# Radiation Oncology/Endometrium/Locally Advanced Stage

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Locally Advanced Endometrial Cancer (III-IV)

## Overview

* Stage III and IV disease represents ~16% of endometrial cancer
* Systemic chemotherapy is superior to whole abdominal radiation, based on GOG 122. However, chemotherapy alone has pelvic relapse rates of 20-40%, and 5-year OS only 50%
* Addition of chemotherapy to pelvic radiation in two European randomized trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) improved progression-free survival and trended to improved overall survival
* GOG 184, which evaluated incorporation of paclitaxel into the chemotherapy regimen, used postoperative radiation as a standard component
* Retrospective multi-institutional data suggests improved OS with combination of chemotherapy and radiation therapy, delivered as a "sandwich" (chemotherapy -> radiation therapy -> chemotherapy)

## Sequential chemotherapy with radiation therapy

* Albert Einstein; 2012 PMID 22035806 -- "Phase II trial of adjuvant pelvic radiation "sandwiched" between combination paclitaxel and carboplatin in women with uterine papillary serous carcinoma." (Einstein MH, Gynecol Oncol. 2012 Jan;124(1):21-5. Epub 2011 Oct 27.)
** Phase II. 81 patients (89% completed chemo->RT and are reported here), surgically staged UPSC, no visible residual. Stage I/II 82%, Stage III/IV 18%. Adjuvant paclitaxel 175 mg/m2 and carboplatin AUC 6 Q3 weeks x 3 cycles, followed by RT (pelvis 45/25, PA if 2+ pelvic nodes or documented PA disease, HDR vaginal brachytherapy 5 Gy x 3 at 0.5 cm), followed by chemotherapy x 3 cycles
** Outcome: Stage I/II OS 6.3 years, Stage III/IV OS 3.0 years. 3-year OS 84% and 50%. PFS 5.4 years and 2.1 years
** Toxicity: G3/4 non-hematologic toxicity 2.5%
** Conclusion: RT-chemotherapy "sandwich" well tolerated and high efficacious in completely resected UPSC
* NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III
** NSGO-9501/EORTC-5591 (1996-2007): endometrial cancer, status post surgery, Stage I (high risk), Stage II, Stage IIIA (only positive cytology) and Stage IIIC (only positive pelvic lymph nodes). Arm 1) adjuvant RT only vs Arm 2) adjuvant chemotherapy and radiation therapy. Sequence of therapy elective. Pelvic RT. Vaginal brachytherapy ~40%. Chemotherapy several alternative regimens. 383 patients accrued.
** MaNGO ILIADE-III (1998-2007): endometrioid cancer, Stage IIB, IIIA-IIIC (arm IIIA with cytology only excluded), serous/clear cell excluded. Arm 1) adjuvant RT only vs Arm 2) adjuvant chemotherapy and radiation therapy. Pelvic RT 45/25, PA-field as needed to L1/L2. Vaginal brachytherapy if cervical stromal involvement. Chemotherapy doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 Q3W x 3 cycles. 157 patients accrued
** Pooled Results; 2010 PMID 20619634 -- "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies." (Hogberg T, Eur J Cancer. 2010 Sep;46(13):2422-31. Epub 2010 Jul 7.)
*** Outcome: 5-year PFS RT 69% vs RT-CT 78% (HR 0.6, SS), 5-year OS RT 75% vs RT-CT 82% (HR 0.7, p=0.07). Subset analysis shows no benefit of chemotherapy for serous/clear cell, while significant benefit for endometrioid
*** Conclusion: Addition of adjuvant chemotherapy to radiation improves progression free survival, with trend to improved overall survival
* University of Western Ontario
** Prospective. Stage III-IV (IIIA 21%, IIIC 70%, IVB 9%) endometrial cancer. Hysterectomy. Adjuvant paclitaxel (175 mg/m2) and carboplatin (350 mg/m2) Q3 weeks x 4 cycles, followed sequentially by pelvic RT 45 Gy (3D-CRT 58% vs IMRT 42%, EFRT 30%), followed by paclitaxel / carboplatin x 2 cycles. Para-aortic RT and HDR vaginal brachytherapy (5-7.5 Gy x 3 at 0.5 cm depth) at discretion.
** Update; 2009 (2002 - 2006) PMID 19406459 -- "Adjuvant carboplatin and paclitaxel chemotherapy interposed with involved field radiation for advanced endometrial cancer." (Lupe K, Gynecol Oncol. 2009 Jul;114(1):94-8. Epub 2009 Apr 29.)
*** 43 patients. Most common Stage IIIC (63%), serous carcinoma (49%). Median F/U 2.5 years
*** Outcome: Local recurrence 3% (2 pelvis, 1 vagina/vulva). Overall recurrences 49% at median 1.5 years. 3-year DFS 53%, 3-year OS 68%
*** Conclusion: Low rate of local recurrence and favorable survival
** Preliminary; 2007 (2002-2005) PMID 17084542 -- "Adjuvant paclitaxel and carboplatin chemotherapy with involved field radiation in advanced endometrial cancer: a sequential approach." (Lupe K, Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):110-6. Epub 2006 Nov 2.)
*** 33 patients. Median F/U 1.75 years
*** Outcome: 2-year DFS 55%, 2-year OS 55%. One pelvic relapse (3%)
*** Toxicity: chemotherapy acute grade 3/4 toxicity 27%; radiation 12%. Late RT toxicity 18%
*** Conclusion: Adjuvant chemotherapy with interposed radiation well tolerated
* Multi-Institutional; 2009 (1993-2007) PMID 19560193 -- "A multicenter evaluation of sequential multimodality therapy and clinical outcome for the treatment of advanced endometrial cancer." (Secord AA, Gynecol Oncol. 2009 Sep;114(3):442-7. Epub 2009 Jun 26.)
** Retrospective. Three institutions (Duke, UNC, Ohio State). 109 patients. Stage III-IV disease, status post surgery. Endometrioid 48%, optimal cytoreduction 90%, chemo->RT->chemo (CRC) 41%, chemo->RT (CR) 42%, RT->chemo (RC) 17%.
** Outcome: 3-year OS CRC 88% vs CR 57% vs RC 54% (SS), adjusted HR for OS CR 2.6 (SS) and RC 5.7 (SS)
** Toxicity: no difference among arms
** Conclusion: Sequential chemo->RT->chemo is associated with improved survival compared to other sequencing, with similar side effect profile

## Concurrent radiation therapy with chemotherapy

* 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.

## Pelvic RT vs. Adjuvant chemotherapy

* 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 (1990-1007) -- 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

## Whole abdominal RT vs. Adjuvant chemotherapy

* GOG 122 (1992-2000)
** 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 0% vs. 15%, neurologic 1% vs. 7%
*** 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

## Whole abdominal irradiation + chemotherapy

* GOG 9001 (1990-92) - PMID 8946862, 1996 — "A phase I study of weekly cisplatin and whole abdominal radiation for the treatment of stage III and IV endometrial carcinoma: a Gynecologic Oncology Group pilot study." Reisinger SA et al. Gynecol Oncol. 1996 Dec;63(3):299-303.
** Phase I. 10 pts. Stage III-IV, maximally debulked. Treated with whole abdomen RT + Pelvic/PA Boost + cisplatin 15 mg/m2 QW
** Conclusion: tolerance comparable to whole abdomen alone

## Whole abdominal irradiation

* GOG 94 (1986-94) - Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer. Also included Stage I-II papillary serous or clear cell.
** Phase II.
** PMID 15913742, 2005 — "Whole abdominal radiotherapy in the adjuvant treatment of patients with stage III and IV endometrial cancer: a gynecologic oncology group study." Sutton G et al. Gynecol Oncol. 2005 Jun;97(3):755-63.
** PMID 16213007, 2006 — "Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: A phase II study of the Gynecologic Oncology Group." Sutton G et al. Gynecol Oncol. 2006 Feb;100(2):349-54.
* MD Anderson; 1983 (1961-1978) PMID 6654180 -- "Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by the whole-abdomen moving-strip technique and pelvic boost irradiation." (Greer GE, Gynecol Oncol. 1983 Dec;16(3):365-73.)
** Retrospective. 31 patients with intraperitoneal metastatic endometrial CA, residual disease <2cm, treated with whole-abdomen moving-strip technique and pelvic boost RT
** Outcome: 5-year absolute OS 63%, corrected OS 80%
** Conclusion: Feasible, toxicity tolerable

## Radioactive Phosphorus (P$^{32}$)

* 1985 (1977-1983) PMID 4037013 -- "Intraperitoneal chromic phosphate P 32 suspension therapy of malignant peritoneal cytology in endometrial carcinoma." (Soper JT, Am J Obstet Gynecol. 1985 Sep 15;153(2):191-6.)
** Prospective. 65 women with positive washings (clinical Stage I 80%, Stage II 14%, Stage III 7%). Adjuvant P-32
** Outcome: 2-year PFS clinical Stage I 89%, surgical Stage I 94%; recurrences: 9% intraperitoneal, 36% intraperitoneal/distal, 55% distal
** Toxicity: Grade 4 GI in 0% if P-32 alone vs. 29% if combined with EBRT
** Conclusion: P-32 effective, but caution if P-32 combined with EBRT
* 1981 PMID 7315922 -- "Prognostic significance of peritoneal cytology in patients with endometrial cancer and preliminary data concerning therapy with intraperitoneal radiopharmaceuticals." (Creasman WT, Am J Obstet Gynecol. 1981 Dec 15;141(8):921-9.)
** Prospective. 23 patients with clinical Stage I, but positive washings on TAH/BSO (IIIA), treated with intra-abdominal P-32
** Outcome: 3 recurrences, none in abdominal cavity
** Conclusion: intraperitoneal P-32 efficacious if positive washings