adjuvant therapy in endometrial cancer Kiron G Junior Resident Radiation oncology

1. ADJUVANT THERAPY IN UTERINE
CARCINOMA
KIRON G

2. Hysterectomy

3. WHAT IS ADEQUATE SURGICAL STAGING?
Total extrafascial hysterectomy with bilateral salpingo-oophorectomy with pelvic and paraaortic lymph node dissection is the
standard staging procedure

4. Adequate surgical staging (GOG)
Removal of :
• uterus
• cervix
• adnexa
• pelvic
• para-aortic lymph node tissues
• obtaining pelvic washings

5. Pelvic lymphadenectomy
• Removal of the nodal tissue from :
• distal half of the common iliac arteries
• anterior & medial aspect of
the proximal ½ of the external iliac
artery & vein
• the distal ½ of the obturator fat pad
anterior to the obturator nerve

6. Para-aortic lymph node dissection
• removal of nodal tissue :
• distal inferior vena cava from the level of the inferior mesenteric artery to the
mid right common iliac artery and
• between the aorta and left ureter from the mid inferior mesenteric artery to
the mid left common iliac artery

7. risk factors for nodal metastases

8. Risk factors for nodal metastases
• Serous, clear cell, or high grade histology
• Myometrial invasion greater than 50 %
• Large tumor (>2 cm in diameter or filling the endometrial cavity)

9. Node sampling versus resection
• Lymph node sampling is to obtain a representative biopsy
• Lymphadenectomy is to remove all node-bearing tissue in a specific
anatomic distribution
• Sampling may be considered in stage IA / IB

10. Adverse risk Factors :
• Age
• LVSI
• Deep myometrial
invasion
• High grade
• Serous
• Clear cell
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

11. STAGE II
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

12. STAGE IIIA, IIIB, IIIC
• Systemic therapy and/or EBRT + Vaginal brachytherapy (VBT)

13. STAGE IVA, IV B
• Systemic therapy + EBRT + Vaginal brachytherapy (VBT)

14. High risk Histologies

15. INCOMPLETELY SURGICALLY STAGED

16. Locoregional recurrence negative for distant
metastasis
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

17. Isolated metastasis

18. Disseminated metastases

19. Role of RT in Stages I and II

20. RT Randomized Trials

21. Observation Versus Pelvic RT
• Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) trial
• statistically significant difference in the rates of vaginal/pelvic recurrence in
favor of adjuvant pelvic RT
• Overall survival was not different between the two groups (81% RT vs. 85%
surgery
• complications with pelvic RT were significantly higher (25% vs. 6%)
• The triad of lack of overall survival advantage, increased toxicity, and
high salvage rate of local recurrence for patients who are observed
have led many to conclude that all forms of adjuvant RT, not simply
pelvic RT, should be abandoned

22. Observation Versus Intravaginal RT
• Sorbe et al.,
OBSERVATION INTRAVAGINAL RT
vaginal recurrence 3.1% 1.2%
pelvic recurrence 0.9% 0.3%
overall survival No significant difference
grade 1 vaginal toxicity significantly more
gastrointestinal (GI) or
genitourinary toxicity.
No significant difference

23. Pelvic RT Versus Intravaginal RT
• PORTEC-2
• This trial showed that intravaginal RT alone is sufficient to control vaginal
recurrence even in patients with intermediate- to high-risk features.
intravaginal RT pelvic RT
3-year vaginal recurrence
rates
0.9% 1.9%
pelvic recurrence 3.5% 0.6%
rates of isolated pelvic
recurrence
0.6% 1.2%
disease-free or overall
survival
no significant difference
grades 1 and 2 acute GI
toxicity
12% 53%

24. Pelvic RT Versus Intravaginal RT
• Sorbe et al.
IVRT EBRT + IVRT
vaginal recurrence 2.7% 1.9%
Pelvic recurrence rate 5.3% 0.4%
overall survival no significant difference
toxicity significantly higher

25. Role of RT in Stage III

26. Role of RT in Stage III
• Connell et al.
• reported on 12 patients treated with postoperative pelvic radiation with a 5-year
disease-free survival of 70.9%.
• The weighted average of 5-year disease-free and overall survival rates from
literature review in that study was 78.6% and 67.1%,

27. Role of RT in Stage III - Jabson et al
ISOLATED ADNEXAL INVOLVEMENT TREATED WITH POST OP RT
5-year disease-free 76.4%
disease specific survival 76.3%
local/regional recurrence 2.2%
distant relapse 26.1%
ISOLATED SEROSAL INVOLVEMENT TREATED WITH POST OP RT
5 year disease free 59.6%
disease-specific survival rates 75.4%
local/regional recurrence 14.3%
distant relapse 33.3%

28. Role of RT in Stage III - Mariani et al.
• This difference was statistically significant on univariate (p < .001) and
multivariate analysis (p = .03) indicating the need for postoperative
radiation even after adequate surgical staging.
inadequate lymph node
dissection and/or no RT
adequate lymph node
dissection
pelvic recurrence 57% 10%

29. Role of Systemic Therapy

30. Chemotherapy Versus RT Trials
• GOG 122 GYNEOCOLOGY ONCOLOGY GROUP
• The reason for the discrepancy is that in this study, there was stage imbalance, in
which there were more stage IIIA patients in the RT arm (28.2%) than in the
chemotherapy arm (18%). Conversely, there were more patients with stage IIIC
disease in the chemotherapy arm (51.5%) than in the RT arm (44.6%)
• failed to show that adjuvant chemotherapy is superior to adjuvant RT.
whole-abdomen radiation doxorubicin/cisplatin for
eight cycles
progression-free 50% 38%
overall survival rate 55% 42%
rate of relapse 54% 50%
5-year progression-free
survival rates
38% 50%

31. Chemoradiation Versus RT Trials
• Hogberg et al
RT CT->RT
5-year progression-
free survival (PFS)
61% 74% NOT significant
5-year overall
survival (OS)
73% 78% Not significant

32. Chemoradiation Versus RT Trials
• RTOG 9708 phase II
• The 4-year disease-free and overall survival rates for those with stage III
disease (66% of patients) were 72% and 77%, respectively.

33. External Beam Pelvic Irradiation

34. SIMULATION
• Patients are scanned in the treatment position supine with arms on
the chest, with knees and lower legs immobilised.
• Anterior and lateral radio-opaque markers are aligned with lasers to
prevent lateral rotation.
• For obese patients, the prone bellyboard may be used to allow small
bowel to fall anteriorly away from the target volume.

35. Belly board device
The prone treatment position has been found to reduce the volume of small bowel within the pelvis, and
special belly board devices have been designed that are more effective in pushing the small bowel out of the
treatment fields than the prone position alone.

36. Group I = empty bladder without the use of belly board
Group II = empty bladder with the use of belly board
Group III = distended bladder without the use of belly board
Group IV = distended bladder with the use of belly board

37. SIMULATION
• A protocol is used to maintain a constant bladder filling ‘comfortably
full’ to push the small bowel superiorly.
• For example, patients are asked to empty the bladder and drink 200
mL water 20 minutes before the scan and treatment each day.
• The introitus is marked with radio-opaque material.
• CT scans are taken from the superior border of L3 to 5 cm beyond the
vaginal introitus.
• Intravenous contrast can be used to visualise primary tumour and
uterus if still in situ and pelvic blood vessels

38. External Beam Pelvic Irradiation
• CTV for pelvic RT consists of the
• Parametrial tissues
• Proximal half of the vagina
• Pelvic lymph node
• internal and external iliac and the lower common iliac lymph node regions)
• cervix involvement and for node +VE disease
• presacral and upper iliac lymph node regions are included
• A four-field box technique has traditionally been employed

39. External Beam Pelvic Irradiation
• PORT dose of 45 Gy to 50 Gy /1.8 Gy to 2.0 Gy /5 weeks

40. External Beam Pelvic Irradiation
Four field box
technique

41. Isodose distribution for pelvic and periaortic
nodes

42. Intensity-Modulated Radiation Therapy
• Treatment planning studies have shown that a substantial reduction
of the doses :
• small bowel
• Rectum
• Pelvic bone marrow can be realized*
*Heron DE, Gerszten K, Selvaraj RN, et al: Conventional 3D conformal versus intensity-modulated radiotherapy for the adjuvant treatment
of gynecologic malignancies: A comparative dosimetric study of dose-volume histograms. Gynecol Oncol 91:39–45, 2003.

43. IMRT

44. Extended-Field Irradiation
• Patients undergoing treatment to the pelvic and paraaortic regions
are usually treated in the supine position to ensure a dorsal position
of the kidneys
• Doses used for pelvic and paraaortic treatment :
45 Gy to 50.4 Gy with standard 1.8-2Gy/ fractions
• For macroscopic involved lymph nodes a boost dose may be used,
preferably using IMRT

45. DOSE CONSTRAINTS - IMRT
OAR DOSE CONSTRAINTS
small bowel <30% to receive 40 Gy;
rectum <60% to receive 30 Gy;
bladder <35% to receive 45 Gy
femoral head ≤15% to receive 30 Gy,
bone marrow ≤37% to receive 40 Gy

46. BRACHYTHERAPY
TECHNIQUES
Intravaginal Radiation

47. Brachytherapy Techniques
• LDR, PDR, HDR brachytherapy
• Manual / Remote afterloading applicators for intracavitary / interstitial Rx
• The type of applicator used is generally a cylinder
• Iridium-192 is used for pulsed and HDR brachytherapy
• HDR techniques may be preferred to
• avoid the increased morbidity of prolonged bed rest with PDR/LDR
• convenience of the patient and staff

48. DOSE
• for post op VBT Alone; dose is
• 6Gy x 5 # prescribed to vaginal surface
• 7Gy x 3 OR 5.5 Gy x 4 prescribed to 5mm below the vaginal surface
• When used as a boost to EBRT, doses of 4 to 6 Gy x 2 to 3 # prescribed
to vaginal mucosa

49. Vaginal Brachytherapy
• Upper vagina is the most common site of recurrence
• Adjuvant VBT is used to decrease the risk of recurrence
• Target is the upper ½ or proximal 3 cm or 4 cm of the vagina

50. Vaginal Brachytherapy
• Vaginal wall thickness of the (2 – 8mm) to be considered
• Vaginal cuff with its often irregular surface and shape POST OP
• A thicker scar or some distance between the applicator and the
mucosa warrants target points to be individually adjusted

51. VAGINAL CYLINDER WITH ISODOSE FROM
ONE OF OUR CASES

52. DUMMY WIRE
Standardised one channel cylindrical applicator
Diameter is 25, 30, 35 mm;
25mm

53. Medically Inoperable Ca Endometrium
Pre-operative VBT

54. CLINICAL STAGING

55. MANAGEMENT
Scenario Treatment
Stage I (uterine confined) Grade 1 or 2 endometrial
cancer with initial MRI demonstrating minimal
myometrial invasion
Brachytherapy alone can be used
Stage I (uterine confined) endometrial cancer with
MRI evidence of deep myometrial invasion
A combination of external beam and brachytherapy
is recommended
Stage II endometrial cancer (involving the cervix) combination of external beam and brachytherapy
is indicated
Stage III endometrial cancer (disease has extended
outside the uterus but is regionally confined to pelvis)
combination of external beam and brachytherapy
is indicated

56. Schwarz et al :Consensus statement for brachytherapy for the treatment of medically inoperable endometrial cancer
Brachytherapy 14 (2015) 587e599

57. Brachytherapy Techniques
• A small uterus can be treated with a single tube, using a stepping
source and increasing the dwell times at the fundus to obtain a pear-
shaped isodose distribution (i.e., inverted pear).
• An intermediate-size uterus can be treated with a two-channel
applicator (one applicator in each uterine cornu), which results in a
pear-shaped isodose distribution at the fundus.

58. A - Norman Simon applicators (modified Heyman Packing for afterloading) with radioopaque marker wire for Iridium sources
The capsules at the top of the flexible tubes are 4, 6, and 8 mm wide
A
B
C

59. Standard two channel applicators
(“Y”/Rotte applicator)

60. Standard one channel applicators in different
diameters and with different intrauterine tubes

61. DOSE LIMITATIONS
OAR DOSE CONSTRAINTS
Upper vaginal mucosa 150 Gy
midvaginal mucosa 80–90 Gy,
lower vaginal mucosa 60–70 Gy
Ovarian failure 5–10 Gy.
Sterilization 2–3 Gy

62. Complications of Pelvic
Irradiation

63. Acute complications
• Acute side effects may be increased when radiotherapy is combined
with concurrent chemotherapy
• Diarrhoea or abdominal discomfort may occur during EBRT, and is
usually controlled by a low residue diet and loperamide
hydrochloride.
• Care of the perineal skin is advised, but erythema and desquamation
are now uncommon with 10–16 MV beams, unless the lower vagina is
affected

64. Complications of Pelvic Irradiation
• Most significant complications
• obstruction of the small bowel,
• chronic diarrhea,
• proctitis,
• fistula formation,
• vaginal stenosis,
• Insufficiency fractures of bone

65. Complications
Less commonly
• Rectal discomfort or bleeding
• Urinary frequency or dysuria
• Premenopausal patients will lose ovarian function

66. Chronic Complications of Pelvic Irradiation
• Pelvic RT is associated with short-term and long-term effects on GI
function, most notably increased frequency of bowel actions, less bile
acid absorption, and faster intestinal transit.
• Diarrhea,Abdominal cramping, Bowel obstruction,
• Rectal ulcer
• Hematuria
• Vaginal shortening, dyspareunia, vaginal vault necrosis, fistula
• Pedal edema

67. GRADING OF VAGINAL TOXITY
https://doi.org/10.2147/IJWH.S106796

68. GRADING OF LOWER GI TOXICITY
Grade 1 Grade 2 Grade 3 Grade 4

69. Complications of Pelvic Irradiation
• PORTEC trial
• Most complications (67%) were mild (grade 1), and almost 50% of symptoms
resolved in the course of 2 year to 3 years.
• GI symptoms were the predominant side effects,
• No severe late genitourinary or vaginal complications occurred.
EBRT CONTROL – NO ADDITIONAL
TREATMENT
Discontinuation of irradiation because of acute
symptoms
2%
5-year rates of any late complication 26% 4%
5-year rate of GI complications 20%.
5-year actuarial rates of severe (grade 3 or 4) late
complications
3% 0%

70. Complications of Pelvic Irradiation
• ASTEC trial
• grades 1, 2, 3, and 4 predominantly GI or urogenital late toxicity was reported
in 30%, 22%, 7%, and 1%, respectively,
RT CONTROL
Any acute toxicity 57% 27%

71. SURVEILLANCE
• Physical examination q 3-6 mo. for 2-3 yrs 6 mo. or annually
• Ca-125 if initially elevated
• Imaging studies for symptomatic cases

72. Chemotherapy regimen

73. IMMUNOTHERAPY
• For patients with mismatch repair deficiency or microsatellite-
instable tumors who have experienced progression despite prior
chemotherapy, either the immune checkpoint inhibitor
pembrolizumab or endocrine therapy is an appropriate option

74. Endometrial stromal sarcoma
ESS

75. LOW GRADE ESS
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

76. HIGH GRADE ESS, UUS*, uLMS*
UUS – undifferentiated uterine sarcoma
uLMS – uterine leiomyosarcoma

77. Thank you