Skip to main content
. 2022 Jan 26;14(3):625. doi: 10.3390/cancers14030625

Table 11.

Prospective clinical studies using RT and CT in combination with HT.

Author(s) Cancer site, n CT Drug(s)
(mg/m2) ×
Cycles		 RT Dose (Gy)
/Fractions		 Temperature
Metrics (°C)		 Session ttreat
(min)		 Thermal
Dose (min)		 tint (min) Sequence Clinical Outcome
(Comment)
Amichetti et al. [152] Locally
advanced
head & neck
cancer, n = 18		 20 cisplatin
once weekly
× 7		 70.0/35 Tmax †: 43.2
(41.5–44.5)
Tmin †: 40.1
(37–42)
T90 †: 40.4
(38.7–42.2)		 Ntotal:
2
Nweek:
2		 30 CEM42.5 °C
Tmin †:
4.36 (0–27)
CEM42.5 °C
Tmax †:
88 (31.8–174)		 20 HT after
RT & CT

  • CR 1: 72.2% (13/18), PR 2: 16.6% (3/18); NC 3: 11.1% (2/18).

  • OS 4: 88.8%, 3-year actuarial survival and probability of remaining free of nodal disease: 50.3% and 53.3%, respectively.

  • No temperature metrics correlated with an increased acute side effects and the amount of skin toxicity.
Maluta et al. [156] Primary or
recurrent
locally
advanced
pancreatic
cancer,
n = 40		 1000
gemcitabine
× 1–2
30
cisplatin
×		 30.0–66.0
/10–33		 T90 †: 40.5
(95% CI:
39.8–41)
Tmax †: 41.1
(95% CI:
40.2–42.5)		 Ntotal:
3–10
Nweek:
2		 60 n.r. n.r. CT before
HT & RT

  • OS ‡: 15 (6–20) months

  • The most common hematological toxicity was grade 2 anemia.

  • Toxicity, grade III: 5 patients.

(correlation of thermometric parameters with clinical outcome not presented)
Asao et al. [151] Locally
advanced
rectal
cancer,
n = 29		 250
5-fluorouracil
for 5 days
× 2
25
for 5 days
× 2		 40.0–50.0
/20–25		 Tmax †:
40.3 ± 0.89
(38.6–41.9)		 Ntotal:
3
Nweek:
1		 60 n.r. n.r. HT after RT
during CT

  • Toxicity, grade III: 2 patients.

  • CR: 55.5% in patients with a total radiation dose of 50 Gy, which was significantly higher compared to patients treated with 40 Gy.

  • 41.4% of patients had significant downstaging.

(correlation of thermometric parameters with clinical outcome not reported)
Westermann et al. [150] Cervix
cancer,
n = 68		 40 cisplatin
once weekly
× 35		 45.0–50.4
/25–28
with
LDR- IRT 7
and
HDR-IRT 7
(192 Ir)		 T90 †: 39.4
T50 †: 40.7		 Ntotal:
8–10
Nweek:
1		 60 n.r. n.r. HT & CT
after/before RT

  • CR: 90%, 2-year DFS 5 and OS: 71.6% and 78.5%, respectively.

  • A significant difference in DFS between Netherlands and US clinical centers.

  • Specific toxicity associated with HT was mild.

(correlation of thermometric parameters with clinical outcome not reported)
Harima et al. [149] Locally
advanced
cervical
cancer, n = 51		 30–40
cisplatin
once weekly
× 3–5		 30.0–50.0
/15–25
with
LDR- IRT7
(192 Ir):
5.0–6.0
/3–5		 Tmax †: 42.2 (40.1–44.6)
Tavg†: 41.1 (39.6–42.5)
Data from Ohguri et al. [155]
T90 ‡: 38.9
(37.7–42.2)
T50 ‡: 39.9
(38.4–42.4)		 Ntotal:
4–6
Nweek:
1		 60 CEM43°CT90 †:
3.8 (0.1–46.6)		 20 HT after RT&CT

  • CR: 88% (44/50).

  • 5-year OS, DFS, and LPFS 6 were 77.8%, 70.8% and 80.1%, respectively.

  • It was well tolerated and caused no additional acute or long term toxicity.

  • Ohguri et al. [155]: CEM43°CT90 ≥ 1 min tended to predict better DFS and CR.
Kouloulias et al. [153] Recurrent breast
cancer,
n = 15		 40–60
liposomal
doxorubicin
once monthly
× 6		 30.6/17 Tmax †: 43.2
(41.5–44.5)
Tmin †: 45.0
(44.2–45.7)		 Ntotal:
6
Nmonthly: 1		 60 n.r. 180–240 HT after CT&RT

  • CR: 2% (3/15), PR: 80% (12/15);

  • CR or PR obtained more quickly with a shorter tint between HT and CT.

  • DFILR 7 was better for T90 > 44 °C of ≥16 min compared with those for whom T90 > 44 °C of <16 min.

  • DFILR was significantly correlated with Tmin † but not with Tmax †.
Herman et al. [146] Locally
advanced
malignancies,
n = 24		 20–50
cisplatin
once weekly
× 6		 60.0–66.0
/30–33
or
24.0- 36.0
/12–18		 Tmax †:
43.7 ± 2.6
Tmin †:
38.2 ± 2.0
Tavg †:
40.8 ± 1.9		 Ntotal:
6
Nweek:
1		 60 CEM42 °CT90 †:
11.2 ± 21.3
CEM43°CT90 †:
3.1 ± 5.4		 n.r. HT before CT&RT

  • CR: 50% (12/24), PR: 50% (12/24);

  • No grade IIII acute toxicity.

  • Late toxicity, grade IV: only 1 patient.

  • With thermal dose of CEM43°CT90 † = 4.6 min, 50% of patients achieved CR and with CEM43°CT90 † = 2.0 min, 50% patients achieved PR.

  • Cisplatin concentration amount correlated with CR.

Barsukov et al. [157] Locally
advanced
rectal
cancer,
n = 68		 650
capecitabine on days 1–22
× 6–8
50
oxaliplatin on days 3, 10 and 17 after
× 6–8
10 metronidazole on days 8 and 15		 40.0/10 n.r. Ntotal:
4
Nweek:
2		 60 n.r. 60 n.r.

  • 2-year OS: 91%, DFS: 83% and local RR: 13.6%

  • R0 resection was achieved in 59 (92.2%). only five (7.8%) untreated patients remained inoperable.

  • 12 (18.7%) and 1 (1.6%) patients had grade III and IV toxicity, respectively.

(correlation of thermometric parameters with clinical outcome not presented)
Ott et al. [158] Locally
advanced
or recurrent rectal
cancer,
n = 105		 250
5-fluorouracil
on days 1–14 and 22–35
or
1650
capecitabine
on days 1–14 and 22–35
50 oxaliplatin
× 4		 LARC
50.4/28
LCC
45/25		 n.r. Ntotal ‡:
10
Nweek:
2		 60 LARC 19
CEM43°C †:
6.4 ± 5.2
LCC 20
CEM43°C †:
6.4 ± 4.9		 n.r. HT before RT

  • 11% (2/19) and 27% (16/59) DLT 8 criteria, corresponding to FR 9: 90% and 73%, respectively.

  • Pathological CR: 20% (19/95), CTR 10: 28% (18/64) and 38% (3/8) in patients with LARC and LRRC, respectively.

  • 5-year OS: 75% for the whole group.

  • No grade 4–5 adverse events.

(correlation of thermometric parameters with clinical outcome not presented)
Gani et al. [154] Locally
advanced
rectal
cancer,
n = 78		 1000
5-fluorouracil
× 4		 50.4/28 T90 ‡: 39.5
(IQR: 39.1–39.9)		 Ntotal:
8
Nweek:
2		 60 CEM43°C ‡: 4.5
(IQR: 2.2–8.2)		 n.r. n.r.

  • 19/78 (24%) patients: died or had tumor recurrence.

  • 3-year OS: 94%, DFS: 81%, LC 11: 96% and DC: 87%.

  • Pathological CR: 14% (the threshold not met).

  • Patients with good tumor regression had higher values for CEM43°C.

  • Comparable global health status with the data from general population based on EORTC-QLQ-C30 12.
Rau et al. [159] Locally
advanced
rectal
cancer,
n = 37		 300–350
5-fluorouracil
50 * mg
leucovorin
5 times weekly
× 2		 45.0–50.0
/25		 Data from Rau
et al. [160]:
T90 †: 40.2 ± 1.2
Tmax †: 41.4 ± 0.6		 Ntotal ‡:
5
Nweek:
1		 60 Data from Rau et al. [160]
CEM43°CT90 †:
7.7 ± 5.6
CEM43°CTmax †:
33.1 ± 28.0		 n.r. RT after
concurrent HT&CT

  • Grade III toxicity: 16%.

  • ORR 13: 89%, and 31 resection specimens had negative margins.

  • RR 14: 59.4%, CR: 14%, OS: 56%.

  • Cumulative minutes at T90 ≥ 40.5 °C and T90 correlate with the RR but not with long term OS and DFSR 15 [160] but Tmax showed no significant influence on RR.

  • RR: 33% when T90 < 40.5 °C and RR: 75% response, T90 > 40.5 °C.
Wittlinger et al. [161] Bladder
cancer,
n = 45		 20 cisplatin
5 times weekly
× 2
600
5-fluorouracil
5 times weekly
× 2		 50.4–55.8/
28–31		 Tavg †: 40.8
(95%CI:
40.5–41.6)		 Ntotal:
5–7
Nweek:
1		 60 CEM43°C †:57 (95%CI:
40.5–41.6)		 60 RT after
concurrent
CT&HT

  • CR: 96%, NC: 4%.

  • Freedom from any local and distant relapse: 69% and relapse: 16%.

  • 3-year bladder preservation: 96%, LPFS: 81%, DSS: 88%, DFS: 71%, OS: 80% and MFS 16: 89%.

  • One of significant prognostic factors for OS: Nweek.

  • Acute toxicity, grades III–IV: 27%.

  • Late toxicity, grades III-IV: 24%.
Milani et al. [162] Recurrent
rectal
cancer,
n = 24		 350
5-fluorouracil
5 times weekly
× 4
(continuous
infusion)		 30.0–45.0/
16–25		 T90 †: 41.4
T50 †: 42.9
T20 †: 43.5		 Ntotal ‡:
8
Nweek:
2		 60 n.r. 60 HT after
concurrent
RT&CT

  • CR: 0% (0/20), PR: 10% (2/20), NC: 85% (17/20), PD: 5% (1/20).

  • 1-year OS, DMFS 17, LPFR 18: 87%, 82%, 61%, respectively.

  • 2-year OS, DMFS, LPFR: 60%, 52%, 30%, respectively.

  • 3-year OS, DMFS, LPFR: 30%, 39%, 15%, respectively.

  • Acute toxicity, grade III: 12.5% of the patients.

(correlation of thermometric parameters with clinical outcome not presented)

n: number of patients assigned to be treated with HT in combination with RT and CT; †: mean value (±standard deviation) or mean value (range); ‡: median (range); 1 CR: complete response; 2 PR: partial response; 3 NC: no change; 4 OS: overall survival, 5 DFS: disease free survival; 6 LPFS: local progression free survival; 7 DFILR: disease-free interval to local relapse; 8 DLT: dose limiting toxicities; 9 FR: feasibility rate; 10 CTR: complete tumor regression; 11 LC: local control; 12 EORTC-QLQ: European Organization for research and treatment of cancer-quality of life questionnaire; 13 ORR: objective response rate; 14 RR: response rate; 15 DFSR: disease-free survival rate; 16 MFS: metastasis-free survival; 17 DMFS: distant metastases-free survival; 18 LPFR: local progression-free survival; 19 LARC: locally advanced rectal cancer; 20 LCC: recurrent rectal cancer.