival not a good metric. Number of events even less than GOG-99, since high risk IC G3 disallowed. Trial not really powered to show survival difference.
** 15 years, 2011 -- Outcome and QOL PMID 21444867 -- "Long-Term Outcome and Quality of Life of Patients With Endometrial Carcinoma Treated With or Without Pelvic Radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) Trial." (Nout RA, J Clin Oncol. 2011 May 1;29(13):1692-700. Epub 2011 Mar 28.) -- Mean f/u 13.3 yrs
*** 15 yr LRR 5.8% (RT) vs 15.5% (no RT); OS 52% vs 60%, NS.
*** Pts treated with RT had significant increases in urinary incontinence, diarrhea, fecal leakage, and more limitations in daily activities.
*** Conclusion: EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower functioning. "Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC."
** 15-year outcome of HIR and second cancers, 2011 PMID 21640520 — "Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma." (Creutzberg CL, et al. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e631-8.)
*** High-intermediate risk (HIR) was 2 of: grade 3, age ≥ 60, and deep invasion.
*** Outcome: Median F/U for alive patients 13.3 years. 15-year failure-free survival 50% (RT) vs. 54% (no RT) (NS), 15-year distant metastasis 9% vs 7% (NS), second cancers 22% vs 16% (NS). For HIR, 15-year OS 41% vs 48% (NS), 15-year EC death 14% vs 13%. Multivariate analysis: Grade 3, age ≥ 60, and deep invasion were prognostic for LRR and EC death.
* GOG 99 (1987-1995) — pelvic EBRT vs no additional treatment
** Randomized. 392 patients, treated with TAH/BSO, selective PLN and PALND. Originally included "intermediate risk" — stages IB, IC, and II (occult), any grade, with negative LN. Excluded clear cell and papillary serous adenoCA. Revised during the course of study to define "high intermediate risk (HIR)" group expected to have 25% recurrence risk based on increasing age, G2-3 tumor, LVI, or outer 1/3 myometrial invasion: 1) ≥ 70 yrs old with only 1 other risk factor, 2) ≥ 50 yrs old with 2 risk factors; 3) any age with 3 risk factors. Others were considered "low intermediate risk (LIR)". Randomized to Arm 1) no additional treatment (NAT) vs Arm 2) postoperative pelvic EBRT. Fields: superior border at L4/L5 interspace, lateral borders 1 cm beyond pelvis, posterior border at posterior border of S3, anterior border at symphysis pubis. Dose: 50.4 Gy. No brachytherapy allowed.
** 1998 Abstract — "A phase III randomized study of surgery vs surgery plus adjunctive radiation therapy in intermediate-risk endometrial adenocarcinoma (GOG No. 99)." (Roberts JA, et al. Gynecol Oncol. 1998 Jan;68(1):135.) Median F/U 56 months (4.7 years).
*** Outcome: 2-year progression-free interval 88% (NAT) vs 96% (RT) (SS). Loco-regional recurrences 17 vs 3 patients (p-value not reported). 36-month OS 89% vs 96% (NS).
** 4-years, 2004 PMID 14984936 — "A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study." (Keys HM, et al. Gynecol Oncol. 2004 Mar;92(3):744-51.) Median F/U 5.7 years
*** Outcome: 2-year recurrence rate: 3% vs 12% (SS). 2-year isolated LR 2% vs 7%. 4-year OS 92% vs 86% (NS). In HIR subgroup (34%): 4-year recurrence 13% (RT) vs 27% (NAT) (SS).
*** Conclusion: Strong benefit for adjuvant EBRT in high intermediate risk group
** Comment: OS not primary survival, not powered for it. Primary end-point DFS, which was significantly better with RT
* Norwegian Radium Hospital -- VBT alone vs VBT + EBRT
** Randomized. 540 patients with surgical Stage I. All patients had TAH/BSO (no lymphadenectomy) + postoperative brachytherapy 60 Gy to the surface of the vagina (~40 Gy LDR @ 0.5cm and ~ 24 Gy HDR @ 0.5 cm). Then randomized to no further treatment vs pelvic RT 40 Gy (central shielding after 20 Gy)
** Preliminary, 1976 (1968-1972) PMID 821824 — "Postoperative external pelvic irradiation in carcinoma of the corpus stage I: a controlled clinical trial." Onsrud M, et al. Gynecol Oncol. 1976 Jun;4(2):222-31.
*** Outcome: 5-year OS 90% (BT) vs 88% (BT+EBRT) (NS). Loco-regional recurrence 7.2% (4.6% vagina, 2.5% pelvic wall) vs 2.1% (all vagina). Distant metastasis 5.1% vs 9.9%. In BT alone arm, recurrence rate 4.1% (≤ 50% myometrial invasion) vs 12.7% (> 50% myometrial invasion).
** 9-years, 1980 (1968-1974) PMID 6999399 — "Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients." Aalders J et al. Obstet Gynecol. 1980 Oct;56(4):419-27.
*** 9-year outcome: OS BT alone 90% vs BT+EBRT 87% (NS). EBRT decreased LR (7% vs 2%) but there were more distant mets (5% vs 10%, borderline SS). Similar recurrence rate in both groups, but more deaths in XRT group.
*** Subset analysis: Improved OS for BT+EBRT in IC Grade 3 (82% vs. 72%); probably due to improved local control (LR 5% vs. 20%) with comparable DM (14% vs. 15%). IC G1-2 had no difference in OS, LR, and DM.
*** Poor prognosis: Age ≥ 60, Stage IC, Grade 3, LVI+
*** Conclusion: No benefit for EBRT after vaginal BT, except for Stage IC G3 patients
** Long-term outcomes, 2013 PMID 24019546 — "Long-term outcomes after pelvic radiation for early-stage endometrial cancer." Onsrud M, et al. J Clin Oncol. 2013 Nov 1;31(31):3951-6.
*** Outcome: Median F/U 20.5 years. Median OS 20.5 years in both groups. Age < 60 years had higher death in EBRT arm, but not in ≥ 60 years subgroup. Secondary cancer 24.5% (BT) vs 30.5% (BT+EBRT) (SS), with median time of 15.0 years. Patients aged < 60 years had higher secondary cancer after EBRT (39.7% vs 25.6%, SS), but not in ≥ 60 years. Third cancer were also more common after EBRT (7% vs 2%)
*** Toxicity: 4 treatment-related deaths, all in EBRT arm (1 before EBRT, 3 after surgery for radiation-induced ileus). Grade 3-4 events 0 (BT) vs 2.9% (BT+EBRT). Grade ≥ 2 complications 4.5% vs 27.4%.
*** Conclusion: Addition of EBRT had no survival benefit. On the other hand, EBRT decreased survival and increased secondary cancer for those aged < 60.
Risk of Vaginal Relapse
* In PORTEC: risk of vaginal relapse in surgery only arm was IBG2 5%, IBG3 14%, ICG1 10%, and ICG2 13% (personnal communication in PMID 16814156)
* In ASTEC/EN.5: risk of isolated vaginal or pelvic relapse: observation (50% received BT): 6% vs. EBRT 3%
* Rosewell Park (PMID 19944453): 3.4% in "high risk" patients treated with VB alone
* PORTEC2 editorial (PMID 20206759): Without any radiotherapy the risk of vaginal relapse is 10-14% based on GOG92 and PORTEC

### Retrospective

* 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.)
** SEER database. 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."
* Roswell Park; 2010 PMID 19944453 -- "Adjuvant vaginal brachytherapy alone for high risk localized endometrial cancer as defined by the three major randomized trials of adjuvant pelvic radiation." (McCloskey SA, Gynecol Oncol. 2010 Mar;116(3):404-7. Epub 2009 Nov 27.)
** Retrospective. 87 patients (out of 464), Stage I-IIA endometrial CA, high risk by PORTEC (n=37) or GOG 99 (n=77) or Aalders (n=14), treated with VB alone. PLND in 46%. ICG3 16%; LVI+ 18%. Median F/U 4.3 years
** Outcome: locoregional recurrence 3.4% (1 vaginal recurrence, 1 pelvic recurrence, and 1 vagina+pelvis recurrence)
** Conclusion: VB alone reasonable for high risk localized endometrial CA
* SEER Registry; 2006 (1988-2001) PMID 16434629 -- "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
* U.Chicago; 1999 (1986-95) PMID 10214841 PDF -- "External pelvic radiation therapy in stage IC endometrial carcinoma." (Weiss MF, Obstet Gynecol. 1999 Apr;93(4):599-602.)
** Purpose: to evaluate the results of patients treated with EBRT alone without VB.
** Retrospective. 61 pts with Stage IC. EBRT alone to a median dose of 48.6 Gy (range: 43.2-50.4 Gy). No pts received VB.
** Median f/u 69.5 months. 5-yr DFS 86.7%, OS 97.6%. No pt had a local / vaginal recurrence.
** Conclusion: local control was excellent with EBRT without VB

## Adjuvant RT +/- Chemo

* EORTC 55991 (1996-2006) -- RT vs sequential RT→Chemo
** Randomized. Terminated due to slow accrual. 372 patients. Initially, surgical Stage I; later amended to include occult II, IIIA (positive peritoneal fluid only), or IIIC (positive LNs only) with high risk features. Typically 2 or more of grade 3, deep myometrial invasion, DNA non-diploidy). PLND optional. Pelvic RT 44 Gy (vaginal BT optional, given in 41%) +/- 4 cycles of chemo (several regimens allowed). 25% didn't receive full chemo
** 2007 ASCO Abstract -- "A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991)." (Hogberg T, et al. J Clin Oncol. 2007 Jun 20;25(18_suppl):5503.) Median F/U 3.5 years
*** Outcome: PFS RT alone 75% vs. RT+CT 82% (SS)
*** Conclusion: RT+CT better than RT alone
** 2010 PMID 20619634 -- "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer-Results from two randomised studies." (Hogberg T, et al. Eur J Cancer. 2010 Sep;46(13):2422-31.)
*** Merged outcomes from EORTC 55991 (n=378) and MaNGO ILIADE-III (n=156). MaNGO trial was same format, but enrolled primarily Stage IIB and III patients
*** EORTC Outcome: 5-year PFS RT 76% vs RT→chemo 85% (HR 0.6, SS), no difference OS. Signficant OS benefit for chemo in endometrioid subset (5-year OS 69% vs 80%, SS) but not in serous and clear cell subset (NS)
*** Pooled Outcome: 5-year PFS RT 72% vs RT→chemo 80% (HR 0.6, SS), CSS 82% vs 89% (SS), OS 79% vs 84% (p=0.07)
*** Conclusion: Addition of adjuvant chemotherapy improves PFS in high risk endometrial patients, though no benefit on subgroup analysis for serous/clear cell
* RTOG 99-05 (1999-2003)
** Randomized. High risk endometrial CA (Stage IC G2-3, II, III). Arm 1) Adjuvant EBRT 50.4/28 (BT optional) vs. Arm 2) concurrent cisplatin 50 mg/m2 + EBRT 50.4/28, followed by cisplatin 50 mg/m2 + paclitaxel 160 mg/m2 (based on RTOG 97-08)
** Closed due to nonaccrual.
* RTOG 97-08 (1997-99)
** Phase II. Post-operative chemo+RT for "high risk" endometrial adenocarcinoma (Stage IC G2-3, II, III). 45 Gy pelvic RT with concurrent cisplatin on weeks 1+5, plus vaginal brachytherapy, followed by 4 cycles cisplatin + taxol.
** Final; 2006 PMID 16545437, 2006 — "Final analysis of RTOG 9708: adjuvant postoperative irradiation combined with cisplatin/paclitaxel chemotherapy following surgery for patients with high-risk endometrial cancer." Greven K et al. Gynecol Oncol. 2006 Oct;103(1):155-9.
*** Median f/u 4 yrs. Excellent local control. Tolerable regimen.
** Preliminary; 2004 PMID 15093913, 2004 — "Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer." Greven K et al. Int J Radiat Oncol Biol Phys. 2004 May 1;59(1):168-73.
* Finland (1992-1996) -- pelvic EBRT vs. interdigitated chemo-RT
** Randomized. 156 patients with Stage IA-B G3 (n=28) or Stage IC-IIIA (n=128), who underwent TAH/BSO. 80% had at least PLND. Arm 1) Pelvic EBRT split course 56 Gy (28 Gy x2 with 3 week break) vs. Arm 2) Interdigitated chemo-RT, given as chemo - RT 28 Gy - chemo - RT 28 Gy - chemo. Chemo was cisplatin 50 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 500 mg/m2 x3 courses. Brachytherapy not mentioned (not given?)
** 2008 PMID 18534669 -- "Surgically staged high-risk endometrial cancer: Randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy." (Kuoppala T, et al. Gynecol Oncol. 2008 Aug;110(2):190-5.)
*** Outcome: 5-year DFS RT 85% vs. chemo-RT 82% (NS). LRR 3% in both arms; DM 14% vs. 20%
*** Toxicity: Grade 3 bowel toxicity RT 3% vs. chemo-RT 9%
*** Conclusion: Adjuvant interdigitated chemo-RT failed to improve OS or lower recurrence rate over EBRT alone
* GOG 34 (1977-1986) -- pelvic RT +/- doxorubicin
** Randomized. 181 patients with high risk endometrial cancer (>50% myometrial invasion (Stage IC), cervical involvement (Stage II), pelvic or para-aortic LN+ (Stage IIIC), adnexal mets (Stage IIIA)). Surgery + RT (whole pelvis 50 Gy; if PA LN+ then PA field to top of T12 45/30). Arm 1) observation vs. Arm 2) doxorubicin
** 1990 PMID 2298404 -- "Doxorubicin as an adjuvant following surgery and radiation therapy in patients with high-risk endometrial carcinoma, stage I and occult stage II: a Gynecologic Oncology Group Study." (Morrow CP, Gynecol Oncol. 1990 Feb;36(2):166-71.)
*** Outcome: No difference in 5-year PFS or OS
*** Toxicity: 7% SBO; treatment-related deaths DOX 25% vs. RT 2%
*** Conclusion: Due to protocol violations, small size, and loss to follow-up, unable to determine effect of doxorubicin

## Adjuvant RT vs. Adjuvant Chemo

* GOG 0249
** Randomized. 601 patients, Stage I endometrial with high risk features, Stage II endometrial, Stage I-II serous or clear cell. Arm 1) pelvic radiation versus Arm 2) Vaginal brachytherapy followed by chemotherapy with paclitaxel 175 mg/m2 + carboplatin AUC 6 every 3 weeks x 3 cycles. Median age 63, Stage I disease 74%, endometrioid 71%, serous 15%, clear cell 5%, PLND 89%
** Preliminary Results; 2014 SGO Abstract -- "A randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy (VCB/C) in patients with high risk (HR), early stage endometrial cancer (EC): a Gynecologic Oncology Group trial" (McMeekin DS, Gynecol Oncol. 2014 Aug;134(2):438. SGO 2014 Late-Breaking Abstract 1A). Median F/U 2 years
*** Outcome: vaginal recurrence PXRT 5 versus VCB/C 2; pelvic recurrence 2 vs 19; distant failure 32 vs 24. RFS 82% vs 84% (NS); OS 93% vs 92% (NS)
*** Toxicity: acute toxicity more common with VCB/C
*** Conclusion: Study did not demonstrate superiority of VCB/C to PXRT
** 2017 ASTRO Abstract -- "A phase 3 trial of pelvic radiation therapy versus vaginal cuff brachytherapy followed by paclitaxel/carboplatin chemotherapy in patients with high-risk, early-stage endometrial cancer: a Gynecology Oncology Group study" (Randall M, et al. Int J Radiat Oncol Biol Phys. 2017 Dec 1;99(5):1313. ASTRO 2017 Late-Breaking Abstract)
*** to be continued ...
** 2019 PMID 30995174 -- "Phase III trial: adjuvant pelvic radiation therapy versus vaginal brachytherapy plus paclitaxel/carboplatin in high-intermediate and high-risk early stage endometrial cancer." (Randall ME, et al. J Clin Oncol. 2019 Jul 20;37(21):1810-8.)
*** to be continued ...
* JGOG 2033 (1994-2000) -- adjuvant pelvic RT vs. adjuvant cisplatin/doxorubicin/cyclophosphamide
** Randomized. 103 institutions. 385 patients with Stage IC-IIIC and >50% myometrial invasion (Stage II-III with <50% invasion ineligible). IC 61%, II 14%, IIIA 13%, IIIC 12%. Age <75. S/P TAH/BSO and surgical staging (96% PLND, 29% PALND). Arm 1) RT AP/PA 45-50 Gy. BT boost in only 6 patients (3%). Arm 2) CAP (cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) x3+ courses
** 5-years; 2007 PMID 17996926 -- "Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: A Japanese Gynecologic Oncology Group study." (Susumu N, Gynecol Oncol. 2007 Nov 8). Median F/U
*** Outcome: 5-year PFS 83% vs 82% (NS); OS 85% vs. 87% (NS)
*** By risk: No difference in low/intermediate risk patients. High risk (IC and >70, IC G3, II, IIIA) PFS RT 66% vs. chemo 84% (SS), OS 74% vs. 90% (SS)
*** Toxicity: No difference
*** Conclusion: Adjuvant chemo useful alternative, especially in higher risk patients
* GOG 156
** Randomized. Stage IB-IIB. Arm 1) Adjuvant pelvic RT vs. Arm 2) Adjuvant adriamycin/cisplatin
** Closed due to nonaccrual
* Italy (1990-1997) -- adjuvant EBRT vs. cisplatin/doxorubicin/cyclophosphamide
** Randomized. 345 patients. High-risk endometrial (IC G3, II G3 and >50% invasion, III). Arm 1) EBRT 45-50 Gy vs. Arm 2) cisplatin 50 mg/m2 + doxorubicin 45 mg/m2 + cyclophosphamide 600 mg/m2. Primary endpoint OS and PFS
** 2006 PMID 16868539 -- "Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial." (Maggi R, Br J Cancer. 2006 Aug 7;95(3):266-71. Epub 2006 Jul 25.) Median F/U 8.0 years
*** Outcome: 5-year OS RT 69% vs. chemo 66% (NS); 5-year PFS 63% vs. 63% (NS). RT delayed local relapse, CT delayed DM
*** Toxicity: both well tolerated
*** Conclusion: No difference between adjuvant RT and adjuvant chemo

## Carcinosarcoma

* Mayo Clinic/Harvard; 2015 PMID 25890795 -- "Vaginal brachytherapy for early-stage carcinosarcoma of the uterus." (Brown LC, et al. Brachytherapy. 2015 Jul-Aug;14(4):433-9.)
** Retrospective. 33 patients from 2 institutions, Stage I-II carcinosarcoma. (15 and 18 respectively). VBT 21/3 or 24/6 fractions. PLND 82%. Chemo 55%
** Outcome: 2 year vaginal cuff control 94%, pelvic control 87%, locoregional control 81%, DFS 66%, OS 79%
** Conclusion: Relatively high risk of local and distant relapse. Risk of pelvic recurrence comparable to women treated with pelvic radiation but no lymph node dissection. Pelvic radiation should be considered based on clinical context

## Primary RT (Inoperable Patients)

* Please see this section

## Lymph node dissection

* See Chino 2012 above (PMID 21640502)

## Salvage

* Montreal; 2006 (1997-2003) PMID 16386785 -- "Salvage treatment with high-dose-rate brachytherapy for isolated vaginal endometrial cancer recurrence." (Petignat P, Gynecol Oncol. 2006 Jun;101(3):445-9.)
** Retrospective. 22 patients with endometrial CA, isolated vaginal recurrence. 82% EBRT + HDR, 18% HDR only. Median EBRT dose 45 Gy (44-50.4), median HDR dose 26 Gy (8-48; dose per fraction 6-8 Gy, median number of fractions 4). Median time to recurrence 1.7 years. Median F/U 2.7 years
** Outcome: no LR recurrence, 1 patient DM; 5-year LC 100%, DFS 96%, DSS 96%
** Toxicity: 18% Grade 3-4 GI (persistent rectorrhagia), 50% grade 3 vaginal (<1/3 vaginal length)
** Conclusion: Recurrent vaginal endometrial CA amenable to salvage

## Toxicity

IMRT vs Conventional
* NRG/RTOG 1203 (2012 - 2015)
** Randomized. 278 patients. Conventional radiation vs IMRT. Dose 45 Gy or 50.4 Gy, stratified. Concurrent cisplatin 40 mg/m2 weekly at physician discretion based on predefined criteria. Primary endpoint acute GI toxicity.
** 2016 ASTRO Abstract -- "A Phase III randomized trial comparing patient-reported toxicity and quality of life (QOL) during pelvic intensity modulated radiation therapy as compared to conventional radiation therapy." Klopp AH, et al. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2 Suppl):S3.
*** to be continued ...
** 2018 PMID 29989857 -- "Patient-reported toxicity during pelvic intensity-modulated radiation therapy: NRG Oncology-RTOG 1203." Klopp AH, et al. J Clin Oncol. 2018 Aug 20;36(24):2538-44.
*** Outcome: EPIC-GI score decreased more in conventional vs IMRT group, at 3 weeks and 5 weeks (p=0.048). At EOT, diarrhea in 52% vs 34% (SS), with more anti-diarrheal medication use. No difference at 4-6 weeks post treatment. EPIC-GU scored also declined more in conventional vs IMRT group.
*** Conclusion: Pelvis IMRT resulted in significantly less GI and GU toxicity from patient's perspective.
** 2019 ASTRO Abstract -- "IMRT improves late toxicity compared to conventional RT: An Update on NRG Oncology-RTOG 1203." Yeung AR, et al. Int J Radiat Oncol Biol Phys. 2019 Sep 1;105(1 Suppl):S50.
*** to be continued ...
** 2020 PMID 32073955 -- "Improvement in patient-reported outcomes with intensity-modulated radiotherapy (RT) compared with standard RT: a report from the NRG Oncology RTOG 1203 study." Yeung AR, et al. J Clin Oncol. 2020 May 20;38(15):1685-92.
*** to be continued ...
Diarrhea
* Lippe Hospital, Germany (2000-2006) -- selenium vs control
** Randomized. 81 patients with uterine (88%) or cervical (12%) cancer. If pretreatment selenium <84 ug/l randomized to Arm 1) selenium 500 ug PO daily vs Arm 2) control. Primary endpoint: efficiency of supplementation
** 2010 PMID 20133068 -- "Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology." (Muecke R, et al. Int J Radiat Oncol Biol Phys. 2010 Nov 1;78(3):828-35.)
*** Outcome: Selenium level post RT significantly higher with supplement. Grade 2+ diarrhea selenium 20% vs no selenium 44% (SS). No difference in other measures
*** Conclusion: Selenium supplementation effective in improving blood selenium status in deficient patients, and reduces RT-induced diarrhea

## RT Technique

* RTOG 1203 -- post op 3D vs IMRT
** Chronic Toxicity; 2022 PMID 35960897 -- "Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results of a Phase III Trial" (Yeung AR, J Clin Oncol. 2022 Sep 20;40(27):3115-3119.)
*** 279 eligible patients. EPIC surveys and EuroQOL EQ-5D through 3 years after RT. (3-year completion rate 55%). Median F/U 3.1 years
*** Outcome: 3 year OS IMRT 92% vs 3D 97% (NS), DFS 86% vs 81% (NS), or LRF 3% vs 2% (NS)
*** GI toxicity: 1 year CRT 15% vs IMRT 6% (SS), antidiarrheal use 9% vs 1% (SS). No difference in fecal incontinence. No difference at 3 years.
*** GU toxicity: 1 year no difference. 3 years 3D worsening vs IMRT improving (SS)
*** Quality of Life: no difference at 1 year or 3 years
*** Conclusion: IMRT improves chronic GI and urinary toxicity; no difference in treatment efficacy at 3 years
3D Fields
* Example of a post-operative AP radiation therapy treatment field for Stage I-II Endometrial cancer used at Tufts/Brown residency program. Actual patient contours should guide field design.
* Superior border: Consider L5/S1 if PLND negative. Consider L4/L5 if no PLND done or if LN+. PORTEC used L5/S1, GOG 99 used L4/L5.
* Inferior border: inferior edge of pubic ramus
* Lateral borders: ~2cm lateral to bony pelvis, in order to cover lymph nodes
* Brown: rectum
* Orange: common illiac LNs; Yellow: external illiac LNs; Light Green: obturator LNs; Purple: internal illiac LNs; Dark Green: presacral LNs
* Example of a post-operative lateral radiation therapy treatment field for Stage I-II Endometrial cancer used at Tufts/Brown residency program. Actual patient contours should guide field design
* Superior border: same as AP field
* Inferior border: same as AP field
* Anterior border: anterior to symphysis pubis
* Posterior border: S3 to cover some utero-sacral ligament lymph nodes
* Brown: rectum
* Orange: common illiac LNs; Yellow: external illiac LNs; Light Green: obturator LNs; Purple: internal illiac LNs; Dark Green: presacral LNs