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. 2022 Jan 26;14(3):625. doi: 10.3390/cancers14030625

Table 7.

Prospective clinical studies using RT in combination with HT.

Author(s) Cancer Site, n RT Dose (Gy)
/Fractions		 Temperature
Metrics (°C)		 HT
Session		 ttreat
(min)		 Thermal
Dose (min)		 tint
(min)		 Sequence Clinical Outcome
(Comment)
Chi
et al. [96]		 Bone metastases, n = 29 30.0/10 Tmax †:
41.9 ± 1.2		 Ntotal:
4
Nweek:
2		 40 n.r. 120 HT after RT

  • Increased 3-months radiologic CR 1 and PR 2 rate: 37.9% (11/29) and 66.7% (10/15), respectively.

  • No grade III toxicity was reported.

  • HT increased pain control rate, no progression of pain achieved after 29 days.

(correlation of thermometric parameters with clinical outcome not presented)
Valdagni et al. [103] Head & neck,
n = 18		 64.0–70.0
/32–35		 Tmax †:
43.3 ± 0.2
Tmin †:
40.4 ± 0.2
T50:
41.8 ± 0.2
T90:
39.8 ± 0.02		 Ntotal:
6
Nweek:
2		 n.r. max
CEM42.5°C 5:
83.84 ± 9.4
min
CEM42.5°C:
12.8–2.1		 20–25 HT after RT

  • 3-month CR: 83.3% (15/18), PR: 5.56% (1/18), PD 3 rate of 11.1% (2/18), overall improved LC 4.

  • 5-year nodal control rate: 68.6% with TER: 2.83.

  • Ntotal of two or six yielded similar results (80% CR with 6 sessions vs. 87%, with 2 sessions).

  • No enhanced acute or late toxicities were reported.

  • Extensive thermal analysis performed: no relation between thermometric parameters and response or toxicity.
Jones et al. [35] Superficial
cancers, n = 56		 30.0–66.0
/15–33
when
previously
unirradiated
60.0–70.0
/30–35		 n.r. Ntotal:
4–10
Nweek:
2		 60 min CEM43°CT90 †:
14.3
(0.57–36.21)		 n.r. n.r.

  • CR: 66.1%, LC for pre-irradiated tumors: 48%.

  • CEM43°CT90 associated with CR rate.

  • Greater than 10 CEM43°CT90 showed a significant LC benefit.

  • The improvement in LC was most pronounced for patients who were previously irradiated.

  • No significant toxicity or survival benefit was reported.
van der Zee
et al. [104]		 Locally advanced
pelvic tumors,
n = 182		 Bladder:
66.0–70.0
/33–35
Cervix:
40.0–50.0
/23–28
with
HDR-IRT 23
(192 Ir):
14.0
or LDR-IRT 24
(192 Ir):
20.0–30.0
Rectum:
46.0–50.0
/20–22		 n.r. Ntotal:
5
Nweek:
1		 60 n.r. 60–240 HT after RT

  • CR for all patients: 55%, bladder: 73%, cervical: 83%, rectal: 21%.

  • 3-year LC for all patients: 38%, for bladder: 42%, for cervical: 61%, for rectal: 16%.

  • 3-year OS 6 rate for all patients: 30%, for bladder: 28%, for cervical: 51%, for rectal: 22%.

  • 2.2% had grade III-IV HT-related toxicity.

(correlation of thermometric parameters with clinical outcome not presented)
Harima et al. [105] Cervix cancer,
n = 20		 52.2/29
with
HDR-IRT
(192 Ir):
30.0/4		 Tmax †:
41.8 ± 1.1
Tavg †:
40.6 ± 1.0
Tmin †:
39.6 ± 0.9		 Ntotal:
3
Nweek:
1		 60 n.r. 30 HT after RT

  • CR: 80% (16/20), PR: 15% (3/20), NC 7: 5% (1/20).

  • 3-year local LRFS 8, DFS 9 and OS: 79.7%, 63.6% and 58.2%, respectively.

  • Acute toxicity, grade III: 2 patients.

  • Late toxicity, grade III: 1 patient.

(correlation of thermometric parameters with clinical outcome not presented)
Mitsumori et al. [92] Locally advanced non-small cell lung
cancers, n = 40		 66.0–70.0
/33–38		 Tmax †: 41.3
(37.7–44.0)
Tmin †: 39.5
(35.5–41.7)
Tavg †: 40.3
(37.0–42.7)		 Ntotal:
7
Nweek:
1		 60 n.r. n.r. n.r.

  • RR 10: 45.0%.

  • 1-year LRFS and OS: 67.5% and 43%, respectively.

  • Acute toxicity, grade II: 4 patients and grade III: 2 patients.

  • Late toxicity, grade II: 3 patients and no grade III.

(correlation of thermometric parameters with clinical outcome not presented)
Masunaga et al. [100] Urinary bladder
cancer, n = 28		 24.0/6 Tavg †:
41.5 ± 1.1
(39–44)		 Ntotal:
4
Nweek:
2		 15–40 n.r. n.r. HT after RT

  • Tavg ≥ 41.5 °C achieved better results: 83.3% (10/12) tumor down-staging and degeneration, 0% local recurrence, 33% distant metastasis, in contrast with Tavg < 41.5 °C.

  • Survival rate was higher if Tavg ≥ 41.5 °C than Tavg < 41.5 °C.

  • The toxicity associated with HT: pain during treatment.
Berdov et al. [106] Advanced rectal
cancer, n = 56		 40.0/10 n.r. Ntotal:
4–5
Nweek:
n.r.		 60 n.r. 10 HT before RT

  • 1-,2-,3-,4-, and 5-year survival: 61.8 ± 6.6%, 48.1 ± 6.7%, 43.9 ± 6.7%, 35.6 ± 6.4%, and 35.6 ± 6.4%.

  • The mean for CR rate (>50%): 53.6% (30/56) and for CR rate (<50%): 23.3% (13/56).

(correlation of thermometric parameters with clinical outcome not presented)
Maluta et al. [107] Locally advanced high risk prostate cancer, n = 144 70.0–76.0
/35–38		 Rectum
Tmax †:
42.7
T90 †:
40.2
(38.4–42.0)
Bladder
T90 †:
41.3
(39.5–42.3)		 Ntotal:
4
Nweek:
1		 n.r. CEM40 °CT90 †:
24.4
(14.4–34.4)		 15–30 HT before RT

  • 5-year OS: 87% and 5-year biochemical progression-free survival: 49%.

  • No late grade III toxicity or significant acute HT-correlated toxicity.

(correlation of thermometric parameters with clinical outcome not presented)
Leopold et al. [40] Superficial
cancers, n = 111		 24.0–70.0
/7–28		 n.r. Ntotal †:4.5(1–6)
for Nweek=1
and
7 (2–13)
for Nweek=2
Nweek: 1–2		 60 n.r. 30–90 HT after RT

  • CR: 46%, PR: 34%, OS: 80%.

  • T90 was significantly related to CR.

  • Cumulative minutes of T90 ≥ 40 °C and logarithm of RT dose were predictive of both CR and OS.

  • Tmin, Nweek, and Ntotal were not significantly related to either end points.

  • Toxicity, grade IV: 1 patient and grade III: 7 patients.
Nishimura et al. [97] Colorectal cancer, n = 33 40.0–70.0
/25–35		 Abdominal
wall & hip:
Tmax †:
44.2 ± 2.1
Tavg †:
42.6 ± 1.3
Tmin †:
40.5 ± 0.7
Perineum:
Tmax †:
43.1 ± 1.7
Tavg †:
42.2 ± 1.2
Tmin †:
40.5 ± 1.1
Pelvis:
Tmax †:
42.1 ± 1.5
Tavg †:
41.2 ± 1.5
Tmin †:
40.1 ± 1.1		 Ntotal:
2–14
Nweek:
1–2		 40–60 n.r. 10–30 HT after RT

  • 6- and 12-months LC: 59% (17/29) and 31% (8/21), respectively.

  • CR rate: 11% (4/35) and PR: 43% (15/35).

  • Better treatment response of unresectable colorectal cancers than recurrent tumors.

  • Higher response rate of 67% reported when tumors heated with Tavg † > 42 °C for Ntotal=3–5.

  • Ntotal ≥ 5–14 showed not to increase the response rate.
Anscher et al. [108] Prostate cancer,
n = 21		 65–70
/32–35		 Intraprostate median
T90 †:
39.3 ± 0.9
T50 †:
40.4 ± 0.8		 Ntotal:
5–10
Nweek:
1–2		 60 CEM43°CT90 †:
2.34 ± 3.23		 60–154 HT after RT

  • Rectal temperatures were not predictive of prostate temperatures.

  • The mean cumulative minutes with T90 of > 40 °C was 12 min in the prostate versus 28 min in the rectal lumen.

  • 3-year DFS: 25% and 12 patients (67%) had relapsed.

  • No higher complication of Grade III.

  • T90, T50, and log(CEM43°CT90) were not significantly associated with time to relapse.

Gabriele et al. [109] Inoperable or
recurrent parotid
carcinoma, n = 13		 Inoperable:
70.0/35
Recurrent:
30.0/15		 Tmin †:
40.28 ± 0.83
Tmax †:
42.83 ± 1.32		 Ntotal:
4–10
Nweek:
2		 30–45 n.r. n.r. n.r.

  • CR: 80% (16/20), PR: 20% (4/20), LR 11: 20% (16/20), 5-year actuarial LC: 62.3 ± 13.2%.

  • Higher maximum temperatures correlated with acute toxicity and maximum tumor diameter but without statistical significance.

  • Major acute toxicities included three patients (15%) with superficial necrosis, 2/3 healed spontaneously within 4 to 6 months.

  • No correlation between Tmin and Tmax and early or long term response was found.
Maguire et al. [110] Soft tissue sarcomas, n = 35 50.0/25–27 n.r. Ntotal:
10
Nweek:
2		 60 CEM43°CT90 ‡:
38
(0.1–601)		 n.r. n.r.

  • 14% (5/35) of patients had non-heatable tumors.

  • pCR 12: 52% (15/29), LF 13: 10% (3/29) with heatable tumors.

  • DM 14: 14/30 patients with heatable tumors and 2/5 with non-heatable tumors.

  • Thermal goal of CEM43°CT90 ≥ 10 reached for 25 out of 30 patients.

  • Treatment–induced toxicity: 10/30 patients with heatable tumors.

  • No correlation of thermal dose with histologic response was observed.
Tilly et al. [99] Recurrent or
locally advanced
prostate cancer,
n = 22		 68.4/38 Primary
cancer:
T90 †:
40.7 ± 0.3
Tmax †:
41.4 ± 0.4
Recurrent cancer:
T90 †:
40.6 ± 0.8
Tmax †:
41.0 ± 0.7		 Ntotal:
5–6
Nweek:
1		 0–30 n.r. 30 HT before RT
or
HT after RT

  • 6-year OS: 95% and 6-year RrR 15: 60%.

  • Severe acute grade III toxicity: 8 patients and grade II: 2 patients.

  • Late toxicity, grade III: 1 patient and grade II: 2 patients.

  • No correlation between thermal parameters and toxicity.

  • The thermal parameters were correlated with clinical endpoints: toxicity, PSA 16 control.

  • Tmax was the only relevant predictive factor for PSA control.
Lutgens et al. [111] Locally advanced cervical cancer,
n = 42		 50.0/25
with
HDR-IRT
(192 Ir):
21.0/3
weekly
or LDR:
32.0/1–2
or MDR:
29.0/1–2		 n.r. Ntotal:
5
Nweek:
1		 60 n.r. 60–240 HT after RT

  • Treatment failure in the pelvis: 19% (8/42).

  • OS: comparable between RT + CT and RT + HT groups.

  • Toxicity of grade ≥III: 5 patients.

(correlation of thermometric parameters with clinical outcome not reported)
Hurwitz et al. [112] Locally advanced
prostate cancer,
n = 37		 66.60–70.0
/33–37		 Tmin †: 40.1
(37.5–41.8)
Tmax †: 42.5
(40.5–45.9)
Tavg †: 41.2
(39.2–42.8)		 Ntotal:
2
Nweek:
1		 60 CEM43°CT90 †:
8.4		 60 HT before RT

  • 7-year OS: 94% and failure free: 61%.

  • 2-year DFS: 84% compared with a rate of 64% for similar patients on 4-month androgen suppression.

  • The difference in median CEM43°CT90 between these patient groups who achieved 2.8 min and 10.5 min, respectively, was significant (p = 0.004).

  • A small difference in DFS in favor of patients treated with higher temperatures.

Vernon et al. [113] Localized
superficial
breast cancer,
n = 306		 DHG 17 (p):
32.0/16
DHG (r):
40.5–50.0/25
+ boost:
10.0–20.0
MRC 18
BrR (p):
28.8/8
MRC BrI(r) + MRC BrR(r):
50.0/25
+ boost:
15.0/5
ESHO 19:
32.0/8
PMH 20(p):
32.0/18
PMH(r):
50.0/25		 DHG:
T90 †: 39.0
T50 †: 40.7
Tmax †: 43.5
MRC BrR:
T90 †: 40.7
T50 †: 42.5
Tmax †: 45.6
MRC BrI:
T90 †: 40.4
T50 †: 42.3
Tmax †: 45.1
ESHO:
T90 †: 39.5
T50 †: 41.1
Tmax †: 43.3
PMH:
T90 †: 40.7
T50 †: 42.2
Tmax †: 44.6		 n.r. DHG:
60
(55–61)
MRC BrR:
60
(30–60)
MRC BrI:
60
(17–65)
ESHO:
60
(60–60)
PMH:
60		 DGH:
maximum of CEM42 °C †:
0(0–69.5)
CEM43°C †:
3.95 (0–122)
MRC:
maximum of
CEM42 °C †:
9 (0–60)
CEM43°C †:
7.5 (0.1–87.7)
ESHO:
maximum of
CEM42 °C †:
5 (0–59)
CEM43°C †:
8.4 (0.2–74)
PMH:
maximum of
CEM42 °C †:
0 (0–32.8)
CEM43°C †:
1.5 (0–25)
data from
Sherar et al. [39]		 n.r. n.r.

  • Total CR: 59%, DHG: 73.6% (14/19), MRC BrI: 55.5% (10/18), MRC BrR: 56.67% (51/90), ESHO: 77.77% (21/27), PMH: 29.41% (5/17).

  • CR rate of previously non-irradiated: 61% and CR rate of previously irradiated tumor: 46%.

  • 2-year actuarial survival rate for all patients: 40%.

  • Two largest studies (ESHO and MRC BrR) showed a statistically significant (p = 0.004 and 0.001, respectively) advantage for the addition of HT, whereas the other three trials do not show a benefit (ORs < 1).

  • CR rate show dependency on size of tumor, the depth of the lesion, and on a history or presence of metastatic dis-ease outside the target area (univariate analysis).

  • OS did not differ markedly but patients receiving HT has a marginally inferior survival.

  • Sherar et al. [39]: initial CR rate is significantly correlated with thermal dose and no correlation between Ntotal and initial CR rate.
Datta et al. [114] Head & neck
cancer, n = 33		 50.0
/25		 n.r. Ntotal:
8–10
Nweek:
2		 n.r. n.r. n.r. HT before RT

  • RR: 76%, CR: 55%, PR: 21% and DFS: 33%.

  • Particularly significant effect in patients with advanced disease.

(correlation of thermometric parameters with clinical outcome not presented)
Overgaard et al. [115] Recurrent
or metastatic
malignant
melanoma, n = 63		 24.0–27.0
/3		 n.r. Ntotal:
3
Nweek:
1		 60 CEM43°C †:
9 (0–219)
data from
Overgaard
et al. [116]		 30 HT after RT

  • HT did not significantly increase acute or late radiation reactions.

  • 5-year survival rate was 19% and was 38% for the patients for with control of all known disease.

  • RR: 80%, initial CR rate: 62%, PR: 32%, NR: 20%, 2-year actuarial LC: 37%.

  • The response rate was higher receiving 27 Gy than those receiving a lower dose.

  • Both acute and late adverse effects were deemed acceptable.

  • Overgaard et al. [116]: there is a significance of thermal dose relationship with the heat effect but no correlation between Ntotal and the outcome of treatment.
Dinges et al. [41] Uterine cervix
carcinomas, n = 18		 50.4/28
with
HDR-IRT
(192 Ir):
20.0/4		 T20 †: 41.7
(40.3–43.2)
T50 †: 41.1
(39.2–42.5)
T90 †: 39.9
(37.7–41.9)		 Ntotal:
4
Nweek:
2		 60 CEM43°CT20 †:
48.2 (5.9–600.5)
CEM43°CT50†: 15.2 (0.6–54.0)
CEM43°CT90 †: 6.8 (0.4–23.0)		 n.r. n.r.

  • CR: 13/18, PR: 4/18 and NR 21: 1/18.

  • 2-year LC rate: 48.1%, development of distant metastases: 48.5% and DSS 22: 31.8%.

  • CEM43°CT90 was a significant parameter in terms of local tumor control for Ntot = 4 (univariate analysis), but had no impact in terms of metastatic spread.

  • T20, T50, T90, cumulative minutes of T90 > 40 °C, CEM43°CT20 and CEM43°CT50 were not significant in terms of local tumor control and DSS.

  • No acute toxicity, grade III or IV.

  • Late toxicity, grade III and IV: 3 patients.
Kim
et al. [117]		 Inoperable
hepatoma, n = 30		 30.6/17 n.r. Ntotal:
6
Nweek:
2		 30–60 n.r. 30 n.r.

  • Subjective response rate: 78.6%, PR: 40%, stable disease: 46.7%, PD: 13.3%.

  • 1-year survival values for all patients and for the partial responders were 34% and 50%, respectively.

(correlation of thermometric parameters with clinical outcome not presented)
Engin et al. [98] Superficial tumors, n = 50 60.0–70.0
/30–35
when
previouslyirradiated:
40.0/10		 Group A:
Tmin †:
39.6 ± 0.2
Group B:
Tmin †:
39.3 ± 0.2		 Group A:
Ntotal:
4
Nweek:
1
Group A:
Ntotal:
8
Nweek:
2		 60 Group A:
CEM 43°C †:
12.1 ± 3.9
Group B:
CEM43°C †:
15.0 ± 5.1		 15–30 HT after RT

  • Group A patients treated with once-weekly HT session had CR: 59% (12/22), PR: 36% (8/22), NR: 5% (1/22).

  • Group B patients treated with twice-weekly HT sessions had CR: 55% (12/22), PR: 45% (10/22).

  • Tmin did not influence response between Group A and Group B.

  • Neither tumor response, duration of LC nor occurrence of skin reactions were significantly affected by Nweek.

n: number of patients assigned to be treated with HT in combination with RT; †: mean value (±standard deviation) or mean value (range); ‡: median (range); n.r.: not reported; 1 CR: complete response; 2 PR: partial response; 3 PD: progressive disease; 4 LC: local control; 5 CEM42.5 °C: cumulative equivalent minutes at reference temperature 42.5 °C; 6 OS:overall survival, 7 NC: no change; 8 LRFS: local relapse-free survival; 9 DFS: disease free survival; 10 RR: responserate; 11 LR: local response; 12 pCR: pathological CR; 13 LF: local failure; 14 DM: distant metastasis; 15 RrR: recurrence rate; 16 PSA: prostate specific antigen; 17 DHG: Daniel den Hoed Cancer Center in Rotterdam; 18 MRC: Medical Research Council at the Hammersmith Hospital; 19 ESHO: European Society of Hyperthermic Oncology; 20 PMH: Princess Margaret Hospital/Ontario Cancer Institute; 21 NR: no response; 22 DSS: disease specific survival; 23 HDR-IRT: high dose rate interventional radiotherapy; 24 LDR-IRT: low dose rate interventional radiotherapy.