Beneficial effects of modulated electro-hyperthermia during neoadjuvant treatment for locally advanced rectal cancer

Figures & data

Figure 1. CONSORT diagram (RT: radiotherapy; CRT: chemoradiotherapy; mEHT: modulated electro-hyperthermia; fx: fractions).

Table 1. Patient characteristics before neoadjuvant treatment.

Characteristics	mEHT group (n = 62)	non-mEHT group (n = 58)	p value
Median age, yrs. (range)	59 (33–83)	57 (43–82)	.511
Sex, n			.300
Male	46 (74.2%)	38 (65.5%)
Female	16 (25.8%)	20 (34.5%)
Pathology, n			.160
Adenocarcinoma	59 (95.2%)	55 (94.8%)
Mucinous adenocarcinoma	2 (3.2%)	3 (5.2%)
Tubular adenocarcinoma	1 (1.6%)	0 (0.0%)
Differentiation, n			.895
Well differentiated	10 (16.1%)	9 (15.5%)
Moderate differentiated	48 (77.4%)	47 (81.0%)
Poor differentiated	3 (4.8%)	1 (1.7%)
Unknown	1 (1.6%)	1 (1.7%)
Anal verge range, n			.379
<5cm	38 (61.3%)	41 (70.7%)
≥5cm, <10cm	16 (25.8%)	9 (15.5%)
≥10cm	8 (12.9%)	8 (13.8%)
Initial clinical T stage, n			.887
cT2	2 (3.2%)	3 (5.2%)
cT3	46 (74.2%)	43 (74.1%)
cT4	14 (22.6%)	12 (20.7%)
Initial clinical N stage, n			.052
cN0	0 (0%)	4 (6.9%)
cN+	62 (100.0%)	54 (93.1%)
Mean initial primary tumor volume, mL (± SD^*)	62.6 (± 41.8)	61.9 (± 66.7)	.941

^*SD: standard deviation.

Table 2. Neoadjuvant treatment summary.

Treatment	mEHT group (n = 62)	non-mERT group (n = 58)
Radiation dose, n (mEHT No. range)
40 Gy	57 (8–9)	0
50.4 Gy	5^* (1–12)	58
Chemotherapy regimen, n
5-fluorouracil with leucovorin	6 (9.7%)	27 (46.6%)
Capecitabine	55 (88.7%)	31 (53.4%)
others	1 (1.6%)	0 (0%)
Type of resection, n
Low anterior resection	53 (85.5%)	47 (81.0%)
Abdominoperineal resection	4 (6.5%)	9 (15.5%)
Others	5 (8.0%)	2 (3.5%)
Mean overall treatment time^†, day (± SD^‡)	80.2 (± 8.4)	90.9 (± 9.6)

^*One of them had a radiation dose of 47.4 Gy, ^†Overall treatment time: Duration from first radiotherapy day to operation day. ^‡SD: standard deviation.

Figure 2. Box plot with scatter plot between initial primary tumor volume and tumor regression grade (TRG) in mEHT group (A) and non-mEHT group (B). In mEHT group, TRG distribution according to the initial primary tumor volume was relatively uniform. In non-mEHT group, the larger the tumor volume, the lower the TRG as expected, which was found to have a relatively higher distribution of the tumor volume in TRG1 compared to TRG3 or TRG4.

Table 3. Surgical pathology results.

	mEHT group (n = 62)	non- mEHT group (n = 58)	p value
Pathologic T stage, n			.196
ypT0-is	13 (21.0%)	6 (10.4%)
ypT1-2	21 (33.9%)	18 (31.0%)
ypT3-4	28 (45.1%)	34 (58.6%)
T-downstaging rate, n/all	41/62 (66.1%)	33/58 (56.9%)	.299
Pathologic N stage, n			.180
ypN0	50 (80.7%)	41 (70.7%)
ypN+	12 (19.3%)	17 (29.3%)
N-downstaging rate, n/all	56/62 (90.3%)	48/54^† (88.9%)	.800
ypStage, n			.422
ypCR	11 (17.7%)	5 (8.6%)
Stage 0 (ypTisN0)	1 (1.6%)	1 (1.7%)
Stage I	18 (29.0%)	13 (22.4%)
Stage II	20 (32.3%)	22 (38.0%)
Stage III	12 (19.4%)	17 (29.3%)
Downstaging rate, n/all	50/62 (80.7%)	39/58 (67.2%)	.094
Resection margin status, n/all (%)			.841
Negative	56 (90.3%)	53 (91.4%)
Positive	6 (9.7%)	5 (8.6%)
TRG^*, n			.146
TRG1 (Minimal regression)	9 (14.5%)	8 (13.8%)
TRG2 (Moderate regression)	31 (50.0%)	27 (46.6%)
TRG3 (Near total regression)	10 (16.1%)	18 (31.0%)
TRG4 (Total regression)	12 (19.4%)	5 (8.6%)
Good TRG score, TRG 3 + 4/all	22/62 (35.5%)	23/58 (39.7%)	.637
Initial primary tumor volume  <65 mL	16/43 (37.2%)	23/43 (53.5%)	.130
Initial primary tumor volume  ≥65 mL	6/19 (31.6%)	0/15 (0%)	.024

^*TRG: Tumor regression grade. ^†Excluding 4 patients with icN0.

Table 4. Neoadjuvant treatment-related toxicities.

	mEHT group (n = 62)				non- mEHT group (n = 58)				p value
Toxicity (grade)	0	1	2	3	0	1	2	3
Heat-related	45	15	0	2	–	–	–	–
Leukopenia	24	22	16	0	14	27	17	0	.219
Neutropenia	44	11	6	1	37	11	9	1	.802
GI^* toxicity	22	21	19	0	7	25	26	0	.010
GU^† toxicity	49	12	1	0	42	12	4	0	.362

^*GI: gastrointestinal. ^†GU: genitourinary. There was no grade 4 or above.

Figure 3. Survival analysis between the mEHT group and the non-mEHT group. (A) Overall survival, (B) Disease-free survival, (C) Locoregional recurrence-free survival, and (D) Distant metastasis-free survival.

Table 5. Univariate and multivariate Cox analysis of OS, DFS, LRRFS and DMFS for patients.

		Univariate			Multivariate
Variable	Category	HR^†	95% CI^‡	p	HR^†	95% CI^‡	p
OS^*
Sex	Female/Male	2.57	0.64–10.3	.183
Age	<70 / ≥70	0.89	0.18–4.45	.887
icT	icT2, 3 / icT4	1.61	0.32–8.05	.564
icN	icN0, 1 / icN2	0.75	0.19–3.00	.681
ypT	ypT0, 1, 2 / ypT3, 4	0.29	0.06–1.45	.133	0.17	0.03–1.00	.049
ypN	ypN0 / ypN1, 2	2.06	0.49–8.64	.323
RM^\\	Negative / Positive	4.98	0.98–25.2	.052	10.66	1.64–69.3	.013
Group	non-mEHT / mEHT	0.77	0.18–3.33	.728	0.46	0.09–2.24	.333
DFS^**
Age	<70 / ≥70	0.46	0.14–1.54	.206
AV^§	<5cm / ≥5cm	0.47	0.16–1.38	.167
icT	icT2, 3 / icT4	1.84	0.75–4.53	.184
icN	icN0, 1 / icN2	0.67	0.29–1.55	.349
ypT	ypT0, 1, 2 / ypT3, 4	1.38	0.59–3.23	.461
ypN	ypN0 / ypN1, 2	2.82	1.22–6.53	.016	2.69	1.15–6.30	.022
RM	Negative / Positive	4.91	1.91–12.6	.001	6.28	2.36–16.7	.001
Group	non-mEHT / mEHT	0.43	0.17–1.04	.062	0.39	0.16–0.99	.048
Response	TRG^¶ 3, 4 / 1, 2	1.68	0.66–4.28	.282
LRRFS^††
Sex	Female / Male	2.43	0.49–12.0	.278
icT	icT2, 3 / icT4	0.79	0.09–6.75	.827
icN	icN0, 1 / icN2	0.87	0.18–4.31	.864
ypT	ypT0, 1, 2 / ypT3, 4	1.98	0.35–10.3	.462
ypN	ypN0 / ypN1, 2	3.10	0.63–15.4	.166	3.12	0.61–15.9	.171
RM^\\	Negative / Positive	11.39	2.28–56.8	.003	13.51	2.68–68.2	.001
Group	non-mEHT / mEHT	0.19	0.02–1.63	.129	0.16	0.02–1.43	.101
DMFS^‡‡
Age	<70 / ≥70	0.30	0.07–1.30	.109	0.26	0.06–1.17	.079
AV^§	<5cm / ≥5cm	0.50	0.17–1.49	.212
icT	icT2, 3 / icT4	1.97	0.79–4.89	.144	1.44	0.51–4.07	.494
icN	icN0, 1 / icN2	0.59	0.25–1.42	.239
ypT	ypT0, 1, 2 / ypT3, 4	1.24	0.52–2.95	.645
ypN	ypN0 / ypN1, 2	2.49	1.05–5.91	.039	1.83	0.74–4.51	.191
RM^\\	Negative / Positive	4.89	1.89–12.7	.001	4.93	1.64–14.9	.005
Group	non-mEHT / mEHT	0.46	0.18–1.13	.091	0.36	0.14–0.95	.039
Response	TRG^¶ 3, 4 / 1, 2	2.01	0.74–5.50	.173

^*OS: Overall survival. ^†HR: Hazard ratio. ^‡CI: Confidence interval. ^§AV: Anal verge. ^\\RM: Resection margin. ^¶TRG: Tumor regression grade. **DFS: Disease-free survival. ^††LRRFS: Locoregional recurrence-free survival. ^‡‡DMFS: Distant metastasis-free survival.