Clinical outcomes using a 3D printed tandem-needle-template and the EMBRACE-II planning aims for image guided adaptive brachytherapy in locally advanced cervical cancer

Figures & data

Figure 1. (A) Standard and personalized tandem-needle-template [TNT], with corresponding diameters and needle holes for parallel and oblique needles; (B) Personalized TNT fitted over the Varian tandem with both parallel and oblique needles in situ; (C) the tandem and personalized TNT with needles on MRI in coronal view showing oblique and parallel needle position (green dots), stopping positions in the tandem (yellow dots) and at ring level (red dots), CTV_HR (blue dashed line) and isodose distribution (yellow 200%, red 90%, blue 50%).

Figure 2. (A) Total number of tumor score [TS] points per location and needle direction: parallel and oblique [P&O] (red) and parallel [P] (blue). above the bars, the ratio [r] is mentioned, corrected for number of patients [N]; (B) Likelihood of using P&O needles as a function of TS at brachytherapy [TS_BT] is demonstrated by logit analysis; (C) Total dose of external beam radiotherapy and BT for CTV_HR D90 [minimal dose to 90% of the clinical target volume] (circles) and rectal D2cm³ [minimal dose to the most exposed 2 cc of the OAR] (squares) as a function of TS for P&O (red) and P (blue); [D] the mean total reference air kerma [TRAK] as a function of TS for P&O (red) and P (blue).

Table 1. Patient, tumor, and treatment characteristics according to template type: Needle directions in parallel to the tandem (P) or needle directions in parallel and oblique to the tandem (P&0).

A: Patient and tumor characteristics		All	P	P&O	p-value
No. of patients	No. (%)	101 (100)	49 (49)	52 (51)
Age	Mean (SD)	63 (16)	66 (14)	60 (17)	0.073
Performance (WHO)	>0 (%)	48 (48)	19 (39)	29 (56)	0.087
Comorbidity	Present (%)	52 (51)	25 (51)	27 (52)	0.928
Histology	SQ (%)	91 (90)	45 (92.0)	46 (87)	0.570
Tumor score at diagnosis (TSD)	Mean (SD)	9.1 (4.1)	7.7 (3.6)	10.5 (4.2)	0.000
Tumor score at brachytherapy (TSBT)	Mean (SD)	6.3 (3.2)	5.0 (2.0)	7.6 (3.6)	0.000
Tumor score High-High^a	Present (%)	53 (53)	18 (37)	35 (67)^c	0.003
DPPW at BT^b	Present (%)	46 (46)	10 (20)	36 (69)^c	0.000
Nodal status	Positive (%)	61 (60)	27 (55.0)	34 (65)	0.291
FIGO2018 stage	IB (%)	1 (1)	1 (2)	–	0.177^d
	IIB (%)	22 (22)	13 (27)	9 (17)
	IIIA (%)	1 (1)	1 (2)	–
	IIIB (%)	15 (15)	7 (14)	8 (15)
	IIIC1 (%)	39 (39)	18 (37)	21 (40)
	IIIC2 (%)	13 (13)	7 (14)	6 (12)
	IVA (%)	10 (10)^e	2 (4)	8 (15)
B: Treatment characteristics		All	P	P&O	p-value
Concomitant cisplatin	Initiated (%)	56 (55)	27 (55)	29 (56)	0.946
Overall Treatment Time (days)	Median (IQR)	48 (45-50)	47 (42-50)	49 (46-52)
	>50 days (%)	23 (23)	7 (14)	16 (31)	0.048
Extended EBRT^f target	Yes (%)	34 (34)	11 (22)	23 (44)	0.021
TNT^g diameter “small”	Yes (%)	84 (83)	43 (88)	41 (79)	0.232
Number of needles^h	Median (IQR)	9 (8-12)	8 (8-9)	12 (9-13)
Number of active needles^h	Median (IQR)	8 (8-11)	8 (7-8)	10 (9-12)
TRAK^i cGy	Mean (SD)	1.64 (0.49)	1.54 (0.42)	1.73 (0.53)	0.063
CTVHR^j (volume, cm^3)	Mean (SD)	37.9 (24.0)	33.9 (22.0)	41.5 (25.5)	0.111
CTVHR D90 (GyEQD2)	Mean (SD)	93.4 (3.3)	93.9 (3.1)	92.9 (3.4)	0.121
Bladder D2cm^3 (GyEQD2)	Mean (SD)	73.1 (8.0)	71.0 (7.5)	75.1 (8.0)	0.009
Rectum D2cm^3 (GyEQD2)	Mean (SD)	60.8 (5.7)	59.1 (4.4)	62.4 (6.3)	0.004
Sigmoid D2cm^3 (GyEQD2)	Mean (SD)	58.8 (6.0)	58.3 (6.2)	59.2 (5.8)	0.436
Bowel D2cm^3 (GyEQD2)	Mean (SD)	59.2 (8.4)	59.4 (8.5)	59.0 (8.6)	0.774
Recto-vaginal point (GyEQD2)	Mean (SD)	58.9 (5.2)	58.1 (4.9)	59.6 (5.4)	0.137
CTVHR D90 soft constraint^k	Fulfilled (%)	93 (92)	47 (96)	46 (89)	0.165
OAR^l all soft constraints^k	Fulfilled (%)	60 (59)	35 (71)	25 (48)	0.017

^aHigh-High: TS_D AND TS_BT > 5.

^bInvolvement of distal parametrium or pelvic wall at first brachytherapy.

^c3 cases with DPPW were High-Low in TS and 3 cases with High-High in TS did not have DPPW involvement.

^dComparing stage I-II versus III-IV.

^eBiopsy confirmed. Additional 21 patients had bladder wall infiltration/bullous edema on MRI/cystoscopy.

^fExternal beam radiotherapy.

^g Tandem needle template.

^hMaximal number used for first or second bachytherapy implant.

^ITotal reference air kerma.

^jHigh risk clinical target volume, (dose to 90% of the CTV_HR).

^kAccording to the EMBRACE II Study.

^lOrgans at risk.

Table 2. Tumor score at brachytherapy [TS_BT] for all patients and the two patient subgroups according to needle direction. The number of patients receiving different number of points according to nominal scale are shown for each anatomical location.

	No. of patients
Location	Nominal scale	Points	All	P^a	P&O^b
Cervix	Not present	0	0	0	0
	≤20 mm	1	2	2	0
	>20, ≤ 40	2	51	32	19
	mm > 40 mm	3	48	15	33
Left Parametrium	Not involved	0	24	17	7
	Proximal	1	50	27	23
	Distal	2	18	4	14
	Pelvic wall	3	9	1	8
Right Parametrium	Not involved	0	34	22	12
	Proximal	1	39	22	17
	Distal	2	18	3	15
	Pelvic wall	3	10	2	8
Vagina	Not involved	0	61	31	30
	Upper 1/3	1	26	13	13
	Middle 1/3	2	10	4	6
	Lower 1/3	3	4	1	3
Uterine Corpus	Not involved	0	64	32	33
	Lower 1/3	1	24	11	13
	Middle 1/3	2	9	4	5
	Upper 1/3	3	3	2	1
Rectum	Not involved	0	90	48	42
	Mesorectum	1	11	1	10
	Rectal wall	2	0	0	0
	Mucosa involved	3	0	0	0
Bladder	Not involved	0	83	45	38
	Bladder wall	1	18	4	14
	Bullous edema	2	0	0	0
	Mucosa involved	3	0	0	0
Ureter	Not involved	0	74	41	33
	Unilateral	1	16	5	11
	Bilateral	2	1	3	8
Total number of patients (%)			101	49	52
TSBT	Median (range)		6(1-17)	5 (1-10)	7 (3-17)
	Mean (SE)		6.3 (0.3)	5.0 (0.3)	7.6 (0.5)

^aNeedle directions implanted in parallel to the tandem.

^bNeedle directions implanted in parallel and oblique to the tandem.

Figure 3. Kaplan-Meier curves for local control (A) and cancer specific survival (B) in group with parallel [P] and parallel and oblique [O] needles; local control (C) and cancer specific survival (D) corresponding with tumor response, based on tumor score at Diagnose [TS_D] and brachytherapy [TS_BT]: L (TS_D and TS_BT$\le$5), HL [TS_D >5 and TS_BT $\le$5], HH (TS_D and TS_BT >5).

Table 3. Number of events and actuarial 3-year outcome for all patients and the two patient subgroups according to needle direction.

Variable	All^a	P^b	P&O^c	p-value^d
Local failure	13	2	11
Local control (SE)^e	85 (4)	95 (3)	75 (7)	0.009
Pelvic failure (local and regional)	22	8	14
Pelvic control, local and regional (SE)	75 (5)	80 (7)	70 (7)	0.130
Para-aortic failure	10	3	7
Para-aortic control (SE)	88 (4)	91 (5)	85 (6)	0.140
Systemic failure	21	9	12
Systemic control (SE)	74 (5)	77 (7)	71 (7)	0.373
Diseased	49	20	29
Overall Survival	63 (5)	75 (6)	51 (7)	0.058
Cervical cancer deaths	36	13	23
Cancer Specific survival	68 (5)	80 (6)	56 (7)	0.036
Recurrence or death	52	22	30
Disease free Survival	51 (5)	56 (7)	47 (7)	0.108
≥ Grade 3 side effect	10	7	3
≥ Grade 3 side effect (SE)	12 (4)	16 (6)	9 (5)	0.261

^aOne patient in the P&O group died before first follow up leaving 100 patients evaluable for tumor control (local, pelvic, para-aortic, systemic) and 101 evaluable for survival endpoints and grade 3 or worse side effect.

^bNeedles implanted in direction parallel to the tandem.

^cNeedles implanted in directions parallel and oblique to the tandem.

^dlog-rank.

^eStandard error.

Table 4. Patient and tumor characteristics of patients with ≥ grade 3 side effects (CTC-AE version 3.0) including age, WHO performance status (PS), comorbidity, FIGO₂₀₁₈ stage, distal pelvic parametrium or pelvic wall involvement at BT (DPPW), tumour score at diagnosis (TS_D) and at BT (TS_BT). principal treatment related cause of side effects was assessed to be EBRT in patient A, D, F and I, cisplatin in patient B and BT in patient A, C, E, G, H and J.

Patient	Group	Age	PS	Comorbidity (CM) and late effect (LE)	FIGO2018	DPPW	TSD	TSBT
A	P	72	1	CM: Rheumatoid arthritis	IIIC1	No	9	6
				LE: Stenosis of ileum
B	P	71	0	CM: Mammary Cancer	IIIC1	No	8	5
				LE: Cisplatin induced neuropathy
C	P	72	1	CM: Apoplexia cerebri	IIIC1	Yes	10	7
				LE: Hydronephrosis
D	P	58	1	CM: Mammary cancer, previous actinic castration, Kidney insufficiency, Retroperitoneal fibrosis	IIIC2	Yes	14	8
				LE: Gastro-intestinal, urological and vaginal fibrosis
E	P	43	0	CM: None	IIB	No	5	4
				LE: Vaginal necrosis, healed after 3 years
F	P	65	0	CM: None	IIIC1	No	7	7
				LE: Mesenteric arterial thrombosis with subsequent sigmoid necrosis
G	P	50	1	CM: HIV, hepatitis-C	IIIC1	Yes	8	7
				LE: Hydronephrosis, intrabdominal abscess
H	P&O	38	2	CM: Post-traumatic stress	IIIC1	Yes	10	10
				LE: Recto-vaginal fistula
I	P&O	80	1	CM: Mammary cancer	IIIB	No	13	5
				LE: Gastro-enteritis, dead before first follow-up
J	P&O	39	1	CM: Anorexia	IIIC1	Yes	17	12
				LE: Perforation of sigmoid, infection and abscess formation

Data availability statement

Data cannot be shared