# Radiation Oncology/Endometrium/UPSC

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* Staging |
* Overview |
* Early Stage |
* Locally Advanced Stage |
* UPSC |
* Clear Cell |
* Brachytherapy |
* Recurrence |
* Randomized |
* GOG Trials |
* Leiomyosarcoma: Main Page |
Uterine Papillary Serous Carcinoma

## Overview

* Please also see Endometrium Overview page
* First identified at Stanford in 1982, where it comprised ~10% of Stage I endometrial CA but resulted in 50% of relapses. Many relapses were characterized by upper abdominal failure
* 5-year disease-specific survival is worse for USC compared with grade 3 endometrioid carcinoma
** Stage I USC 72% vs ECCG3 76% (NS)
** Stage I/II USC 74% vs ECCG3 85% (SS)
** Stage III/IV USC 33% vs ECCG3 54% (SS)
* Due to similar behavior as ovarian carcinoma, adjuvant abdominal radiation was proposed. *GOG started a trial in 1986 (GOG 94) to evaluate treatment of advanced endometrial cancer with whole abdominal RT (WART), pelvic RT, and para-aortic boost as necessary. Eligible patients included Stage I-II UPSC and CC. Over 50% of failures for UPSC/CC patients were within the radiation field. WART alone is not sufficient

## Pathology

* Endometrioid (75-80%)
* Clear cell (5-10%)
** Clear due to presence of glycogen
** Tubulocystic, papillary, or solid patterns
** Psammoma bodies not as common
** Have to be present in at least 25-50% (depending on pathologist) of sample to qualify as clear cell
** Aggressive, with myometrial invasion in ~80%
* Papillary serous (1-5%)
** Complex papillary architecture, similar to papillary serous CA of ovary
** Presence of psammoma bodies
** Marked nuclear atypia
** Believed to transform from endometrial surface epithelium
* Mixed pattern
** Serous and endometrioid histology present next to each other in the specimen
** If >50% serous component, classified as papillary serous
** If 10-50% serous component, classified as mixed serous
* Rare tumor types (<2%)
** Mucinous, squamous cell, transitional cell, small cell

## Pathology

* Stanford; 1982 PMID 7102898 -- "Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma." (Hendrickson M, Am J Surg Pathol. 1982 Mar;6(2):93-108.)
** Retrospective. 256 Stage I uterine adenoCA reviewed, 26 UPSC identified. High cytologic anaplasia and papillary growth pattern. Frequent LVI+, frequent Stage IC (40% vs. 12%)
** Outcome: relapse rate ~50% vs. 5%; Stage IC relapse 63% vs. 30%. Tendency to relapse over peritoneal surfaces
** Conclusion: Clinically aggressive, similar to ovarian CA

## Sentinel Node Staging

* Memorial Sloan Kettering; 2017 (2005 - 2015) PMID 28258415 -- "Survival of Patients with Serous Uterine Carcinoma Undergoing Sentinel Lymph Node Mapping." (Schiavone MB, Ann Surg Oncol. 2017 Jul;24(7):1965-1971. doi: 10.1245/s10434-017-5816-4. Epub 2017 Mar 3.)
** Retrospective. 248 patients (153 SLN and 95 LND). Stage distribution comparable (I-II in 69% vs 62%, III in 31% vs 38%). Median LN removed 12 vs 21 (SS). Adjuvant chemo or chemo-RT comparable (80% vs 83%), adjuvant RT alone comparable (8% vs 7%). Median F/U 3.3 years
** Outcome: 2-year PFS SLN 77% vs LND 71% (NS)
** Conclusion: Incorporating SLN into staging of uterine serous cancer does not appear to compromise prognosis

## Stage I

* Mayo; 2007 (1982-2005) PMID 17688926 -- "Role of systematic lymphadenectomy and adjuvant therapy in stage I uterine papillary serous carcinoma." (Thomas MB, Gynecol Oncol. 2007 Aug 2; [Epub ahead of print])
** Retrospective. 42 patients (IA 15, IB 21, IC 6). 81% LND, 69% omentectomy, 45% peritoneal biopsies. Median F/U 3.2 years
** Outcome: 5-year OS 85%, PFS 78%. By stage OS IA 100%, IB 89%, IC 60%.
** Recurences: LN recurrence in LND 0/34 vs. no LND 1/8 (NS); none in IA regardless of post-op therapy; 0/20 IB and IC who had vaginal BT vs. 2/7 with no vaginal BT (SS). Hematogenous/peritoneal recurrence in 0/6 patients with chemo vs. 3/13 patients with no chemo.
** Conclusion: Observation reasonable for IA if LND done; for IB and IC consider chemotherapy and vaginal brachytherapy
* Yale; 1998 PMID 9422561 -- "Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy." (Turner BC, Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):77-84.)
** Retrospective. 38 patients treated with TAH/BSO, +/-LND, with combinations of chemo and RT. 20 patients vaginal LDR with WART or WPRT (6/20 had complete surgical staging, 2/20 concurrent chemo). 18 patients vaginal HDR (15/18 had complete surgical staging, 5/18 concurrent chemo).
** Outcome: 5-year OS complete surgical staging and HDR /chemo 100% vs. incomplete staging HDR/chemo 61% vs. complete staging LDR/WART 100% vs. incomplete staging LDR/WART 65%. OS by stage IA 100%, Stage IB 71%, Stage IC 40%
** Toxicity: WART and/or LDR had Grade 3-4 toxicity in 15%, complications from vaginal HDR minimal
** Conclusion: If complete surgical staging, can be effectively and safely treated with vaginal HDR and chemotherapy

## General

* Harvard; 2011 (1980-2006) PMID 21963091 -- "The importance of chemotherapy and radiation in uterine papillary serous carcinoma." (Viswanathan AN, Gynecol Oncol. 2011 Dec;123(3):542-7. doi: 10.1016/j.ygyno.2011.09.005. Epub 2011 Oct 2.)
** Retrospective. 135 women, Stage I-IVA UPSC. Stage I 47%, Stage II 12%, Stage III 37%, Stage IVA 4%. Chemotherapy in 32%. Radiation in 66% (whole abdomen 24%, pelvis 31%, brachytherapy 33%). Mean F/U 5.5 years.
** Outcome: Median 5-year OS 52%, RFS 42%. OS improved by paclitaxel-containing chemotherapy (HR 0.34, SS). RFS improved by radiation (HR 0.44, SS). 5-year LR 15%, reduced by RT (HR 0.2). 5-year DM 26%, not reduced by paclitaxel/carboplatin
** Stage IA outcome: N=21. 5-year OS 71%. No further therapy N=17, pelvic RT N=4. Relapse in 5 patients (24%), vaginal 1, vaginal/pelvic 1, lymphatic 1, peritoneal 1, distant 1.
** Toxicity: Grade 3+ in 3.5% with RT, 2.9% without RT (NS)
** Conclusion: RFS was improved by radiation and chemotherapy, and should be attempted whenever feasible

## "Sandwich" chemotherapy and radiation

* Albert Einstein College of Medicine; 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. Protocol completion 83%
** 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" is well and highly efficacious in completely resected UPSC

## Patterns of Failure

* Westmead Hospital, Sydney, Australia; 2009 (1995-2006) PMID 19694700 -- "Uterine papillary serous carcinoma: patterns of failure and survival." (Wang W, Aust N Z J Obstet Gynaecol. 2009 Aug;49(4):419-25.)
** Retrospective. ? patients, TAH/BSO/surgical staging, majority with platinum-based chemotherapy and radiotherapy
** Outcome: 2-year OS 65%, 5-year OS 43%. Macroscopic residual disease only predictor of survival (if R2, median OS 11 months). Site of recurrence vagina (n=5; for VBT 1/16 recurrences, for EBRT 4/7 recurrences), pelvic LN (n=24), para-aortic LN (n=6), inguinal LN (n=2), abdomen (n=11), and distant mets (n=7)
** Conclusion: Recommend optimal cytoreduction; vaginal brachytherapy should be considered as a component of adjuvant radiotherapy. Abdominal failure most common

## Whole Abdomen RT

* GOG 94 (1986-1994)
** 2006 PMID 16213007 -- "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, Gynecol Oncol. 2006 Feb;100(2):349-54.)
** Phase II. 21 patients treated with TAH/BSO, PPALND, WART 30/20 and pelvic boost to 50 Gy
** Outcome: >50% failures within RT field
*** UPSC: 5-year OS 38%, PFS 38%
*** Clear cell: 5-year OS 54%, PFS 54%
** Toxicity: 17% Grade 3-4 GI toxicity (SBO, proctitis, N/V)
** Conclusion: WART alone not adequate, chemotherapy needs to be a component of treatment. Clear cell better outcome than UPSC
* Stanford; 2000 (1979-1998) PMID 11020574 -- "Treatment of high-risk uterine cancer with whole abdominopelvic radiation therapy." (Smith RS, Int J Radiat Oncol Biol Phys. 2000 Oct 1;48(3):767-78.)
** Retrospective. 48 patients with Stage III-IV endometrial ACA (n=22) or Stage I-IV UPSC or CC (n=26), treated with postop WART. Median dose 30 Gy abdomen (in 1.2-1.5 Gy/fx) and 50 Gy pelvis (in 1.2-1.8 Gy/fx). PALN boost to 44 Gy in 9 patients. Vaginal brachy in 24 patients. Mean F/U 3.1 years
** Outcome: 3-year OS all patients 77%, ACA 89% vs. UPSC/CC 68%; UPSC/CC Stage I-II OS 87% vs. Stage III-IV 61%; DFS 87% vs. 31%
** Toxicity: major complications (SBO) 7%, no deaths, 23% required break >1 week
** Conclusion: WART is safe, effective. Recommend with vaginal cuff brachy for Stage I-II. Recommend with concurrent or sequential chemo in Stage III-IV UPSC/CC until results of GOG 94 and GOG 122 become available (see Advanced Stage chapter).

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

* HOG 97-01 PMID 15721431 -- "Intraperitoneal radioactive phosphorus (32P) and vaginal brachytherapy as adjuvant treatment for uterine papillary serous carcinoma and clear cell carcinoma: a phase II Hoosier Oncology Group (HOG 97-01) study." (Fakiris AJ, Gynecol Oncol. 2005 Mar;96(3):818-23.)
** Phase II. 21 patients s/p TAH-BSO, residual peritoneal disease <3mm, negative PPALN. Intraperitoneal P-32 15 mCi within 8 weeks. Vaginal BT. Median F/U
** Outcome: 2-year OS 89%, DFS 80%; recurrences 5/21, but only 2/21 intraperitoneal
** Toxicity: No Grade 2-4
** Conclusion: Adjuvant intraperitoneal P-32 and vaginal BT feasible, well tolerated

## Reviews

* 2009: SGO PMID 19592079 PDF -- "Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review." (Boruta DM, Gynecol Oncol. 2009 Oct;115(1):142-53.)