Gynecologic Malignancies — Board Review Summary

PART I — ENDOMETRIAL CANCER

Epidemiology and Classification

Most common gyn malignancy in developed world. ~70% diagnosed early stage. Risk factors: obesity, nulliparity, unopposed estrogen, tamoxifen, diabetes, HTN, Lynch (dMMR). Protective: breastfeeding, physical activity, smoking.

Type I (80%): endometrioid grade 1–2, estrogen-responsive, favorable prognosis, ~1/3 MSI.
Type II (10–20%): serous, clear cell, mucinous, grade 3 endometrioid. Hormone-independent, aggressive. Rare MSI; frequent TP53, PIK3CA mutations.

TCGA/ProMisE Molecular Classification (know all 4)

Group	Frequency	Behavior
POLE-mutated (ultramutated)	~6% low grade, 17% high grade	Best prognosis; candidate for de-escalation
MMR-deficient / MSI-high (hypermutated)	29% low grade, 54% high grade	Intermediate prognosis; immunotherapy-responsive
Copy-number low (NSMP / endometrioid-like)	60% low-grade endometrioid	Intermediate prognosis
Copy-number high (serous-like, p53abn)	Serous; 90% have p53 mutations	Worst prognosis

FIGO 2023 Staging (MAJOR REVISION — memorize the changes)

Why this matters: FIGO 2023 fundamentally restructured endometrial staging to incorporate molecular biology and LVSI quantification. Questions on recent boards heavily favor FIGO 2023. Know the key 2009 → 2023 reclassifications cold.

LVSI Grading — Three-Tier (2023)

LVSI Category	Definition	Stage Impact
Absent / Focal	No LVSI or single-vessel focal involvement	No stage change
Substantial	Diffuse/multifocal LVSI in >5 vascular spaces OR >50% of vessels in an area	→ Stage IIB (independent upstager)
Any LVSI + aggressive histology with MI	Combined	→ Stage IIC (combined upstager)

Key 2009 → 2023 Reclassifications

Scenario	FIGO 2009	FIGO 2023
Aggressive histology, no MI	IA	IC (new)
Aggressive histology, <50% MI	IA	IIC (major reclass)
Substantial LVSI (no other HIR feature)	HIR feature only	Stage IIB (independent upstage)
Synchronous uterine+ovarian LG endometrioid*	IIIA	IA3 (downstaged)
Adnexal vs serosal	Both IIIA	IIIA1 (adnexal) vs IIIA2 (serosal, worse)
Nodal disease	IIIC1/IIIC2	Micro (i) vs macro (ii) separated
Peritoneal vs distant mets	Both IVB	IVB (peritoneal) vs IVC (distant)
POLEmut, stage I/II	Not considered	IAm (downstaged)
p53abn, stage I/II	Not considered	IIC p53abn (upstaged)

*Conditions for downstaging synchronous LG to IA3: superficial MI <50%, no substantial LVSI, no additional mets, unilateral ovarian tumor without capsule invasion/rupture (pT1a).

FIGO 2023 Stage II Expansion

Substage	Definition	Risk Group
IIA	Non-aggressive histology invading cervical stroma (no extension beyond uterus)	Intermediate–High
IIB (new)	Substantial LVSI, non-aggressive histology	High Risk
IIC (new)	Aggressive histology with any MI (G3/serous/clear cell/carcinosarcoma)	High Risk
IICm (p53abn)	Any Stage I/II with p53abn (TP53 mut)	Very High Risk

FIGO 2023 Stage III Granularity

Substage	Definition
IIIA1	Adnexal only (ovaries/tubes)
IIIA2	Uterine serosal (worse than IIIA1)
IIIB	Vaginal or parametrial
IIIC1i	Pelvic LN micrometastasis (0.2–2 mm, SLN ultrastaging)
IIIC1ii	Pelvic LN macrometastasis (>2 mm, routine H&E)
IIIC2i / IIIC2ii	Para-aortic micro / macro ± pelvic

Staging technical requirements: (1) surgical (TAH-BSO minimum, preferably minimally invasive); (2) grade, histotype, LVSI documented regardless of molecular; (3) molecular classification (POLEmut/MMRd/p53abn/NSMP) encouraged in all, add modifier "m" when done; (4) infracolic omentectomy required for serous, undifferentiated, carcinosarcoma; (5) SLN ultrastaging with H&E + IHC (AE1/AE3) required for IIIC1i vs IIIC1ii classification.

Nodal Disease Classification

Category	Size	Detection
Negative	0 cells	No tumor on H&E or IHC
Isolated tumor cells (ITC)	<0.2 mm	IHC only (not treatment-changing)
Micrometastasis	0.2–2 mm	Ultrastaging (missed by routine H&E) → IIIC1i
Macrometastasis	>2 mm	Routine H&E → IIIC1ii

Early-Stage Adjuvant Management

Landmark RT Trials (memorize)

Trial	Core question	Bottom line
PORTEC-1 (Creutzberg Lancet 2000)	EBRT vs obs (IC G1-2, IB G2-3)	EBRT ↓ LRR 15%→6%. No OS benefit. 2/3 of recurrences in obs group in upper vagina
GOG-99 (Keys Gynecol Oncol 2004)	EBRT vs obs after surgical staging	EBRT ↓ recurrence 12%→3%. Defined HIR criteria. No OS benefit
PORTEC-2 (Nout Lancet 2010)	VBT vs EBRT in HIR	VBT non-inferior to EBRT; better QOL, ↓ GI toxicity. VBT = new HIR standard
GOG-249 (Randall JCO 2019)	VBT + chemo vs EBRT for HIR/HR	More pelvic and PA nodal failures with VBT+chemo; more acute G3+ toxicity. VBT+chemo NOT superior to EBRT
PORTEC-4a (van den Heerik Lancet 2024)	Molecular-guided vs standard VBT	First prospective molecularly tailored adjuvant RT trial. Locoregional recurrence 8.4% (molecular) vs 30.5% (standard VB) — but "molecular" arm stratified into obs/VBT/EBRT by biology

HIR Definitions

PORTEC-1 HIR	GOG-99 HIR
Age ≥60; or grade 1-2 with ≥50% MI; or G3 <50% MI; or Stage IIA	Age ≥70 + 1 RF; age 50-69 + 2 RFs; any age + 3 RFs. RFs: G2-3, LVSI, outer-third MI

Vaginal Brachytherapy Fractionation

Setting	Regimen	Rx point
Monotherapy	7 Gy × 3	5 mm
Monotherapy	5 Gy × 5	5 mm
Monotherapy	2.5 Gy × 5	5 mm
Monotherapy (MDA)	6 Gy × 5	Surface
Post-EBRT (RTOG 0921/0418)	6 Gy × 3	Surface
Post-EBRT (MDA)	5 Gy × 2	Surface

VBT technical: treat 3–5 cm of upper vagina. Applicators: single-channel vs multi-channel. 3D planning preferred (air gap assessment, normal tissue dose).

Ongoing: TAPER Study

Tests observation vs VBT in p53wt/NSMP endometrioid, ER+ cases with favorable profile. Stage IB grade 1-2 with no/focal LVI → observation; higher risk → VBT. De-escalation for molecular favorable biology.

Ongoing: RAINBO Study

Tests observation in POLE-mutated endometrial cancer across all histologies (stage I–II with favorable features). Rationale: POLE outcomes excellent regardless of histology; may safely omit adjuvant.

Locally Advanced Endometrial: Key Trials

Trial	Design	Takeaway
PORTEC-3 (de Boer Lancet Onc 2018; JAMA Onc 2022)	EBRT 48.6 Gy ± concurrent cis + adjuvant carbo/pac × 4	Eligibility: IA G3 with deep MI + LVSI, IB G3, II or III endometrioid, I-III USC/CC. ChemoRT improves FFS and OS at 10y; p53abn benefits most. POLE does NOT benefit from chemo
GOG-258 (Matei NEJM 2019)	ChemoRT (cis d1+d29 with 45 Gy EBRT) + 4 cycles carbo/pac vs carbo/pac × 6 alone	Eligibility: stage I-II serous/CC or stage III-IVA endometrioid. No OS or PFS benefit from CRT; CRT improved LOCOREGIONAL but not distant control. Chemo alone insufficient for locoregional control. dMMR and p53wt tumors had better RFS

PORTEC-3 vs GOG-258 reconciliation: PORTEC-3 established chemoRT for high-risk, but GOG-258 showed chemo alone is not enough for locoregional control. Current practice for stage III: chemoRT (per PORTEC-3) with sequencing usually being chemo-first or sandwich. For advanced disease with residual measurable disease, chemo-immunotherapy (below) is now increasingly incorporated.

Extended-Field Technique

Upper border: T12/L1 (above renal hilum) for extended-field PA coverage.
Dose: 45 Gy pelvis + 50 Gy SIB to gross nodes → 10 Gy boost to residual if possible.
Duodenum constraints: V55 <15 cc, V60 <2 cc.
Consider neoadjuvant chemo if bulky PA nodes before extended-field RT.

Immunotherapy Integration (NRG-GY018 and RUBY)

Feature	RUBY (Dostarlimab)	NRG-GY018 (Pembrolizumab)
Agent	Dostarlimab 500 → 1000 mg Q6W × 3 yr maintenance	Pembrolizumab 200 → 400 mg Q6W × 14 cycles
N	494 (single trial, MMR-stratified)	816 (610 pMMR, 206 dMMR — two independent cohorts)
Population	Advanced III/IV or 1st recurrent, any histology	Stage III/IVA measurable; IVB/recurrent, any histology
Chemo backbone	Carbo AUC5 + paclitaxel 175 mg/m² × 6	Carbo + paclitaxel × 6
dMMR PFS HR	0.28 (CI 0.16–0.50)	0.30 (CI 0.19–0.48)
Overall PFS HR	0.64 (met)	0.54 pMMR / dMMR NR (met)
OS HR (overall)	0.69 ✓ met (median OS 44.6 vs 28.2 mo)	Immature; trend 0.79 pMMR
OS HR (dMMR)	0.32 ✓	0.55 interim
FDA approval	August 2024 — any MMR	June 2024 — any MMR

Clinical scenario gap: both trials required measurable disease for stage III endometrioid. Stage III endometrioid without measurable residual post-surgery (common after complete debulking) is a recognized evidence gap — not FDA-approved for chemo-IO in that setting. Serous/clear cell/carcinosarcoma stage III without measurable is covered by RUBY but not GY018.

PART II — CERVICAL CANCER

Epidemiology and Pathology

2nd most common cancer in women worldwide; ~13,490 new US cases/yr. Nearly all are HPV-driven.

High-risk HPV: 16 and 18 (70% of cervical cancers), 31 and 45 (10%), others 33/35/39/51/52/56/58/59/68/73/82. Low-risk: 6, 11 (genital warts).
Histology: SCC 85%, adenocarcinoma 10%, clear cell 1% (DES exposure), rare: sarcoma, lymphoma, neuroendocrine.
Workup: H&P, EUA, ± cystoscopy/proctoscopy, PET-CT or CT C/A/P, pelvic MRI (superior for uterine body/PM invasion per ACRIN 6651/GOG 183; superior for vaginal extension).

Risk of Nodal Metastases by Stage

Stage	Pelvic LN+	PA LN+
IA1	<1%	—
IA2	6–7%	<3%
IB	15%	10%
IIB	30%	20%
III	45%	30%

FIGO 2018 Cervical Cancer Staging (recent restructure)

Stage	Definition
IA1 / IA2	Stromal invasion ≤3 mm / >3–5 mm
IB1 / IB2 / IB3	NEW 2018: 3 substages by size — <2 cm / 2–<4 cm / ≥4 cm
IIA1 / IIA2	Upper 2/3 vagina, <4 cm / ≥4 cm (no parametrial)
IIB	Parametrial invasion (any size)
IIIA	Lower 1/3 vagina, no pelvic wall extension
IIIB	Pelvic wall extension and/or hydronephrosis
IIIC1 / IIIC2	NEW 2018: nodal disease upstages — pelvic (IIIC1) or PA (IIIC2), with "r" radiographic or "p" pathologic
IVA	Bladder/rectal mucosa (biopsy-proven; bullous edema alone does NOT qualify)
IVB	Distant organs (lungs, liver, bone, distant LN)

Key 2018 changes: (1) IB now has 3 substages by tumor size; (2) NEW Stage IIIC created for nodal disease — any T with nodal disease gets upstaged; (3) imaging AND pathology now formally permitted for staging (r and p suffixes); (4) LVSI documented but does NOT change stage.

Surgical Management

Types: radical trachelectomy (fertility-sparing for small lesions), total hysterectomy (non-oncologic), radical hysterectomy (parametrium + upper vagina for cervical cancer).
LACC trial (Ramirez NEJM 2018): minimally invasive < open surgery — worse OS and higher locoregional recurrence with MIS. Open radical hysterectomy is standard for early cervical cancer.

Adjuvant Post-Hysterectomy: GOG-92 (Sedlis Criteria)

GOG-92 (Sedlis Gynecol Oncol 1999; Rotman IJROBP 2006): Stage IB s/p radical hyst with high intermediate risk — RT vs observation. 10-year update: PFS 46% ↓ in HR, OS 30% improvement (p=0.074), especially marked for adenocarcinoma/adenosquamous (recurrence 8.8% RT vs 44% obs).

GOG-92 Eligibility ("Sedlis criteria")

LVSI	Stromal Invasion	Tumor Size
Positive	Deep 1/3	Any
Positive	Middle 1/3	≥2 cm
Positive	Superficial 1/3	≥5 cm
Negative	Deep or middle 1/3	≥4 cm

Need 2 of 3 factors for RT benefit (some formulations): +LVSI, middle 1/3 invasion, ≥4 cm.

Adjuvant Chemoradiation: GOG-109 / SWOG-8797 (Peters Criteria)

GOG-109 (Peters JCO 2000): Stage IA2/IB/IIA s/p radical hyst with positive margins, positive LN, or +parametrium → RT alone vs RT + cis/5-FU. 4y PFS 80% vs 63%; 4y OS 81% vs 71%. Established adjuvant chemoRT for "Peters criteria" high-risk pts.

Definitive Chemoradiation for Locally Advanced

Sequencing and Dose

Weekly cisplatin 40 mg/m² × 5–6 during EBRT.
EBRT dose: 45 Gy (or 50.4 Gy — 45 Gy equally effective); SIB to 55–60 Gy for positive nodes.
Brachytherapy: EQD2 40–45 Gy to HR-CTV.
Total package time: <8 weeks — critical for outcomes.

Chemo-RT Meta-analysis (Vale JCO 2008)

Stage	OS benefit of chemoRT
I–IIA	↑ 10%
IIB	↑ 7%
IIIA–IVA	↑ 3%

IMRT / Contouring

TIME-C trial: IMRT vs 3D-CRT pelvic RT → improved EPIC bowel score (p=0.048). IMRT is standard for pelvic nodal/vaginal coverage.
CTV contouring: entire uterus/cervix/parametria bilaterally; inferior to upper border of obturator foramen if no vaginal involvement (or 3 cm below gross if vaginal involved).
Vaginal ITV: empty rectum → extends 2 cm anteriorly into bladder; distended rectum → extends posteriorly to within 1.5 cm of posterior rectal wall.

EMBRACE-II Nodal Coverage by Risk Group

Risk group	Definition	Coverage
Low risk	≤4 cm AND IA/IB/IIA1 AND N0 AND SCC AND no uterine invasion	"Small pelvis" — internal/external iliac, obturator, presacral
Intermediate risk	Not low risk, no high-risk features	"Large pelvis" — small pelvis + common iliac (+ inguinal if distal vaginal; + mesorectal if involved)
High risk	≥1 pathologic node at common iliac or above, OR ≥3 pathologic nodes	"Large pelvis + PA" — up to renal veins (usually L2), 3 cm cranial to highest + node

PA contouring key data (Takiar IJROBP 2013): PA node distribution from aortic bifurcation — 4% upper third, 36% middle third, 60% lower third. Field borders: T12 for PA + imaging involvement; L2 for common iliac + imaging; L3/L4 for standard pelvis only (ext/int iliac + aortocaval bifurcation).

Brachytherapy: Critical for Cervical Cancer

Brachytherapy matters. Han IJROBP 2013 — OS is significantly lower when brachytherapy is omitted. RTOG 0116 and 0128 (Viswanathan IJGC 2012): poor implant geometry → higher LR. Unacceptable symmetry of ovoids/tandem → HR 2.50; ovoid displacement relative to os → HR 2.67; inappropriate packing → HR 2.06. Implant quality is testable.

MR-Based Target Definition (GEC-ESTRO)

Volume	Definition
GTV	Macroscopic tumor at brachytherapy (high signal on T2 FSE in cervix, corpus, parametria, vagina, bladder, rectum)
HR-CTV	GTV + whole cervix + presumed extracervical extension ("grey zones")
IR-CTV	HR-CTV + margins per tumor size/regression (5–15 mm minimum)

GEC-ESTRO Planning Goals

Target	Planning Goal	Upper Limit
D90 HR-CTV EQD2	>90 Gy (upper: <95 Gy)	>85 Gy minimum
D98 HR-CTV EQD2	>75 Gy	—
D98 GTV EQD2	>95 Gy	>90 Gy
D98 IR-CTV EQD2	>60 Gy	—
Point A EQD2	>65 Gy	—

GEC-ESTRO OAR Constraints

OAR	Planning Goal (EQD2)	Upper Limit
Bladder D2cc	<80 Gy	<90 Gy
Rectum D2cc	<65 Gy	<75 Gy
Sigmoid D2cc	<70 Gy	<75 Gy
RV (recto-vaginal) point EQD2	<65 Gy	<75 Gy

EMBRACE Outcomes (Potter Lancet Oncol 2021)

5-year local control 92%, pelvic control 87%, nodal control 93% (N0) vs 81% (N1).
Morbidity: fistula 3.2%, GI stenosis 2.8%, ureteric stricture 2.9%, vaginal stenosis 4.0%.

RetroEMBRACE (Tanderup Radiother Oncol 2016)

HRCTV volume matters: <30 cc vs ≥30 cc drives outcomes. Dose-response: higher EQD2 to HRCTV correlates with better LC.

Immunotherapy and Induction Chemo: Current Practice-Changers

KEYNOTE-A18 (Lorusso NEJM 2024; Monk Lancet 2025 OS)

High-risk LACC (FIGO 2014 IB2–IIB N+; III–IVA): pembro + CRT (cis weekly × 5) + brachy + pembro maintenance × 15 vs placebo + CRT. PFS HR 0.68; OS HR 0.67 (p=0.0040). 3y OS: 82.6% pembro vs 74.8% placebo. FDA approved for FIGO 2014 III–IVA.

GCIG INTERLACE (McCormack Lancet 2024)

FIGO IB1 N+ through IVA: induction carbo AUC2 + paclitaxel 80 mg/m² weekly × 6 → standard CRT vs CRT alone. OS HR 0.60 (p=0.015); PFS HR 0.65 (p=0.013). Feasible in LMICs. G3+ AEs 59% vs 48%. Key exclusion: PA+ disease, FIGO 2008 IIIA.

Clinical integration of A18 and INTERLACE: Both positive. Pembro appropriate for FIGO 2014 III/IVA. INTERLACE regimen useful when RT initiation will be delayed (gives something to do during setup). Not established to combine both.

PART III — VULVAR CANCER

Pathology: Three Molecularly Distinct Forms

Category	HPV-associated	HPV-independent / TP53 wt	HPV-independent / TP53 mut
Frequency	~1/3 of cases	Subset	Subset
Precursor	HSIL	vaVIN (verrucous)	dVIN (differentiated)
Carcinoma type	SCC	Verrucous	SCC
Prognosis	Best (p16+ more RT-responsive)	Intermediate	Worst — worse OS than HPV-ind TP53 wt

5th edition WHO (2020) classification groups by HPV status, better aligned with biology than the 4th edition histologic grouping.

FIGO 2021 / AJCC 8 Staging

T/N	FIGO	Definition
T1a	IA	≤2 cm, stromal invasion ≤1 mm
T1b	IB	>2 cm, OR any size with invasion >1 mm
T2	II	Extension to distal 1/3 urethra, distal 1/3 vagina, or anus
T3	IIIA / IVA	Upper 2/3 urethra, upper 2/3 vagina, bladder or rectal mucosa / T3 + fixed to bone
N1a	IIIA	1–2 LN mets each ≤5 mm
N1b	IIIB	1 LN met >5 mm
N2a	IIIA	3+ LN mets each ≤5 mm
N2b	IIIB	2+ LN mets >5 mm
N2c	IIIC	LN met with extracapsular spread
N3	IVA	Fixed or ulcerated LN
M1	IVB	Distant (including pelvic nodes)

Regional nodes = inguinofemoral. Pelvic node involvement = M1/stage IVB (unlike cervical).

Heaps Criteria for Recurrence / Nodal Spread

Margins <8 mm · Tumor thickness ≥10 mm · DOI >9 mm · Infiltrative growth · LVSI

Risk of Groin Node Metastasis (Homesley Gynecol Oncol 1993)

Factor	Risk
DOI ≤1 mm	2.6%
DOI 3 mm	18.6%
DOI ≥5 mm	~48%
LVSI (+)	75%
Tumor >3 cm	~54%
Grade 3	54.8%
Clinically suspicious node	76.2%
Fixed/ulcerated LN	92.6%

Adjuvant Vulva RT Doses (NCCN)

Scenario	Dose
Postop, negative margins	45–50.4 Gy
Postop, close/positive margins	54–60 Gy (up to 60–66 Gy if unresectable +)
Uninvolved inguinofemoral LNs	45–50 Gy
Inguinofemoral LN+, no ECE	50–55 Gy
Inguinofemoral LN+ with ECE	54–64 Gy

Node-Positive Vulvar: Landmark Trials

GROINSS-V1 (Van der Zee JCO 2008; Te Grootenhuis 2016)

276 unifocal vulvar pts, tumor <4 cm, clinically N0, DOI >1 mm → SLN mapping. If SLN−, observe. 2y actuarial groin recurrence rate 3% (unifocal). Established SLN as acceptable for well-selected vulvar pts.

GOG-37 (Homesley Obstet Gynecol 1986; Kunos 2009)

Node+ vulvar: Pelvic LND vs bilateral groin + pelvic EBRT 45–50 Gy. RT significantly reduced cancer-related death (HR 0.5, p=0.02); 6y OS 51% RT vs 41% PLND (p=0.18). Subgroup with 2+ nodes or extracapsular spread benefited most. Established RT over pelvic LND for node+ vulvar.

AGO CaRE-1 (Mahner JNCI 2015)

Retrospective; adjuvant RT improved PFS in node+ pts. Supports current NCCN guidelines.

GROINSS-V2 / GOG-270 (Oonk JCO 2022)

SLN+ management: Micromets (≤2 mm) → groin recurrence 2y 3.8% with RT alone vs 11.8% with SLN alone only (HR 0.11). Macromets (>2 mm) → groin recurrence 22% with RT alone vs 6.9% with IFL ± RT (HR 3.2). Takeaway: RT alone sufficient for micromets; macromets need IFL ± RT.

GROINSS-VIII (ongoing)

Tests hypothesis that concurrent cisplatin + 56 Gy RT can replace IFL for macromets or ECE SLN. Weekly cis 40 mg/m² × 5.

NCCN Algorithm by SLN Status

SLN negative → observe
SLN micrometastasis → adjuvant RT
SLN macrometastasis → inguinofemoral LND
≥2 LN+ or ECE → adjuvant RT

Locally Advanced / Unresectable Vulvar

Trial	Regimen	Results
GOG-101	Neoadj cis/5-FU + RT 47.6 Gy	48% cCR, 31% pCR; 2.8% persistently unresectable
GOG-205 (Moore 2012)	EBRT 45 Gy + 57.6 Gy boost + weekly cisplatin 40 mg/m²	64% cCR, 50% pCR; established as current standard
GOG-279 (Horowitz JCO 2024)	Gem + cis + IMRT	73.1% pCR, 85% G3+ toxicity, 2y PFS 70%

NCCN Doses for Locally Advanced

Uninvolved vulva and LNs: 45–50 Gy
Gross primary vulva: 60–70 Gy
LN gross residual or unresectable: 60–70 Gy

Locally Advanced Contouring (per Gaffney IJROBP 2016)

Primary tumor CTV: GTV + 2 cm (respecting skin and bone unless involved). Entire vulva (spare mons if posterior lesion). If vaginal involved → entire vagina. If anus involved → ≥2 cm superior into anorectum. If urethra involved → ≥2 cm up urethra; if mid/proximal urethra → full urethra ± bladder neck.

Nodal CTV: Bilateral inguinofemoral, external iliac, obturator, internal iliac. + presacral (S1-3) if upper vaginal or cervical involvement. + perirectal/mesorectal/presacral if anal canal involved.

Simulation Pearls

Supine, frog-legged in vac bag.
Wire scars, primary GTV, vulva skin borders. Markers at anus, urethra, clitoris.
MRI sim preferred; otherwise CT sim with MR fusion.
Use bolus (TLD/OSLD verification) for skin dose.
Keep package time ≤15 weeks.

PART IV — VAGINAL CANCER

Key Principles

Nearly all cases HPV-driven (like cervix; contrasts with vulvar where only 1/3 HPV+).
Early-stage strongly favors RT over surgery — surgical complication rates remain high.
FIGO staging similar conceptually to vulvar (location-based).

NCCN Stage-Based Management

Stage	Treatment
Stage IA (≤2 cm)	Vaginal brachytherapy preferred. Surgery only if margin-negative resection feasible with acceptable morbidity
Stage IB (>2 cm)	EBRT to pelvis + intracavitary/interstitial brachy boost (preferred)
Stage II–IVA	Platinum-based chemoradiation + brachy boost

Surgical Complication Data (Yang Gynecol Oncol 2020)

Upfront surgery: intraop complications 16.3%, G3+ postop 30.2%.
Surgery after RT: intraop 9.1%, G3+ postop 27.3%.
NNT5 to prevent death of any cause: 9 (comparing brachy vs surgery for early stage).

Brachytherapy Boost (retroEMBRACE for cervix, extrapolated to vagina)

Target definition (Schmid Radiother Oncol 2020):
GTV-Tres: residual tumor at brachy
CTV-THR (high-risk): GTV-Tres + abnormal/thickened/irregular vaginal wall within initial tumor extent
CTV-TIR (intermediate-risk): HR + margins for initial extent

Vaginal Brachy Boost Dosing (Common Clinical Practice)

Situation	Dose	EQD2
Upper/mid vagina, no nearby OARs	8 Gy × 3 (interstitial)	~80 Gy
Lower vagina or abutting bowel/urethra/rectum	6 Gy × 3 (interstitial)	~70 Gy

Transvaginal and transrectal ultrasound-guided interstitial brachytherapy. Place gold fiducial markers prior to EBRT.

Vaginal Cancer EBRT

45–50 Gy in 25 fx to vagina + pelvic/groin nodes ± PA nodes + concurrent weekly platinum.
Lower-third vaginal → include inguinal nodes (like vulvar).

CROSS-CUTTING HIGH-YIELD POINTS

Endometrial FIGO 2023 is heavily tested — especially POLEmut downstaging to IAm, p53abn upstaging to IICm, aggressive histology no-MI becoming IC, and substantial LVSI as independent IIB upstager.
Substantial LVSI = >5 vascular spaces OR >50% of vessels (memorize both thresholds).
Nodal classifications: endometrial separates micro (0.2–2 mm, IIIC1i) vs macro (>2 mm, IIIC1ii). Cervical FIGO 2018 uses "r" (radiographic) vs "p" (pathologic) suffixes. Vulvar uses sizes (≤5 mm vs >5 mm) plus number of nodes.
PORTEC-2 made VBT the HIR standard. PORTEC-3 made chemoRT the stage III standard. GOG-258 disproved chemo-alone replacement for locoregional.
Sedlis (GOG-92) = post-op RT for high intermediate risk. Peters (GOG-109) = post-op chemoRT for margins+, LN+, or parametrium+.
Brachytherapy cannot be omitted in definitive cervical treatment — OS penalty (Han IJROBP 2013). Quality of implant matters (RTOG 0116/0128). GEC-ESTRO D90 HR-CTV target >90 Gy EQD2.
Total package time <8 weeks for definitive cervical.
KEYNOTE-A18 (pembro + chemoRT) for FIGO 2014 III/IVA cervical; INTERLACE (induction carbo/pac → CRT) as alternative. Both positive for OS.
GOG-37 established RT over pelvic LND for node+ vulvar.
GROINSS-V2 / GOG-270: micromets → RT alone; macromets → IFL ± RT.
Vulvar "package time ≤15 weeks" — unlike cervix (≤8 weeks).
LACC trial: open > MIS radical hysterectomy for cervix (worse OS with MIS).
Vaginal dilators should be encouraged in all women receiving RT for intact cervical/vaginal cancer regardless of sexual activity.
Duodenum constraints for extended-field RT: V55 <15 cc, V60 <2 cc.

KEY LANDMARK TRIALS (memorize)

Trial	Disease	One-line takeaway
PORTEC-1 (2000)	EC IC G1-2 / IB G2-3	EBRT ↓ LRR 15→6%; no OS; 2/3 of obs recurrences in upper vagina
GOG-99 (2004)	EC IB-II post-staging	Defined HIR; EBRT ↓ recurrence; no OS
PORTEC-2 (2010)	EC HIR	VBT non-inferior to EBRT with better QOL
GOG-249 (2019)	EC HIR/HR	VBT+chemo NOT superior to EBRT; more nodal failures
PORTEC-3 (2018/2022)	EC high-risk	ChemoRT improves FFS and 10y OS; p53abn benefits most; POLE doesn't benefit
GOG-258 (2019)	EC III/IVA or I-II serous/CC	Chemo alone insufficient for locoregional; CRT doesn't improve OS vs chemo alone
PORTEC-4a (2024)	EC HIR	Molecular-guided adjuvant feasible; LRR 8.4% vs 30.5%
NRG-GY018 (2023)	Advanced/recurrent EC	Pembro + carbo/pac: dMMR PFS HR 0.30, pMMR 0.54
RUBY (2024)	Advanced/recurrent EC	Dostarlimab + carbo/pac: OS HR 0.69, dMMR 0.32
GOG-92 / Sedlis (1999)	Cervical post-RH	EBRT for HIR defined by LVSI/invasion/size
GOG-109 / Peters (2000)	Cervical post-RH, margin/LN/PM+	ChemoRT > RT alone (PFS 80 vs 63%)
LACC (2018)	Early cervical	Open > MIS radical hyst (worse OS with MIS)
Vale meta-analysis (2008)	Cervical CRT	CRT OS benefit greatest in I-IIA (10%), IIB (7%), III-IVA (3%)
EMBRACE I (Potter 2021)	Cervical IGBT	5y LC 92%; established MR-IGBT dose constraints
KEYNOTE-A18 (2024)	LACC FIGO 2014 III/IVA	Pembro + CRT → OS HR 0.67
INTERLACE (McCormack 2024)	LACC IB1 N+ through IVA	Induction carbo/pac → CRT: OS HR 0.60
GROINSS-V1 (2008/2016)	Vulvar early SLN	SLN− observe; 2y groin recur 3%
GROINSS-V2 / GOG-270 (2022)	Vulvar SLN+	Micromets → RT alone OK; macromets → IFL ± RT
GOG-37 (1986/2009)	Node+ vulvar	RT + groin > pelvic LND (↓ cancer death HR 0.5)
GOG-205 (Moore 2012)	Unresectable vulvar	Weekly cis + 57.6 Gy → 64% cCR, 50% pCR
GOG-279 (Horowitz 2024)	Unresectable vulvar	Gem/cis + IMRT → 73.1% pCR, high toxicity