Quantification of thermal dose in moderate clinical hyperthermia with radiotherapy: a relook using temperature–time area under the curve (AUC)

Figures & data

Figure 1. Schematic representation of the radiotherapy and hyperthermia schedules in unifocal and multifocal muscle invasive bladder cancers (Reproduced with permission from Datta et al. [17]).

Figure 2. A representative time–temperature plot from a patient of urinary bladder cancer undergoing hyperthermia. Temperature represents the intraluminal temperature in bladder at every 10 s during the entire 90 min of deep hyperthermia. The area under the curve (AUC) for >37 °C (AUC > 37 °C) and ≥39 °C (AUC ≥ 39 °C) represents the corresponding areas enclosed within these temperatures.

Table 1. Patient demography: all evaluable patients, patients with or without local failure in bladder at follow-up.

Characteristics	All patients (n = 18)	Post-HTRT tumor status in bladder		Significance
		No failure (n = 16)	Failure (n = 2)
Age (years)	77.1 ± 9.4	76.4 ± 9.7	83.0 ± 1.4	0.026^a
Sex
Male	16	14	2	NS^b
Female	2	2	0
KPS
60	5	5	0	0.049^b
70	7	7	0
80	4	2	2
90	2	2	0
T stage
1	2	1	1	NS^b
2	14	13	1
3	1	1	0
4	1	1	0
N stage
0	16	14	2	NS^b
1	2	2	0
M stage
0	18	16	2
Number of lesions
Solitary	7	5	2	NS^b
Multiple	11	11	0
Post-TURBT status
R0	16	14	2	NS^b
R1–2	2	2	0
Histology
Urothelial	18	18	0
Grade
III	18	18	0

^at-test; ^bχ² test.

NS: not significant; HTRT: hyperthermia and radiotherapy; KPS: Karnofsky performance status; TURBT: transurethral bladder resection.

Table 2. Details of the thermal dose parameters for summated hyperthermia sessions – AUC >37 °C, AUC≥ 39 °C, CEM 43, CEM43 (>37 °C), CEM 43(≥ 39 °C), T_mean, T_max, T_min, duration of hyperthermia session, radiotherapy dose and the local disease status for each patient.

Pt. Nos.	AUC > 37 °C	AUC ≥ 39 °C	CEM43	CEM43 > 37 °C	CEM43 ≥ 39 °C	Time (min)	Tmean (°C)	Tmax (°C)	Tmin (°C)	RT dose (Gy)	Local disease status
1	1740.27	898.13	70.02	70.02	69.93	458.07	40.72	42.26	36.72	50	No failure
2	1636.66	980.14	169.59	169.59	169.54	361.57	41.53	43.30	36.95	48	No failure
3	1481.56	813.35	112.42	112.42	112.35	381.63	40.82	42.82	36.48	48	No failure
4	1330.00	647.28	32.19	32.19	32.13	312.60	40.3	41.57	37.13	50	No failure
5	1665.98	838.96	85.74	85.74	85.63	482.28	40.42	42.28	36.52	50	No failure
6	1414.96	744.82	51.75	51.74	51.68	385.45	40.57	42.07	36.23	50	No failure
7	1310.53	622.36	33.93	33.93	33.86	390.97	40.4	42.00	37.10	50	No failure
8	1328.35	625.94	26.85	26.85	26.78	382.25	40.42	41.77	36.78	50	No failure
9	1454.92	745.55	53.79	53.79	53.71	384.50	40.75	42.00	36.75	50	No failure
10	1571.51	903.91	114.40	114.40	114.34	368.58	41.22	42.87	36.93	50	No failure
11	988.42	350.43	9.86	9.86	9.75	356.18	39.925	41.25	36.78	48	No failure
12	1140.05	443.35	16.48	16.48	16.37	379.45	40.00	41.55	36.43	48	Failure
13	1142.56	475.80	14.01	14.01	13.93	381.30	39.95	41.52	36.55	50	No failure
14	1103.43	404.03	11.54	11.54	11.43	387.03	39.825	40.95	36.78	48	Failure
15	1701.59	988.47	110.63	110.62	110.58	380.78	41.425	42.825	36.68	50	No failure
16^a	936.75	436.52	26.79	26.79	26.72	280.87	40.30	41.80	36.93	48	No failure
17	1472.90	752.77	40.77	40.77	40.72	384.73	40.77	41.87	36.63	48	No failure
18	1616.87	922.09	95.45	95.45	95.40	383.82	40.92	42.25	36.18	50	No failure

^aDetails of 4th hyperthermia sessions was not available. Thus, the data pertains to 3 hyperthermia sessions.

Table 3. Hyperthermia treatment characteristics both for individual and combined hyperthermia sessions of all patients and those with or without local failure in bladder at follow-up.

Characteristics	All patients (n = 18) (74 sessions)^a	Post-HTRT tumor status in bladder
		No failure (n = 16) (66 sessions)^a	Failure (n = 2) (8 sessions)	Significance^b
Individual hyperthermia session
Tmin (°C)	36.7 ± 0.5	36.7 ± 0.5	36.6 ± 0.6	NS
Tmax (°C)	42.0 ± 0.8	42.2 ± 0.8	41.2 ± 0.7	0.007
Tmean (°C)	40.5 ± 0.7	40.6 ± 0.6	39.9 ± 0.6	0.015
Duration (min)	92.5 ± 10.4	92.1 ± 10.9	95.8 ± 2.0	0.016
CEM43	14.5 ± 13.7	15.9 ± 13.9	3.5 ± 3.0	<0.001
CEM43 (>37 °C)	14.5 ± 13.7	15.9 ± 13.9	3.5 ± 3.0	<0.001
CEM43 (≥39 °C)	14.5 ± 13.7	15.9 ± 13.9	3.5 ± 3.0	<0.001
AUC > 37 °C (°C-min)	338.3 ± 69.2	345.4 ± 67.3	280.4 ± 59.6	0.018
AUC ≥ 39 °C (°C-min)	170.2 ± 61.9	177.9 ± 58.0	105.9 ± 58.3	0.010
Combined hyperthermia session
Nos. of sessions	4.17 ± 0.4	4.2 ± 0.4	4.0 ± 0.0	NS
Tmin (°C)	36.7 ± 0.3	36.7 ± 0.3	36.6 ± 0.2	NS
Tmax (°C)	42.0 ± 0.6	42.1 ± 0.6	41.2 ± 0.4	NS
Tmean (°C)	40.6 ± 0.5	40.6 ± 0.5	39.9 ± 0.1	0.002
Duration (min)	380.1 ± 43.5	379.7 ± 46.3	383.2 ± 5.3	NS
CEM43	59.8 ± 45.6	65.5 ± 45.1	14.0 ± 3.5	<0.001
CEM43(>37 °C)	59.8 ± 45.6	65.4 ± 45.1	14.0 ± 3.5	<0.001
CEM43(≥39 °C)	59.7 ± 45.6	65.4 ± 45.1	13.9 ± 3.5	<0.001
AUC > 37 °C (°C-min)	1390.9 ± 248.2	1424.6 ± 242.7	1121.7 ± 25.9	<0.001
AUC ≥ 39 °C (°C-min)	699.7 ± 208.7	734.1 ± 194.6	423.7 ± 27.8	<0.001

^aTotal hyperthermia sessions were 75 (4 each in 15 patients and 5 each in 3 patients). Record of one session was not available. Thus, total number of hyperthermia sessions evaluated were 74. ^bt-test.

Figure 3. Time–temperature plots for each of the four hyperthermia sessions in a patient who had (a–d) local bladder tumor control and (e–h) who had local bladder tumor failure. Corresponding CEM43 (≥39 °C) and AUC ≥ 39 °C for each of these sessions are stated. The graphs correspond to patient number 15 (a–d) who had no local failure and patient nos. 14 (e–h) who had local failure. The details of the CEM and AUC values for these patients are given in Supplementary Table 1.

Figure 4. Box plots and superimposed scatter plots of AUC > 37 °C, AUC ≥ 39 °C, CEM43(>37 °C) and CEM43(≥39 °C) in patients with or without local failure in bladder (a) Individual hyperthermia sessions (n = 74) [AUC > 37 °C, p = 0.018; AUC ≥ 39 °C, p = 0.01; CEM43(>37 °C), p < 0.001 and CEM43(≥39 °C), p < 0.001)] and (b) Summated hyperthermia sessions (n = 18) [AUC > 37 °C, p < 0.001; AUC ≥ 39 °C, p < 0.001; CEM43(>37 °C), p < 0.001 and CEM43(≥39 °C), p < 0.001].

Figure 5. (a) CEM43 (≥39 °C) values for the temperature range 39–45 °C (r² = 0.999). The slope for changes in CEM43(≥39 °C) values for temperature ranging between 39 °C and 41.5 °C is minimal. The slope changes abruptly at 43 °C due to change of the value of constant ‘R’ from 0.25 for T ≤ 43 °C and 0.50 for T > 43 °C (indicated by black filled arrow). (b) AUC ≥ 39 °C values for the temperature range 39–45 °C (r² = 1.000). For both CEM43(≥39 °C) and AUC ≥ 39 °C, duration of hyperthermia beyond 39 °C is considered for 60 min to mimic the hyperthermia treatment in clinical situation beyond the initial heating phase.

Figure 6. AUC and CEM43 values for patients with or without local bladder failure. (a) CEM43(>37 °C) vs AUC > 37 °C for each hyperthermia session; (b) CEM43(≥39 °C) vs AUC ≥ 39 °C for each hyperthermia session; (c) Summated CEM43(>37 °C) vs AUC > 37 °C for all hyperthermia sessions; (d) summated CEM43(≥39 °C) vs AUC ≥ 39 °C for all hyperthermia sessions.

Figure 7. Computation of the additional temperature that is needed to be acquired during the active heating phase of 60 min following attaining 39 °C during the preheating phase. The target AUC ≥ 39 °C to be achieved during each hyperthermia session is 190 °C-min.

Table 4. Temperature required to be achieved during the active heating phase of 60 min following 30 min of preheating to achieve a target of AUC ≥ 39 °C.

Time (in minutes) to reach 39 °C during pre-heating phase	Additional temperature (in °C) required to be achieved during remaining heating phases^a (ΔT)	Final temperature (in °C) to be maintained during remaining heating period of each hyperthermia session
10	2.7	41.7
11	2.8	41.8
12	2.8	41.8
13	2.8	41.8
14	2.8	41.8
15	2.8	41.8
16	2.9	41.9
17	2.9	41.9
18	2.9	41.9
19	2.9	41.9
20	2.9	41.9
21	3.0	42.0
22	3.0	42.0
23	3.0	42.0
24	3.0	42.0
25	3.1	42.1
26	3.1	42.1
27	3.1	42.1
28	3.1	42.1
29	3.2	42.2
30	3.2	42.2

^aDetails of computations are given in Figure 6.

Datta NR, Stutz E, Puric E, et al. A pilot study of radiotherapy and local hyperthermia in elderly patients with muscle-invasive bladder cancers unfit for definitive surgery or chemoradiotherapy. Front Oncol. 2019;9:889.

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Data availability statement

All data generated and analyzed during this study are included in this published article.