World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Original Article

Volume 13, Number 3, June 2022, pages 145-154

Abdominopelvic Lymphatic Drainage Area Irradiation for Consolidative Radiotherapy of Advanced Ovarian Carcinoma: Analysis of Clinical Application Efficacy and Dosimetric Verification

Figure 2. Clinical outcomes. OS: overall survival; DFS: disease-free survival; LRFS: local recurrence free survival; DMFS: distant metastasis free survival.

Figure 3. Failure map for patients treated with APLN. *The yellow line represents the area of APLN (vaginal stump and pelvic lymphatic drainage area (common iliac, external iliac, internal iliac, closed foramen region, and anterior sacral region), abdominal aorta PALN (upper border at the level of T12). The pink line represents the radiation area of WART. The red rods represent LR. The failure map shows 20 patients with LR: 13 para-aortic or pelvic lymph nodes, two vaginal stump, three mesenteric area, and one inguinal and one abdominal wall, and three with recurrence between the area of WART and APLN. APLN: abdominopelvic lymphatic drainage area irradiation; PLAN: para-aortic lymphatic drainage area; WART: whole abdominal radiotherapy; LR: local recurrence.

**Table 1.** Baseline and Clinical Characteristics of the Patients (n = 99)
Characteristics	Number	%
FIGO: Federation of Gynecology and Obstetrics; CA125: carbohydrate antigen 125.
Age (years)
< 60	76	76.76
≥ 60	23	23.23
Number of surgeries
< 2	56	56.57
≥ 2	43	43.43
Histology
Epithelial carcinoma	92	92.93
Interstitial tumors of the sex cords	5	5.05
Germ cell tumors	2	2.02
FIGO stage
III	89	89.90
IV	10	10.10
Preoperative CA125
< 100	55	55.56
≥ 100	44	44.44
Postoperative chemotherapy courses
< 6	17	17.17
≥ 6	82	82.93
CA125 decreased to normal
< 3 chemotherapy courses	53	53.54
≥ 3 chemotherapy courses	46	46.46

Table 1. Baseline and Clinical Characteristics of the Patients (n = 99)

Characteristics

Number

FIGO: Federation of Gynecology and Obstetrics; CA125: carbohydrate antigen 125.

Age (years)

< 60

76.76

≥ 60

23.23

Number of surgeries

< 2

56.57

≥ 2

43.43

Histology

Epithelial carcinoma

92.93

Interstitial tumors of the sex cords

5.05

Germ cell tumors

2.02

FIGO stage

III

89.90

10.10

Preoperative CA125

< 100

55.56

≥ 100

44.44

Postoperative chemotherapy courses

< 6

17.17

≥ 6

82.93

CA125 decreased to normal

< 3 chemotherapy courses

53.54

≥ 3 chemotherapy courses

46.46

**Table 2.** Failure Pattern for Patients Treated With APLN
Failure mode	No.	%
APLN: abdominopelvic lymphatic drainage area irradiation.
Local recurrence	2	2.02
Distant metastasis	32	32.32
Local recurrence and distant metastasis	18	18.18

Table 2. Failure Pattern for Patients Treated With APLN

Failure mode

No.

APLN: abdominopelvic lymphatic drainage area irradiation.

Local recurrence

2.02

Distant metastasis

32.32

Local recurrence and distant metastasis

18.18

**Table 3.** Univariate Analysis of Factors Influencing 5-year OS, DFS, LRFS and DMFS
	n	OS (%)	P value	DFS (%)	P value	LRFS (%)	P value	DMFS (%)	P value
*Statistically significant difference (paired, two-tailed t-test, P < 0.05). OS: overall survival; DFS: disease-free survival; LRFS: local recurrence free survival; DMFS: distant metastasis free survival; FIGO: Federation of Gynecology and Obstetrics; CA125: carbohydrate antigen 125.
Age (years)
< 60	76
≥ 60	23
Number of surgeries									0.999
< 2	56	67.9	0.491	52.6	0.569	82.7	0.049*	63.4
≥ 2	43	53.5		45.9		65.8		71.9
Surgical resection status									0.761
Complete resection	70	62.9	0.910	49.0	0.321	72.6	0.717	74.7
Basic resection	21	66.7		56.1		81.5		57.4
Major resection	8	37.5		32.2		66.2		55.5
Histology									0.385
Epithelial carcinoma	92	62.0	0.945	49.3	0.823	77.4	0.222	64.0
Interstitial tumors of the sex cords	5	60.0		46.4		47.0		48.5
Germ cell tumors	2	50.0		42.6		43.4		43.4
FIGO stage									0.128
III	89	61.6	0.151	50.2	0.055	78.8	0.819	70.8
IV	10	50.0		20.2		48.8		24.0
Preoperative CA125 (U/mL)									0.512
< 100	48	64.6	0.616	48.4	0.716	79.2	0.773	74.6
≥ 100	41	61.6		50.0		75.9		48.9
Postoperative chemotherapy courses									0.332
< 6	17	70.6	0.064	54.8	0.652	76.5	0.769	58.8
≥ 6	82	61.6		50.0		79.8		46.2
CA125 decreased to normal									0.523
< 3 chemotherapy courses	53	60.4	0.794	48.3	0.842	77.4	0.920	57.5
≥ 3 chemotherapy courses	46	66.7		50.0		79.8		70.8

Table 3. Univariate Analysis of Factors Influencing 5-year OS, DFS, LRFS and DMFS

OS (%)

P value

DFS (%)

P value

LRFS (%)

P value

DMFS (%)

P value

*Statistically significant difference (paired, two-tailed t-test, P < 0.05). OS: overall survival; DFS: disease-free survival; LRFS: local recurrence free survival; DMFS: distant metastasis free survival; FIGO: Federation of Gynecology and Obstetrics; CA125: carbohydrate antigen 125.

Age (years)

< 60

≥ 60

Number of surgeries

0.999

< 2

67.9

0.491

52.6

0.569

82.7

0.049*

63.4

≥ 2

53.5

45.9

65.8

71.9

Surgical resection status

0.761

Complete resection

62.9

0.910

49.0

0.321

72.6

0.717

74.7

Basic resection

66.7

56.1

81.5

57.4

Major resection

37.5

32.2

66.2

55.5

Histology

0.385

Epithelial carcinoma

62.0

0.945

49.3

0.823

77.4

0.222

64.0

Interstitial tumors of the sex cords

60.0

46.4

47.0

48.5

Germ cell tumors

50.0

42.6

43.4

FIGO stage

0.128

III

61.6

0.151

50.2

0.055

78.8

0.819

70.8

50.0

20.2

48.8

24.0

Preoperative CA125 (U/mL)

0.512

< 100

64.6

0.616

48.4

0.716

79.2

0.773

74.6

≥ 100

61.6

50.0

75.9

48.9

Postoperative chemotherapy courses

0.332

< 6

70.6

0.064

54.8

0.652

76.5

0.769

58.8

≥ 6

61.6

50.0

79.8

46.2

CA125 decreased to normal

0.523

< 3 chemotherapy courses

60.4

0.794

48.3

0.842

77.4

0.920

57.5

≥ 3 chemotherapy courses

66.7

50.0

79.8

70.8

**Table 4.** Multivariate Analysis of Factors Influencing 5-Year LRFS
Characteristic		P-value	HR (95% CI)
*Statistically significant difference (paired, two-tailed t-test, P < 0.05). LRFS: local recurrence free survival; HR: hazard ratio; CI: confidence interval; CA125: carbohydrate antigen 125.
Number of surgeries	< 2	0.048*	2.708 (1.009 - 7.266)
	≥ 2
Surgical resection status	Complete resection	0.939	0.969 (0.427 - 2.199)
	Basic resection
	Major resection
Postoperative chemotherapy courses	< 6	0.963	1.015 (0.548 - 1.880)
	≥ 6
CA125 decreased to normal	< 3 chemotherapy courses	0.291	0.808 (0.544 - 1.200)
	≥ 3 chemotherapy courses
Histology	Epithelial carcinoma	0.096	2.444 (0.854 - 6.992)
	Interstitial tumors of the sex cords
	Germ cell tumors

Table 4. Multivariate Analysis of Factors Influencing 5-Year LRFS

Characteristic

P-value

HR (95% CI)

*Statistically significant difference (paired, two-tailed t-test, P < 0.05). LRFS: local recurrence free survival; HR: hazard ratio; CI: confidence interval; CA125: carbohydrate antigen 125.

Number of surgeries

< 2

0.048*

2.708 (1.009 - 7.266)

≥ 2

Surgical resection status

Complete resection

0.939

0.969 (0.427 - 2.199)

Basic resection

Major resection

Postoperative chemotherapy courses

< 6

0.963

1.015 (0.548 - 1.880)

≥ 6

CA125 decreased to normal

< 3 chemotherapy courses

0.291

0.808 (0.544 - 1.200)

≥ 3 chemotherapy courses

Histology

Epithelial carcinoma

0.096

2.444 (0.854 - 6.992)

Interstitial tumors of the sex cords

Germ cell tumors

**Table 5.** Dosimetric Differences Between Two Groups
	APLN, mean dose (Gy)	WART, mean dose (Gy)	Difference
*Statistically significant difference (paired, two-tailed t-test, P < 0.05). PTV: planning target volume; APLN: abdominopelvic lymphatic drainage area irradiation; WART: whole abdominal radiotherapy.
PTV	46.38 ± 0.20	31.30 ± 0.24	15.08 ± 0.43*
Liver	4.27 ± 3.01	29.54 ± 1.14	-25.27 ± 3.63*
Spleen	4.55 ± 2.52	29.25 ± 3.04	-24.71 ± 3.91*
Kidney R	10.21 ± 3.58	18.98 ± 2.65	-8.77 ± 5.03*
Kidney L	9.75 ± 2.83	18.43 ± 3.36	-8.68 ± 5.89*
Small intestine	23.50 ± 1.56	31.64 ± 0.26	-8.14 ± 1.51*
Femoral R	25.26 ± 2.08	18.93 ± 1.16	6.32 ± 2.61*
Femoral L	25.49 ± 1.58	18.23 ± 0.98	7.26 ± 1.44*
Bladder	35.11 ± 3.23	29.41 ± 2.02	5.70 ± 4.24*
Rectum	39.68 ± 3.29	25.64 ± 3.15	14.04 ± 4.01*
Bone marrow	27.77 ± 2.87	22.84 ± 0.82	4.93 ± 2.90*
Stomach	7.14 ± 5.88	31.56 ± 0.33	-24.42 ± 5.72*
Spine cord	18.05 ± 2.19	21.10 ± 1.31	-3.05 ± 2.00*

Table 5. Dosimetric Differences Between Two Groups

APLN, mean dose (Gy)

WART, mean dose (Gy)

Difference

*Statistically significant difference (paired, two-tailed t-test, P < 0.05). PTV: planning target volume; APLN: abdominopelvic lymphatic drainage area irradiation; WART: whole abdominal radiotherapy.

PTV

46.38 ± 0.20

31.30 ± 0.24

15.08 ± 0.43*

Liver

4.27 ± 3.01

29.54 ± 1.14

-25.27 ± 3.63*

Spleen

4.55 ± 2.52

29.25 ± 3.04

-24.71 ± 3.91*

Kidney R

10.21 ± 3.58

18.98 ± 2.65

-8.77 ± 5.03*

Kidney L

9.75 ± 2.83

18.43 ± 3.36

-8.68 ± 5.89*

Small intestine

23.50 ± 1.56

31.64 ± 0.26

-8.14 ± 1.51*

Femoral R

25.26 ± 2.08

18.93 ± 1.16

6.32 ± 2.61*

Femoral L

25.49 ± 1.58

18.23 ± 0.98

7.26 ± 1.44*

Bladder

35.11 ± 3.23

29.41 ± 2.02

5.70 ± 4.24*

Rectum

39.68 ± 3.29

25.64 ± 3.15

14.04 ± 4.01*

Bone marrow

27.77 ± 2.87

22.84 ± 0.82

4.93 ± 2.90*

Stomach

7.14 ± 5.88

31.56 ± 0.33

-24.42 ± 5.72*

Spine cord

18.05 ± 2.19

21.10 ± 1.31

-3.05 ± 2.00*

**Table 6.** TCP and NTCP Comparison of APLN and WART
	TCP (%)
APLN (TCD50=30)	96.95	53.68
APLN (TCD50=40)	76.20	10.13
APLN (TCD50=38)	82.84	14.65
*Statistically significant difference (paired, two-tailed t-test, P < 0.05). APLN: abdominopelvic lymphatic drainage area irradiation; WART: whole abdominal radiotherapy.
APLN	1.05	0.04	0.01	< 0.001
WART	0.02	2.99	0.77	< 0.001
Difference	1.04*	0.19*	0.04*	-

Table 6. TCP and NTCP Comparison of APLN and WART

TCP (%)

APLN

WART

APLN (TCD50=30)

96.95

53.68

APLN (TCD50=40)

76.20

10.13

APLN (TCD50=38)

82.84

14.65

NTCP (%)

Small intestine

Kidney

Liver

Spine cord

*Statistically significant difference (paired, two-tailed t-test, P < 0.05). APLN: abdominopelvic lymphatic drainage area irradiation; WART: whole abdominal radiotherapy.

APLN

1.05

0.04

0.01

< 0.001

WART

0.02

2.99

0.77

< 0.001

Difference

1.04*

0.19*

0.04*

**Table 7.** Literature and Reported Results on WART for Consolidative Radiotherapy
Author	Type of study	Reported stage	Population	Trial design	Radiation therapy dose	Outcomes	Toxicity
CT: chemotherapy; WART: whole abdominal radiotherapy; OS: overall survival; WHO: World Health Organization; GI: gastrointestinal; CRT: chemoradiotherapy; PFS: progression-free survival; SIB: simultaneous integrated boost; IMRT: intensity-modulated radiotherapy; PTV: planning target volume; DFS: disease-free survival; HT: helical tomotherapy.
Bruzzone et al [15]	Randomized trial	Stage III-IV (minimal residual disease)	41 total (21 in CT arm and 20 in WART arm)	CT arm (three additional courses of the same front-line CT) and WART arm	43.2 Gy/24 fractions to the pelvis and 30.2 Gy to the upper abdomen	3-year OS (CT arm): 85%; 3-year OS (WART arm): 45%	CT arm - grade 3 N/V events (WHO): 36.9%; WART arm - grade 3 N/V events (WHO): 14.2%; bowel obstruction: 5%
North Thames Ovary Group Study [16]	Randomized trial	Stage IIB-IV (≤ 2 cm residual disease )	117 total (59 in CT arm and 58 in WART arm)	CT arm (five additional courses of carboplatin-based CT) and WART arm	24 Gy/20 fractions/5 #, boost up to a dose of 40 Gy (residual disease)	5-year OS (CT arm): 30%; 5-year OS (WART arm): 25%	CT arm - grade 4 N/V events (WHO): 2%; WART arm - grade 3 myelotoxicity (WHO): 5%; WART arm - bowel obstruction (WHO): 1.7%
Pickel et al [17]	Randomized trial	Stage IC-IV (no clinical disease)	64 total (32 IN WART arm and 32 in observation arm)	Surgery (no residual disease) and adjuvant platinum-based CT and randomization to WART arm and observation arm	WART: 30 Gy (1.5 Gy/5 treatments per week). Additional boost of 21.6 Gy to the pelvis and boost of 12 Gy to para-aortic region	5-year OS: 59%; 5-year OS: 33%	Treatment breaks: 37.5%; bowel obstruction: 3.1%
Swedish-Norwegian Ovarian Cancer Study Group [18]	Prospective randomized trial	Stage III	172 total (98 in CRT arm and 74 in observation arm)	Randomization to: consolidation with RT (WART); consolidation with CT (six courses); observation	Abdominal RT dose of 20 Gy (1 Gy, 5 days a week, 20 fractions) + abdominopelvic boost dose of 20.4 Gy (1.7 Gy per fraction, 12 fractions)	5-year PFS: 56.3%; 5-year OS: 68.8%; 5-year PFS: 36%; 5-year OS: 57.1%	Early side events radiotherapy group: grade 3 myelotoxicity: 4.4%; grade 3 bowel events: 4.4%; late side events radiotherapy group: grade 3 intestinal obstruction: 10%
Stevens et al [21]	Pre-approved	Ic1-IIIa2	Five patients	SIB-WART (IMRT)	25 Gy (PTV_Low) and SIB 45 Gy (PTV_High), 25 fractions	All DFS (median follow-up: 77 months)	One grade 3 GI. Two grade 2 osteoporotic fragility fractures
Shetty et al [22]	A feasibility study	IIc-IIIc	Eight patients	SIB-WART (HT)	25 Gy/25 fractions and SIB 45 Gy/25 fractions	Three recurrences in peritoneum (median follow-up: 15 months)	One grade 3 GI

Table 7. Literature and Reported Results on WART for Consolidative Radiotherapy

Author

Type of study

Reported stage

Population

Trial design

Radiation therapy dose

Outcomes

Toxicity

CT: chemotherapy; WART: whole abdominal radiotherapy; OS: overall survival; WHO: World Health Organization; GI: gastrointestinal; CRT: chemoradiotherapy; PFS: progression-free survival; SIB: simultaneous integrated boost; IMRT: intensity-modulated radiotherapy; PTV: planning target volume; DFS: disease-free survival; HT: helical tomotherapy.

Bruzzone et al [15]

Randomized trial

Stage III-IV (minimal residual disease)

41 total (21 in CT arm and 20 in WART arm)

CT arm (three additional courses of the same front-line CT) and WART arm

43.2 Gy/24 fractions to the pelvis and 30.2 Gy to the upper abdomen

3-year OS (CT arm): 85%; 3-year OS (WART arm): 45%

CT arm - grade 3 N/V events (WHO): 36.9%; WART arm - grade 3 N/V events (WHO): 14.2%; bowel obstruction: 5%

North Thames Ovary Group Study [16]

Randomized trial

Stage IIB-IV (≤ 2 cm residual disease )

117 total (59 in CT arm and 58 in WART arm)

CT arm (five additional courses of carboplatin-based CT) and WART arm

24 Gy/20 fractions/5 #, boost up to a dose of 40 Gy (residual disease)

5-year OS (CT arm): 30%; 5-year OS (WART arm): 25%

CT arm - grade 4 N/V events (WHO): 2%; WART arm - grade 3 myelotoxicity (WHO): 5%; WART arm - bowel obstruction (WHO): 1.7%

Pickel et al [17]

Randomized trial

Stage IC-IV (no clinical disease)

64 total (32 IN WART arm and 32 in observation arm)

Surgery (no residual disease) and adjuvant platinum-based CT and randomization to WART arm and observation arm

WART: 30 Gy (1.5 Gy/5 treatments per week). Additional boost of 21.6 Gy to the pelvis and boost of 12 Gy to para-aortic region

5-year OS: 59%; 5-year OS: 33%

Treatment breaks: 37.5%; bowel obstruction: 3.1%

Swedish-Norwegian Ovarian Cancer Study Group [18]

Prospective randomized trial

Stage III

172 total (98 in CRT arm and 74 in observation arm)

Randomization to: consolidation with RT (WART); consolidation with CT (six courses); observation

Abdominal RT dose of 20 Gy (1 Gy, 5 days a week, 20 fractions) + abdominopelvic boost dose of 20.4 Gy (1.7 Gy per fraction, 12 fractions)

5-year PFS: 56.3%; 5-year OS: 68.8%; 5-year PFS: 36%; 5-year OS: 57.1%

Early side events radiotherapy group: grade 3 myelotoxicity: 4.4%; grade 3 bowel events: 4.4%; late side events radiotherapy group: grade 3 intestinal obstruction: 10%

Stevens et al [21]

Pre-approved

Ic1-IIIa2

Five patients

SIB-WART (IMRT)

25 Gy (PTV_Low) and SIB 45 Gy (PTV_High), 25 fractions

All DFS (median follow-up: 77 months)

One grade 3 GI. Two grade 2 osteoporotic fragility fractures

Shetty et al [22]

A feasibility study

IIc-IIIc

Eight patients

SIB-WART (HT)

25 Gy/25 fractions and SIB 45 Gy/25 fractions

Three recurrences in peritoneum (median follow-up: 15 months)

One grade 3 GI