# Radiation Oncology/Endometrium/Randomized

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Endometrial Cancer: Randomized Evidence

## Surgery

* The Netherlands -- total abdominal hysterectomy vs total laparoscopic hysterectomy
** Randomized. 283 patients, 21 hospitals, Stage I endometrioid CA or complex atypical hyperplasia. Arm 1) total laparoscopic hysterectomy (TLH) vs Arm 2) total abdominal hysterectomy (TAH). Primary outcome major complication rate
** 2010 PMID 20638901 -- "Safety of laparoscopy versus laparotomy in early-stage endometrial cancer: a randomised trial." (Mourits MJ, Lancet Oncol. 2010 Aug;11(8):763-71. Epub 2010 Jul 16.)
*** Outcome: major complications TLH 15% vs TAH 15% (NS); minor complications 13% vs 12% (NS). Conversion to laparotomy 11%. TLH significantly less blood loss, pain medication use, hospital LOS and faster recovery; however, procedure took longer
*** Conclusion: No difference in complication rate, less pain and better resumption of daily activities with TLH
* ILIADE Study, Italy (1998-2004) -- extrafascial hysterectomy vs modified radical hysterectomy
** Randomized. 520 patients, clinical Stage I endometrial CA. Arm 1) Standard extrafascial (Class I) hysterectomy vs Arm 2) Modified radical (Class II) hysterectomy. Adjuvant therapy risk adapted: if low risk, observation; if intermediate risk (IC and no PLND, IIIA cytology) +/- EBRT +/- BT; if high risk (IIB, IIIA adnexal mets) doxorubicin/cisplatin + EBRT. No difference in adjuvant therapies between arms. Primary endpoint OS
** 2009 PMID 19834767 -- "Modified Radical Hysterectomy Versus Extrafascial Hysterectomy in the Treatment of Stage I Endometrial Cancer: Results From the ILIADE Randomized Study." (Signorelli M, Ann Surg Oncol. 2009 Oct 16. [Epub ahead of print]) Median F/U 5.8 years
*** Outcome: Median length of vagina removed standard 5mm vs. modified radical 15mm (SS); length of parametria 15mm vs 20mm (SS). OR time and blood loss higher for modified radical. 5-year DFS 88% vs. 90% (NS); 5-year OS 89% vs. 92% (NS). Vaginal cuff recurrence 1% vs. 1% (NS), pelvic recurrence 4% vs. 4% (NS), distant recurrence 5% vs. 5% (NS)
*** Conclusion: Class II hysterectomy didn't improve LRC or survival for clinical Stage I patients. However, if adequate cuff transection not feasible with Class I, recommend modified radical hysterectomy

## Early Stage
### Preop BT vs Preop 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: 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

### Surgery +/- Pelvic EBRT

* PORTEC (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, G3, IC predictive for LR; If 2 of 3 criteria, LR 23% vs. 4% (SS)
*** 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
** 8-years, 2003 PMID 12713981 Full Text — "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
*** 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)
*** Salvage: 3-year OS: after vaginal relapse 73%, after pelvic relapse 8%, after DM relapse 65%.
*** Vaginal salvage: 5-year OS: control group better 65% vs. RT group 43% (SS).
*** Conclusion: Limit pelvic RT to only if >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: age >60, Stage IC, Grade 3. LVI poor prognosis for DM
*** Conclusion: In view of significant LR control benefit, RT indicated if high-risk features (2 of 3: age >60, G3, IC)
** 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.
* GOG 99 (1987-1995)
** 392 pts randomized to postoperative XRT vs no further therapy. Fields: superior border at L4/L5, lateral borders 1cm beyond pelvis, posterior border at posterior border of S3, ant border at symphysis pubis. Dose: 50.4 Gy. No brachytherapy
** Originally included "intermediate risk" -- stages IB, IC, and II (occult), any grade, with negative LN. Revised during the course of study to enroll only "high intermediate risk" group: 1) >70 yrs old with only 1 other risk factor (Grade 2 or 3 tumor; lymphovascular invasion; outer third myometrial invasion), 2) >50 yrs old with 2 risk factors; 3) any age with 3 risk factors. All pts had TAH/BSO, selective bilateral pelvic and para-aortic lymphadenectomy.
** 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.
*** 2-yr recurrence rate: 3% vs 12%. 2-yr LR 1.6% vs 7.4%. 4-year OS 92% vs 86% (NS). In HIR subgroup: 2-yr recurrence, 6% vs 26%.
*** Conclusion: limit RT to high intermediate risk group.
** Comment: OS not primary survival, not powered for it. Primary end-point DFS, which was significantly better with RT

### Surgery and Vaginal BT +/- EBRT

* Norwegian Radium Hospital, 1980
** 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.
*** 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)
*** 9-year outcome: OS BT alone 90% vs BT+EBRT 87% (NS). RT 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

### Surgery + Pelvic EBRT vs. Vaginal BT

* PORTEC 2 (2002-2006) -- Pelvic EBRT 46/23 vs. vaginal BT 21/3
** 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, Clin Oncol 26: 2008 (May 20 suppl; abstr 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, 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, 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

### Surgery + Pelvic EBRT vs. Chemo-RT

* Finland (1992-1996) -- adjuvant 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, Gynecol Oncol. 2008 Jun 3. [Epub ahead of print])
*** 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

### Surgery + Pelvic EBRT vs. Chemo

* JGOG 2033 (1994-2000) -- adjuvant EBRT vs. adjuvant CAP
** 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
* Italy (1990-1997) -- adjuvant EBRT vs. adjuvant CAP
** 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

### Vaginal Brachytherapy Dose

* Oreboro; Sweden (1989-2003)
** Randomized. 290 low-risk (endometrioid, Stage IA-B, Grade 1-2, <50% myometrial infiltration, diploid DNA, pLN-, washings-), Stage IA 62%, Stage IB 38%. Vaginal cylinders 20-30 mm, dose prescription 5mm depth. All received 6 fractions in 8 days, randomized to Arm 1) 2.5 Gy/fractions (total 15 Gy) or Arm 2) 5.0 Gy/fx (total 30 Gy). Colpometric measurements of vaginal shortening pretreatment and at 5 years
** 2005 PMID 16029797 -- "Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: a randomized study of two dose-per-fraction levels." (Sorbe B, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1385-9.)
*** Outcome: CSS 98.5% (NS), OS 95.3% (NS), no distant mets. Recurrence 1.4% (NS), 0.7% pelvic (NS) and 0.7% vaginal (NS)
*** Toxicity: no vaginal shortening for 2.5 Gy/fx group (pre vs. post) compared with 25% vaginal shortening (mean 2.1 cm) for 5.0 Gy/fx group. Also more vaginal atrophy and mucosal bleeding in 5.0 Gy/fx group
*** Conclusion: Recommend six fractions of 2.5 Gy/fx in low-risk endometrial Ca

## Advanced Stage
### Surgery + Pelvic EBRT vs. Chemo-RT

* Finland (1992-1996) -- adjuvant 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, Gynecol Oncol. 2008 Jun 3. [Epub ahead of print])
*** 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

### Surgery + Pelvic EBRT vs. Chemo

* JGOG 2033 (1994-2000) -- adjuvant CAP vs adjuvant pelvic RT
** 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
* Italy (1990-1997) -- adjuvant CAP vs adjuvant pelvic RT
** Randomized. 345 patients, high risk endometrial carcinoma (ICG3 in 26%, IIG3 and myometrial invasion >50% in ~10%, III in 65%), excluded clear cell or UPSC. TAH/BSO with selective pelvic/PA LN sampling. Arm 1) adjuvant chemotherapy (cyclophosphamide 600 mg/m2, doxorubicin 40 mg/m2, cisplatin 50 mg/m2) x5 cycles vs Arm 2) Pelvic RT 45-50 Gy, upper border at L5, if PA LN+ then PA field 45/25, upper border at L1. Primary endpoint PFS and OS
** 7-years; 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 years
*** Outcome: 5-year OS chemo 66% vs RT 69% (NS), 7-year OS 62% vs 62% (NS). No difference in PFS. RT delayed local relapse, chemo delayed mets, but neither (SS).
*** Conclusion: No difference between adjuvant chemotherapy and adjuvant RT. Different patterns of failure

### Surgery + Whole abdominal RT vs. Chemo

* GOG 122 (1992-2000) -- WAI vs. AP
** 388 pts. Stage III-IV, all histologies. Required TAH/BSO, surgical staging, and <2cm residual tumor. Para-aortic LN allowed but no mets to chest or SCLV. Randomized to WAI (30 Gy, 20 fx, AP/PA plus boost to pelvic +/- para-aortic LN 15 Gy in 8 fx) vs chemotherapy (AP; doxorubicin + cisplatin q3w x 8 cycles).
** 2006 PMID 16330675 — "Randomized Phase III Trial of Whole-Abdominal Irradiation Versus Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study." Randall ME et al. J Clin Oncol. 2006 Jan 1;24(1). Median F/U 6.2 years
*** 5-year outcome: PFS raw RT 38% vs. chemo 42% (p not given), stage-adjusted 38% vs. 50% (SS); raw OS RT 42% vs. chemo 53% (p not given), stage-adjusted (despite it being ranomized trial) 42% vs. 52% (SS)
*** Recurrence locations: WAI: recurrence in 54% (pelvic in 13%, abdomen in 16%, distant 22%). For chemo: 50% recurrence (18%,14%,18%)
*** Grade 3-4 Toxicity: hematologic RT 14% vs. chemo 88%, GI 13% vs. 20%, cardiac 15% vs. 0%, neurologic 7% vs. 1%
*** Conclusion: chemotherapy improves PFS and OS for advanced disease, compared with whole abdomen RT, though with significant toxicity
** Comment: Despite this being a randomized trial, the chemo arm was stage-adjusted during analysis. Argument was that it had worse prognosis patients (presumably the Stage IIIC, however, LN+ was not a prognostic variable in the study itself). The whole abdomen arm also had bad prognosis patients (IIIA with serosal/adnexal mets). The raw OS result are still significantly better for the chemo arm, but raw PFS was comparable in the two arms (38% vs. 42%). The statistical rationale is not justified, and thus questionable

## Vaginal and/or nodal recurrence

* GOG 238 (2008 - 2020) - RT vs cisplatin-RT
** Randomized. 165 patients. Recurrent endometrial cancer confined to vagina and/or lymph nodes. 1) Arm 1 - EBRT 45/25. Boost with HDR intracavitary brachy (60%), interstitial brachy (~12%), or EBRT boost to 65+ Gy (~25%). 2) Arm 2 - radiation + weekly cisplatin 40 mg/m2 weekly. Median age 66 years. Majority grade 1-2 endometrioid (82%) and vaginal only recurrence (86%)
** 2024 PMID 38662968 -- "Radiation Therapy With or Without Cisplatin for Local Recurrences of Endometrial Cancer: Results From an NRG Oncology/GOG Prospective Randomized Multicenter Clinical Trial" (Klopp AH, J Clin Oncol. 2024 Apr 25:JCO2301279. doi: 10.1200/JCO.23.01279. Online ahead of print.)
*** Outcome: PFS RT only 63% vs CRT 57% (NS). Median OS 8.0 years vs. 8.3 years (NS). Most common further recurrence vagina (30% vs 20%), pelvis (25% vs 10%), abdomen (26% vs 20%), liver (0% vs 10%), lung (9% vs 20%)
*** Toxicity: Acute effects worse for chemo-RT group, except for GI symptoms. Long terms effects no difference.
*** Conclusion: Radiation therapy alone can results in good outcomes, chemotherapy does not improve PFS and increases toxicity

## Uterine Sarcoma and Carcinosarcoma

* EORTC 55874 (1987-2000) -- observation vs. pelvic RT
** Randomized. 224 patients with high grade uterine sarcoma (leiomyosarcoma 46%, carcinosarcoma 41%, endometrial stromal sarcoma 13%), Stage I-II, treated with TAH/BSO + washings (75%), nodal sampling optional (25%). Arm 1) observation vs. Arm 2) pelvic RT 50.4/28 Field: top border L4/L5, lower border lower margin of obturator foramina, posterior border S2/S3
** 2008 PMID 18378136 -- "Phase III randomised study to evaluate the role of adjuvant pelvic radiotherapy in the treatment of uterine sarcomas stages I and II: An European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group Study (protocol 55874)." (Reed NS, Eur J Cancer. 2008 Mar 28 [Epub ahead of print])
*** Outcome: LRR only observation 18% vs. RT 3%, LRR at any time 40% vs. 21% (SS); no impact on PFS or OS
*** By subset: No benefit for LMS, improved local control for CS
*** Conclusion: Pelvic RT improves local control but not PFS or OS for carcinosarcoma, there is no benefit in leiomyosarcoma