Five Years Treatment Outcomes of Postoperative Radiotherapy in Saudi Women with Uterine Cancers

Asiri MA, Tunio MA, Mohamed R, Bayoumi Y, Alhadab A, Saleh RM, AlArifi MS, Alobaid A ,K Salama, B Obaidat

Introduction: Uterine cancers are the tenth most common in KSA.

Second most common gynecologic malignancies in KSA

Surgery is the primary treatment (TAH+BSO & PND

Five year survival rates of 78%

(PORTEC) and (GOG-99) shown significant reduction of

the risk of pelvic and vaginal recurrence by adjuvant

radiotherapy,

PORTEC-1 trial

426 patients

15-year actuarial locoregional recurrence (LRR) rates

6% for EBRT

15.5% for no adjuvant radiation therapy

(p < 0.0001).

Uterine sarcomas :3%-7% of all uterine malignancies

Dismal prognosis.

Histologically divided into three parts :

Leiomyosarcoma,

Carcinosarcoma or MMM

Endometrial stromal sarcoma .

(a)TAH+ BSO followed by adjuvant radiotherapy and systemic

chemotherapy due to increased tendency to metastasize

PURPOSE:

Evaluation of long term treatment outcomes and toxicity profile of postoperative radiotherapy (PORT) in Saudi women with uterine cancers treated in Radiation Oncology Department , CCC-KFMC

METHODS AND MATERIALS:

Medical records review.2007 and 2012FIGO IB- IVATAH-BSO +/- PLND. All uterine cancers who received PORT post TAHBSO.45-50.4 Gy in 25-28 fractions+HDR .Data :

The safety profile, Pathology & RadiologyLocoregional control (LRC) Distant metastases control (DMC) Overall survival (OS)

Postoperative Radiation therapy techniques:

(CT) simulator with Contrast , 5 mm slice .CTV : [vaginal cuff, parametrial soft tissue, external, internal iliac, presacral and common iliac lymph nodes](PTV) = CTV + 1 cm margin.OAR : (urinary bladder, rectum, small bowel).(RTOG) contouring guidelines (3DCRT)/IMRT treatment planning

Dose : 45-50.4 Gy in 25-28 fractions, 1.8 Gy per fraction,(HDR) vaginal brachytherapy (VBT) :15-20 Gy in 3-4 sessions .

Adjuvant chemotherapy:Indications :

Papillary serous Clear cell types CarcinosarcomaFIGO III, IVA endometrial cancers.

Before starting radiation therapy. 4 cycles of Paclitaxal (175mg/m2) and Carboplatin (350 mg/m2) every 21 days.

Toxicity and Response evaluation:

Weekly evaluation .weight, performance status, hematology/chemistry and side effects. The National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0,(RTOG) Late Radiation Morbidity Scoring Criteria .3 monthly FU for first two years 6 monthly for 3rd to 5th year .Physical and per vaginal examination, Pap smear .CT chest, abdomen and pelvis annually.

RESULTS: Median follow-up period was 60 months (range, 12-70)

89 patients.

histological type

Endometrial (59 patients), (66.3%)

Carcinosarcoma (17 patients) (19.0%)

Leiomyosarcoma (13 patients) (14.7%).

Median age at time of diagnosis was 57.6.

Median time between surgery and radiotherapy was 7.1 weeks

Variables Endometrial carcinoma (n = 59)

Leiomyosarcoma (n = 13)

Carcinosarcoma (n = 17)

Age (years) 57.6 (44-80) 51.1 (40-65) 56.0 (40-75) Symptoms

PV bleeding PV discharge

Pelvic pain

51 (86.5%) 31 (52.4%) 6 (10.1%)

8 (61.5%) -

5 (38.5%)

12 (70.5%) 3 (17.7%) 2 (11.8%)

Co-morbids

HTN DM

HTN+DM

31 (52.4%) 31 (52.4%) 21 (35.7%)

5 (38.5%) 6 (46.0%)

-

8 (47.1%) 9 (52.9%)

- Median BMI (kg/m2) 35.9 25.7 30.1

FIGO staging

I II III

IVA

38 (64.4%) 9 (15.3%) 10 (16.0%) 2 (3.3%)

3 (23.1%) 8 (61.5%) 2 (15.4%)

-

6 (35.3%) 7 (41.2%) 4 (23.5%)

- Elevated baseline CA125

levels 5 (8.5%) - 7 (41.2%)

Presence of LVSI 40 (67.8%) - 1 (5.9%) Cell type

Papillary serous Clear cell

3 (5.1%) 1(1.7%)

- -

- -

Positive pelvic lymph nodes 6 (10.1%) - - Positive PALN 1 (1.7%) - -

Tumor size above 5 cm 12 (20.4%) 7 (54.0%) - Grade

GI GII GIII

12 (20.4%) 15 (25.4%) 32 (54.2%)

13(100%) - -

- -

17 (100%) ER/PR (+) 6 (10.1%) 3 (23.1%) 1 (5.9%)

Squamous metaplasia (+) 3 (5.1%) - - Adjuvant chemotherapy 22 (37.3%) - 13 (76.5%)

Median chemotherapy cycles 4 (3-6) - 6 (4-8) Adjuvant EBRT

45.0 Gy 50.4 Gy

37 (62.7%) 22 (37.3%)

6 (46.0%) 7 (54.0%)

5 (29.5%) 12 (70.5%)

Vaginal brachytherapy

Patients characteristics

Variables

Endometrial carcinoma

(n = 59)

Leiomyosarcoma

(n = 13)

Carcinosarcoma

(n = 17)

Age (years)

57.6 (44-80)

51.1 (40-65)

56.0 (40-75)

Symptoms

PV bleeding

PV discharge

Pelvic pain

51 (86.5%)

31 (52.4%)

6 (10.1%)

8 (61.5%)

-

5 (38.5%)

12 (70.5%)

3 (17.7%)

2 (11.8%)

Co-morbids

HTN

DM

HTN+DM

31 (52.4%)

31 (52.4%)

21 (35.7%)

5 (38.5%)

6 (46.0%)

-

8 (47.1%)

9 (52.9%)

-

Median BMI (kg/m2)

35.9

25.7

30.1

FIGO staging

I

II

III

IVA

38 (64.4%)

9 (15.3%)

10 (16.0%)

2 (3.3%)

3 (23.1%)

8 (61.5%)

2 (15.4%)

-

6 (35.3%)

7 (41.2%)

4 (23.5%)

-

Elevated baseline CA125 levels

5 (8.5%)

-

7 (41.2%)

Presence of LVSI

40 (67.8%)

-

1 (5.9%)

Cell type

Papillary serous

Clear cell

3 (5.1%)

1(1.7%)

-

-

-

-

Positive pelvic lymph nodes

6 (10.1%)

-

-

Positive PALN

1 (1.7%)

-

-

Tumor size above 5 cm

12 (20.4%)

7 (54.0%)

-

Grade

GI

GII

GIII

12 (20.4%)

15 (25.4%)

32 (54.2%)

13(100%)

-

-

-

-

17 (100%)

ER/PR (+)

6 (10.1%)

3 (23.1%)

1 (5.9%)

Squamous metaplasia (+)

3 (5.1%)

-

-

Adjuvant chemotherapy

22 (37.3%)

-

13 (76.5%)

Median chemotherapy cycles

4 (3-6)

-

6 (4-8)

Adjuvant EBRT

45.0 Gy

50.4 Gy

37 (62.7%)

22 (37.3%)

6 (46.0%)

7 (54.0%)

5 (29.5%)

12 (70.5%)

Vaginal brachytherapy

15 Gy 3

20 Gy 4

49 (84.0%)

10 (16.0%)

10 (76.9%)

3 (23.1%)

13 (76.5%)

4 (23.5%)

RESULTS: LRC :

80.9%, for leiomyosarcoma87.1% for carcinosarcoma100%, for endometrial carcinoma

DMC :69.3% for endometrial45% for leiomyosarcoma16.3% for carcinosarcoma

RESULTS: Five-year OS rates :

71.1%, for endometrial60% for leiomyosarcoma16.3%, for carcinosarcoma

Acute grade 3 and 4 proctitis/enteritisseen only in 4 patients (4.5%) and latetoxicities were minimal.

Toxicity

Grade 1, 2 n (%) Acute Late

Grade 3, 4 n (%) Acute Late

Hematological Anemia Neutropenia Thrombocytopenia

- - - - - -

- - 2 (2.25%) - - -

skin 5 (5.6%) 2 (2.25%) - 1 (1.1%) Small bowel 4 (4.5%) 4 (4.5%) - 1 (1.1%) Nausea/vomiting 4 (4.5%) - - - Vaginitis

3 (3.4%) 1 (1.1%) - -

Cystitis 2 (2.25%) - - -

Incidence of grade 2 and 3 acute and late toxicities

Toxicity

Grade 1, 2 n (%)

Acute Late

Grade 3, 4 n (%)

Acute Late

Hematological

Anemia

Neutropenia

Thrombocytopenia

-

-

-

-

2 (2.25%) -

-

skin

5 (5.6%) 2 (2.25%)

1 (1.1%)

Small bowel

4 (4.5%) 4 (4.5%)

1 (1.1%)

Nausea/vomiting

4 (4.5%) -

-

Vaginitis

3 (3.4%) 1 (1.1%)

-

Cystitis

2 (2.25%) -

-

Factors

Locoregional recurrence

OR (95% CI)

Distant metastasis

OR (95% CI)

Overall survival

OR (95% CI) Age (>50 vs. 30 vs. 30)* 3.4 (1.6-9.4) 1.1 (0.9-2.0) 3.6 (1.8-9.7)

FIGO (> IB vs. < IB) 1.7 (1.2-3.2) 3.9 (1.4-7.6) 3.6 (1.2-6.2) N (N1 vs. N0)* 1.1 (0.9-2.0) 1.1 (0.89-1.9) 1.8 (1.2-2.2)

ogy (endometrial vs. non-endometrial)* 1.2 (1.1-2.1) 2.3 (2.0-5.5) 4.2 (3.8-8.2) Grade ( > G2 vs. < G2)* 0.9 (0.8-1.1) 0.8 (0.6-1.1) 0.8 (0.7-1.1)

Tumor size ( > 5 cm vs. < 5 cm)* 0.9 (0.8-1.1) 4.2 (3.9-9.2) 3.8 (3.2-8.9) LVSI ( present vs. absent)* 3.3 (2.5-10.2) 1.1 (0.9-2.0) 1.1 (0.9-1.2) SCM (present vs. absent)* 0.9 (0.8-1.1) 1.0 (0.9-1.1) 1.1 ((0.9-1.2)

ER/PR (present vs. absent)* 0.9 (0.8-1.1) 1.1 (0.8-1.9) 1.1 (0.9-1.2) Elevated CA-125 (Yes vs. No)* 1.1 (0.9-1.2) 1.1 (0.9-2.0) 1.1 (0.9-1.2)

Adjuvant CT (No Vs. Yes)* 1.1 (0.9-1.1) 2.3 (1.8-7.2) 1.9 (1.4-3.2) juvant RT dose ( 50.4 Gy vs. 45 Gy)* 1.1 (0.9-1.2) 1.1 (1.0-1.2) 0.9 (0.9-1.1)

Cox Proportional Hazard analysis of prognostic factors on Locoregional, distant control and overall survival

Factors

Locoregional recurrence

OR (95% CI)

Distant metastasis

OR (95% CI)

Overall survival

OR (95% CI)

Age (>50 vs. 30 vs. 30)*

3.4 (1.6-9.4)

1.1 (0.9-2.0)

3.6 (1.8-9.7)

FIGO (> IB vs. < IB)

1.7 (1.2-3.2)

3.9 (1.4-7.6)

3.6 (1.2-6.2)

N (N1 vs. N0)*

1.1 (0.9-2.0)

1.1 (0.89-1.9)

1.8 (1.2-2.2)

Histology (endometrial vs. non-endometrial)*

1.2 (1.1-2.1)

2.3 (2.0-5.5)

4.2 (3.8-8.2)

Grade ( > G2 vs. < G2)*

0.9 (0.8-1.1)

0.8 (0.6-1.1)

0.8 (0.7-1.1)

Tumor size ( > 5 cm vs. < 5 cm)*

0.9 (0.8-1.1)

4.2 (3.9-9.2)

3.8 (3.2-8.9)

LVSI ( present vs. absent)*

3.3 (2.5-10.2)

1.1 (0.9-2.0)

1.1 (0.9-1.2)

SCM (present vs. absent)*

0.9 (0.8-1.1)

1.0 (0.9-1.1)

1.1 ((0.9-1.2)

ER/PR (present vs. absent)*

0.9 (0.8-1.1)

1.1 (0.8-1.9)

1.1 (0.9-1.2)

Elevated CA-125 (Yes vs. No)*

1.1 (0.9-1.2)

1.1 (0.9-2.0)

1.1 (0.9-1.2)

Adjuvant CT (No Vs. Yes)*

1.1 (0.9-1.1)

2.3 (1.8-7.2)

1.9 (1.4-3.2)

Adjuvant RT dose ( 50.4 Gy vs. 45 Gy)*

1.1 (0.9-1.2)

1.1 (1.0-1.2)

0.9 (0.9-1.1)

Toxicity profile

Grade 1 and 2 acute side effects : 4 patients (3.42%) had grade 3 enteritis.

Systemic chemotherapy, Febrile neutropenia :

2 patients (5.7%) Late toxicity :

1 patient who presented with sub-acute intestinal obstruction which was managed conservatively.

Locoregional control, distant control and overall survival ratesEndometrial carcinoma:

LRC, DMC, DFS and OS were 80.9%, 69.3%, 70.6% and 71.1% respectively.

5 patients developed locoregional recurrences (in-field).

1 patient had vaginal recurrences (1.7%)

3 patients had pelvic nodal recurrence (5.1%).

8 patients had Distant metastases (13.6%) 2 patients (3.4%) had simultaneous locoregional failures.

Lungs (4 patients),

liver (1 patient) and

para-aortic lymph nodes (3 patients)

Carcinosarcoma:

LRC, DMC, DFS and OS were 87.1%, 16.3%, 17.9% and 16.3% respectively.

Despite excellent LRC rates, majority of patients (59%) developed metastases lungs (6 patients), bones (3 patients) brain (one patient).

carcinosarcoma and absence of chemotherapy are poor prognostic factors for DMC.

Leiomyosarcoma:

LRC, DMC, DFS and OS were 100%, 45%, 64.3% and 60%

respectively.

4 patients developed distant metastasis;

lungs (3 patients and bones (1 patient).

Tumor size above 5 cm was found important prognostic

factor for DMC.

Discussion: Postoperative pelvic radiation therapy (PORT) (IMRT) in

uterine malignancies were not studied in Saudi population previously.

endometrial carcinoma and carcinosarcoma were in obese with median BMI > 30 Kg/m2 and associated with poor LRC and OS

(leiomyosarcoma and carcinosarcoma) was significantly high in our study as compared to reported western literature

LRC, DMC, DFS and OS for endometrial carcinoma and sarcoma were equal to other studies .

Tumor size above 5 cm was found important prognostic factor for DMC and OS in leiomyosarcoma .

Discussion:Incorporation of adjuvant chemotherapy prior to adjuvant radiotherapy was associated with reduced LRC (p value 0.003)

Minimal impact of additional adjuvant chemotherapy on distant control, dfs and os.

The possible explanation : delayed pelvic radiotherapy,

Conclusion:

Saudi women with endometrial cancers were found

more obese with BMI > 30 k/m2 and are associated with

co-morbidities, which warrant a national level obesity

awareness campaign.

Our results did not support the incorporation of sequential chemotherapy in adjuvant care of early endometrial carcinoma due to poor LRC .

Five Years Treatment Outcomes of Postoperative Radiotherapy in Saudi Women with Uterine CancersIntroduction:PORTEC-1 trialUterine sarcomas :PURPOSE: METHODS AND MATERIALS: Postoperative Radiation therapy techniques:Adjuvant chemotherapy:Toxicity and Response evaluation: RESULTS: Slide Number 11RESULTS: RESULTS: Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Toxicity profileLocoregional control, distant control and overall survival ratesEndometrial carcinoma:Carcinosarcoma:Leiomyosarcoma:Discussion:Discussion:Conclusion: