Radiation Oncology: A Question-Based Review

66
Endometrial Cancer

Kristin Janson Redmond and Fariba Asrari

image Background


What is the incidence of endometrial cancer in the U.S.?

Endometrial cancer is the most common gyn malignancy in the U.S., with an incidence of ~44,000 cases/yr annually. It is the 2nd most common cause of gyn cancer deaths.

What are the 2 forms of endometrial cancer?

Forms of endometrial cancer:

1.     Type I: endometrioid, 70%–80% of cases, estrogen related

2.     Type II: nonendometrioid, typically papillary serous or clear cell, high grade, not estrogen related, aggressive clinical course

What are the risk factors for endometrial cancer?

Risk factors for endometrial cancer:

1.     Exogenous unopposed estrogen

2.     Endogenous estrogen (obesity, functional ovarian tumors, late menopause, nulliparity, chronic anovulation/polycystic ovarian syndrome)

3.     Tamoxifen

4.     Advancing age (75% postmenopausal)

5.     Hereditary (HNPCC)

6.     Family Hx

7.     HTN

What are protective factors for endometrial cancer?

Protective factors for endometrial cancer include combination oral contraceptives and physical activity.

What is the most common clinical presentation of endometrial cancer?

Endometrial cancer presents with abnl vaginal bleeding in 90% cases.

What % of post-menopausal women with abnl vaginal bleeding have endometrial cancer?

Only 5%–20% of postmenopausal women with abnl vaginal bleeding have endometrial cancer.

What are the 3 layers of the uterine wall?

The 3 layers of the uterine wall are the endometrium, myometrium, and serosa.

What is the primary lymphatic drainage of the uterus?

The primary lymphatic drainage of the uterus is to the pelvic LNs (parametrial, internal and external iliacs, obturator, common iliac, presacral). Also, direct spread to the para-aortic (P-A) nodes (from the fundus) can occur.

What % of endometrial cancer pts with positive pelvic LNs also will harbor Dz in the P-A LNs? What is the chance of P-A nodal involvement if pelvic nodes are negative?

~33% of pts with pelvic LN involvement also have involvement of the P-A nodes. Isolated P-A nodal mets in the setting of negative pelvic nodes occur in ~1% of surgically staged endometrial cancer cases. This low rate seems consistent for low- and high-grade lesions.

What determines the grade of endometrial tumors?

The grade of endometrial tumors depends on the glandular component:

1.     Grade I: ≤5% nonsquamous solid growth pattern

2.     Grade II: 6%–50% nonsquamous solid growth pattern

3.     Grade III: >50% nonsquamous solid growth pattern

What is the risk of LN involvement by DOI and grade per GOG 33?

According to GOG 33, the risk of LN involvement is <5% for tumors limited to the endometrium (all grades) and 5%–10% for tumors invading the inner and middle 3rd of the myometrium (all grades). For tumors invading the outer 3rd of the myometrium, the risk is approximately 10% for grade 1, 20% for grade 2, and 30% for grade 3. (Creasman WT et al., Cancer 1987)

What are the most aggressive histologies of endometrial cancer?

The most aggressive histologies of endometrial cancer are papillary serous, clear cell, and pure squamous cell.

What % of endometrial cancers are adenocarcinoma?

75%–80% of endometrial cancers are adenocarcinomas.

According to the American College of Obstetricians and Gynecologists (ACOG), how should women be screened for endometrial cancer?

According to the ACOG, there is no appropriate cost-effective screening test for endometrial cancer.

image Workup/Staging


Per the NCCN, what is the workup for endometrial cancer?

NCCN endometrial cancer workup: CBC, PAP smear, endometrial Bx, and CXR. If extrauterine Dz is suspected, consider CA 125, MRI/CT, cystoscopy, and sigmoidoscopy.

What are the sensitivity and specificity of an endometrial Bx?

Endometrial Bx has 90%–98% sensitivity and 85% specificity.

When is D&C recommended?

D&C is recommended if endometrial Bx is nondiagnostic.

What is involved in the surgical staging of pts with endometrial carcinoma?

Surgical staging for endometrial cancer:

1.     Vertical incision

2.     Peritoneal washing/cytology (controversial)

3.     Exploration of all peritoneal surfaces with Bx of any lesions

4.     Total abdominal hysterectomy (TAH)/bilateral salpingo-oopherectomy (BSO)

5.     Uterus bivalved in operating room

6.     Omental Bx (omentectomy for uterine papillary serous carcinoma [UPSC]/clear cell carcinoma [CCC])

7.     Pelvic/P-A LN sampling vs. dissection

During the surgical staging procedure for endometrial cancer, what features are an indication for P-A nodal sampling? Approximately what % of pts have these features?

PA sampling should take place in endometrial cancer pts with the following:

1.     Gross P-A Dz

2.     Positive pelvic LN

3.     Gross adnexal mass

4.     More than one third myometrial involvement

~25% of pts have these features, but they account for 98% of all positive P-A LNs.

Per the NCCN, when is cystoscopy or sigmoidoscopy indicated?

Per the NCCN, cystoscopy or sigmoidoscopy are indicated only for Sx or advanced lesions.

What is the AJCC 7th edition (2009)/FIGO (2008) pathologic staging for endometrial cancer?

1.     Stage T1a/IA: limited to endometrium or less than one half of myometrium

2.     Stage T1b/IB: invades half or more of myometrium

Note: Endocervical glandular involvement only is considered AJCC T1 and FIGO stage I.

1.     Stage T2/II: invades connective tissue of cervix but does not extend beyond uterus

2.     Stage T3a/IIIA: tumor involves serosa and/or adnexa by direct extension of mets

3.     Stage T3b/IIIB: vaginal involvement or parametrial involvement

4.     Stage T4/IVA: tumor invades bladder mucosa (bullous edema is not sufficient) and/or bowel mucosa

5.     Stage N0: no regional LN mets

6.     Stage N1/IIIC1: regional LN mets to pelvic nodes

7.     Stage N2/IIIC2: regional LN mets to P-A nodes

8.     Stage M1/IVB: DMs

Note: Per the AJCC 7th edition (2009) and FIGO (2008), positive cytology no longer alters stage.

image Treatment/Prognosis


What is the primary Tx modality for endometrial cancer?

Surgery is the primary Tx modality for endometrial cancer.

What is resected in a TAH?

TAH removes the uterus and a small rim of vaginal cuff.

What is resected in a modified radical hysterectomy?

Modified radical hysterectomy:

1.     Removal of uterus and 1–2 cm of vaginal cuff

2.     Wide excision of parametrial and paravaginal tissues (including median one half of cardinal and uterosacral ligaments)

3.     Ligation of uterine artery at ureter

What is resected in a radical hysterectomy?

Radical hysterectomy:

1.     Resection of uterus and upper vagina

2.     Dissection of paravaginal and parametrial tissues to pelvic sidewalls

3.     Ligation of uterine artery at its origin at internal iliac artery

4.     Dissection of pelvic LNs

Pelvic and P-A lymphadenectomy is recommended in which pts with endometrial cancer?

Although controversial, LNs are commonly assessed at the time of initial surgery for endometrial cancer. Pelvic lymphadenectomy may not be indicated in women with Dz clinically confined to the uterus. The ASTEC trial randomized 1,408 pts with endometrial cancer that was clinically confined to the uterus to standard surgery (TAH + BSO, peritoneal washing, palpation of P-A nodes) vs. standard surgery + pelvic lymphadenectomy. Those at intermediate or high risk for recurrence (independent of nodal status) were further randomized to rcv pelvic RT or not. There was no benefit to pelvic lymphadenectomy in terms of OS or RFS. (ASTEC Study Group et al., Lancet 2009)

What is the risk of lymphedema following surgery for uterine malignancies?

According to an MSKCC retrospective review of 1,289 pts, the rate of lymphedema at a median follow-up of 3 yrs was 1.2%. When ≥10 LNs were removed, the rate of symptomatic lymphedema was 3.4%. (Abu-Rustum NR et al., Gyn Onc 2006)

What are considered negative prognostic factors for endometrial cancer?

Negative prognostic indicators for endometrial cancer:

1.     LVSI

2.     Age >60 yrs

3.     Grade 3

4.     Deep myometrial invasion

5.     Tumor size

6.     Lower uterine segment involvement

7.     Anemia

8.     Poor Karnofsky performance status

What adj therapy is indicated for completely surgically staged endome-trial cancers limited to the endometrium?

No adj therapy is indicated for endometrial cancers limited to the endometrium, except for grade 3, where vaginal cuff brachytherapy is considered. In grade 3 tumors with adverse risk factors and incomplete surgical staging, pelvic RT is considered.

What adj therapy is indicated for completely surgically staged endome-trial cancers that invade less than half of the myometrium?

Endometrial cancers that invade less than half of the myometrium could be observed or treated with adj vaginal cuff brachytherapy.

Note:

1.     If the tumor is grade 3 with adverse risk factors, pelvic RT should be considered.

2.     If the tumor is incompletely surgically staged and grade 1–2, consider observation or vaginal brachytherapy +/− RT.

3.     Endocervical glandular involvement favors the use of vaginal brachytherapy.

What adj therapy is indicated for completely surgically staged endometrial cancers that invade half or more of the myometrium?

Endometrial cancers that invade half or more of the myometrium can be observed or treated with adj vaginal cuff brachytherapy.

Note:

1.     If grade 3 or any grade with adverse prognostic factors, whole pelvic RT +/− brachytherapy should be considered.

2.     If the tumor is incompletely surgically staged, consider pelvic RT + vaginal brachytherapy. For incompletely staged grade 3 tumors, consider chemo as well.

3.     Endocervical glandular involvement favors the use of vaginal brachytherapy.

What adj therapy is indicated for completely surgically staged, stage II endometrial cancer?

Adj pelvic RT and vaginal brachytherapy is indicated for endometrial cancers that invade the cervical stroma. If grade 3, consider chemo.

What adj therapy is indicated for completely surgically staged, stage III endometrial cancer?

Adj chemo + / − RT should be given for stage III endometrial cancer. RT in addition to chemo is needed if there is gross residual Dz or unresectable Dz.

Describe the whole pelvic RT field for endometrial cancer. What total doses are typically prescribed?

Borders of the whole pelvis (WP) RT field for endometrial cancer:

1.     Superior: L4-5

2.     Inferior: bottom of obturator foramen

3.     Lateral: 1.5–2.0 cm lat to pelvic brim

4.     Anterior: front of pubic symphysis

5.     Posterior: split sacrum to S3

Treat to 45–50 Gy.

What is the border of an extended RT field for endometrial cancer, and when should extended fields be used?

The sup border of an extended RT field for endometrial cancer is T10-11 or T11-12. It should be used if there are positive P-A LNs.

According to the American Brachytherapy Society (ABS), what are the Tx site and depth for vaginal cuff brachytherapy for endometrial cancer?

According to the ABS, for endometrioid carcinoma of the endometrium, the proximal 3–5 cm of the vagina (approximately one half) should be treated. For CCC, UPSC, or stage IIIB, the target is the entire vaginal canal. Prescribe to 0.5 cm beyond the vaginal mucosa. (Nag S, IJROBP 2000)

What LDR and HDR are typically used for adj intracavitary RT alone for endometrial cancer?

For adj intracavitary RT therapy alone, the LDR is 50–60 Gy over 72 hrs (70–80 cGy/hr). The HDR is 21 Gy (7 Gy × 3) at 0.5 cm depth.

What are the LDR and HDR recommendations for adj intracavitary RT + WP RT for endometrial cancer?

When given in combination with WP RT, the LDR for endometrial cancer is 30 Gy, and the HDR is 15 Gy (5 Gy × 2 or 3) at 0.5 cm depth.

When should vaginal cuff brachytherapy begin relative to EBRT?

At the Johns Hopkins Hospital, the institutional practice is for vaginal cuff brachytherapy to begin within a wk of completion of EBRT. Give 2 Tx/wk.

How are nonbulky vaginal cuff recurrences treated in endometrial cancer pts with no prior RT?

For nonbulky vaginal cuff recurrences in pts with no prior RT, a combination of pelvic RT and brachytherapy is typically used. Treat to 45 Gy pelvic RT, and assess the response. If the residual is <0.5 cm, add HDR vaginal brachytherapy at 7 Gy × 3 to 0.5 cm depth of the vaginal mucosa. (Nag S et al., IJROBP 2000)

How are vaginal cuff recurrences that are bulky or within a previously irradiated field treated in endometrial cancer pts?

For endometrial cancer pts with vaginal cuff recurrences that are bulky (>0.5 cm thickness) or in a previously irradiated field, consider interstitial brachytherapy.

When do inguinal nodes need to be included in the RT fields for endometrial cancer?

In cases with distal vaginal involvement, the entire vagina and inguinal nodes need to be included in EBRT fields.

How should inoperable endometrial cancer be treated with RT?

Consider pelvic RT to 45 Gy → intracavitary RT boost using 2 tandem intrauterine applicators to 6.3 Gy × 3 prescribed to 2 cm depth (serosal surface). If pelvic RT is contraindicated, consider definitive intracavitary RT alone (7.3 Gy × 5 prescribed to 2 cm depth). (Nag S et al., IJROBP 2000)

Describe the design and results of PORTEC-1.

In PORTEC-1, 714 pts with more than one half myometrial invasion and grade 2–3 or one half or more myometrial invasion and grade 1–2 underwent TAH/BSO with washings with no lymphadenectomy and were randomized to adj EBRT (46 Gy) vs. observation. EBRT reduced LRR from 14% to 5% at 10 yrs. 75% of LRs were in the vaginal vault. There was no difference in 10-yr OS. Note that with central pathology review, there was a significant shift from grade 2 to grade 1. (Scholten AN et al., IJROBP 2005Creutzberg CL et al., Lancet 2000)

Describe the design and results of GOG 99.

In GOG 99, 392 endometrial cancer pts with myometrial and/or occult cervical invasion underwent TAH/BSO, pelvic and P-A LN sampling, and peritoneal cytology and then were randomized to observation vs. WP RT (50.4 Gy). Inclusion criteria were revised during the trial to include only high-intermediate–risk pts defined as: (1) age >70 yrs with 1 risk factor (grade 2 or 3, LVI, outer one third myometrial invasion), (2) age >50 yrs with 2 risk factors, and (3) any age with 3 risk factors.

RT improved LR from 12% to 3%. The greatest benefit in LR was in high-intermediate–risk pts from 26% to 6% vs. low-intermediate–risk pts from 6% to 2%. There was no change in OS, but the study was not powered to detect this. Conclusion: Limit pelvic RT to high-intermediate–risk pts. The major flaw of this study is that grade 2 was grouped with grade 3 even though grade 2 Dz tends to behave more similarly to grade 1. (Keys HM et al., Gyn Onc 2004)

Describe the design and results of the Aalders Norwegian study.

The Aalders Norwegian study enrolled 540 pts with surgical stage I endometrial cancer s/p TAH/BSO (with no lymphadenectomy). All pts rcv vaginal cuff brachytherapy ( ~40 Gy LDR at 0.5 cm or ~24 Gy HDR at 0.5 cm). They were then randomized to no further therapy vs. pelvic RT (40 Gy with central shielding after 20 Gy). Overall, the pelvic RT arm had decreased 9-yr LR (7% to 2%) but more DM (5% vs. 10%). There was no difference in 9-yr OS. On subset analysis of pts with invasion of one half or more of the myometrium and grade 3 Dz, pelvic RT improved 9-yr OS (72% to 82%) and improved 9-yr LR (20% to 5%). There was no change in DM. There was no difference in OS, LR, or DM for pts with invasion of one half or more of the myometrium and grade 1–2 Dz. (Aalders J et al., Ob Gyn 1980)

Describe the design and results of GOG 122.

In GOG 122, 388 pts with endometrial tumors invading beyond the uterus (all histologies) underwent TAH/BSO and surgical staging with <2-cm residual tumor. P-A LNs were allowed, but mets to the chest or supraclavicular nodes were not allowed. Pts were randomized to whole abdomen irradiation (30 Gy AP/PA +15 Gy boost to pelvic +/− P-A LNs) vs. chemo (doxorubicin/cisplatin q3wks × 8 cycles). At 5 yrs, chemo had improved stage-adjusted OS (55% vs. 42%) and PFS (38% vs. 50%). Chemo had increased grade 3–4 heme toxicity (88% vs. 14%) and increased GI, cardiac, and neurologic toxicity. Note that results were questioned b/c though this was a randomized trial, the analysis was based on stage-adjusted results that may not be justified. (Randall ME et al., JCO 2006)

Describe the design and results of PORTEC-2.

PORTEC-2 randomized 427 pts with intermediate-high–risk endometrial cancer defined as:

1.     Age >60 yrs and less than one half myometrial invasion and grade 3

2.     Age >60 yrs and one half or more myometrial invasion and grades 1–2

3.     Invasion of cervical glandular epithelium and grades 1–2

4.     Invasion of cervical glandular epithelium and grade 3 with less than one half myometrial invasion

All pts were s/p TAH/BSO without pelvic LND and were randomized to EBRT (46 Gy) vs. vaginal brachytherapy alone (HDR 21 Gy in 3 fx or LDR 30 Gy). At median follow-up at 3.8 yrs, vaginal brachytherapy was similar to EBRT with respect to 5-yr outcomes: vaginal relapse (1.8% vs. 1.6%), isolated pelvic relapse (1.5% vs. 0.5%), LRR (5.1% vs. 2.1%), or OS (85% vs. 80%). However, there were significantly higher rates of acute grade 1–2 GI toxicity in the EBRT group. The authors concluded that vaginal brachytherapy should be standard in intermediate-high–risk endometrial cancer. (Nout RA et al., Lancet 2010)

Describe the design and results of the Finnish randomized trial comparing adj EBRT vs. interdigitated CRT in endometrial cancer.

The Finland trial included 156 endometrial cancer pts with (1) less than one half myometrial invasion and grade 3 or (2) one half or more myometrial invasion or extrauterine extension up to stage IIIA and any grade.

All were s/p TAH/BSO (with pelvic LAD in 80%) and randomized to split-course pelvic EBRT (28 Gy × 2 with a 3-wk break) vs. interdigitated CRT (28 Gy → chemo → 28 Gy → chemo, where chemo used was cisplatin/epirubicin/cyclophosphamide). There was no difference in 5-yr DFS, LR, or DM. Note the atypical Tx paradigms including split-course therapy. (Kuoppala T et al., Gyn Onc 2008)

Describe the design and results of the Japanese GOG (JGOG) 2033.

JGOG 2033 enrolled 385 pts with more than one half myometrial invasion, including pts with stage II–III Dz. All were s/p TAH/BSO and surgical staging and were randomized to 40–50 Gy EBRT AP/PA vs. ≥3 cycles of chemo (cyclophosphamide/doxorubicin/cisplatin). At 5 yrs, there was no difference in PFS, OS, or toxicity. An unplanned subset analysis defined high-intermediate risk:

1.     Stage I and age >70 yrs or grade 3 Dz

2.     Stage II or +cytology

In this subset, chemo improved PFS (83.8% vs. 66.2%). The authors concluded that adj chemo is a reasonable alternative to RT in intermediate-risk endometrial cancer. (Susumu N et al., Gyn Onc 2007)

Describe the design and results of the Nordic Society of Gynaecological Oncology (NSGO)-EORTC trial that evaluated adj RT +/− chemo in high-risk endometrial cancer.

The NSGO-EORTC trial enrolled 367 endometrial cancer pts with surgical stage I–II, positive peritoneal fluid cytology or positive pelvic LNs. Most had ≥2 risk factors: grade 3, deep myometrial invasion, or DNA nondiploidy. Pts with serous, clear cell, or anaplastic carcinomas were eligible regardless of risk factors. Pts were randomized to RT vs. RT + chemo (various regimens allowed). RT was pelvic EBRT (44 Gy) +/− vaginal brachytherapy. 5-yr PFS favored the RT + chemo arm (82% vs. 75%). (Hogberg T et al., ASCO abstract 2007)

Describe the design and results of GOG 94–the study of UPSC and CCC.

GOG 94 (Sutton G, Gyn Onc 2006) was a phase I–II trial enrolling 21 pts with UPSC or CCC of the uterus s/p TAH/BSO, pelvic/P-A nodal sampling, and peritoneal washing. Pts were treated with whole abdomen irradiation (30 Gy in 20 fx) and pelvic boost (19.8 Gy in 11 fx). At 5 yrs, >50% failures were within the RT field, and 5-yr PFS was 38% for UPSC and 54% for CCC. The authors concluded that chemo likely is necessary for these radioresistant histologies. (Sutton G et al., Gyn Onc 2006)

image Toxicity


What are the RT tolerances of the mucosa of the upper, middle, and lower vagina?

The RT tolerance of the mucosa of the proximal vagina is 120 Gy and distal vagina is 98 Gy. (Hintz BL et al., IJROBP 1980)

At what RT dose does ovarian failure occur?

Ovarian failure occurs after 5–10 Gy.

At what RT dose does sterilization occur in women?

Sterilization in women occurs after 2–3 Gy.

What are the expected acute and late RT toxicities associated with RT Tx for endometrial cancer?

1.     Acute toxicities: diarrhea, proctitis, abdominal cramps, fatigue, bladder irritation, drop in blood counts, n/v

2.     Late toxicities: vaginal dryness and atrophy, pubic hair loss, vaginal stenosis and fibrosis (recommend vaginal dilators), urethral stricture, fistula formation, SBO, chronic urinary and bowel frequency