Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology

Figures & data

Table I.  Characteristics of 128 evaluable tumours.

	Rad alone	Rad + Heat
All tumours	65	63
Tumour size
Median (range)	3 (1–14)	3 (1–13)
≤4 cm	41	40
>4cm	24	23
Depth under skin (cm)
Median (range)	2 (1–7)	2 (1–7)
Radiation
24 Gy	31	29
27 Gy	34	34
Number of tumours in pt.
Single	15	22
Median (range)	2 (1–7)	2 (1–7)
Site
Lymph node	19	19
Skin/subcutis	49	44
Type
Local recurrence	9	7
Metastasis	56	56
Months to recurrence
Median (range)	14 (0–113)	13 (0–203)
Observation time (months)
Median (range)	7 (3–65)	9 (3–73)
Female sex	26	26
Age (years)
Median (range)	57 (32–88)	59 (19–88)

Figure 1. Complete response in malignant melanoma treated with radiation alone or combined with hyperthermia as a function of radiation dose (left) and tumour volume (right).

Table II.  Initial tumour response in 128 evaluable tumours.

	Rad alone (%)	Rad + Heat (%)	All tumours (%)
No response (NR)	28	11	20
Partial response (PR)	37	27	32
Complete response (CR)	35†	62†	48
Response rate (CR + PR)	72‡	89‡	80

†p = 0.003;

‡p = 0.02.

Table III.  Univariate analysis of initial complete response and 2-year actuarial local control value as a function of treatment or stratification group.

Stratification group		No. tumours	CR rate (%)	2-years control (%)
All tumours		128	48	37 ± 5
Treatment	Rad alone	65	35†	28 ± 6†
	Rad + Heat	63	62†	46 ± 8†
Dose	24 Gy	60	40†	25 ± 6†
	27 Gy	68	56†	56 ± 6†
Size	≤4 cm	81	54	42 ± 6
	>4 cm	47	38	29 ± 9

†p < 0.05

Table IV.  Final multivariate analysis of tumour response.

	Stepwise logistic regression using complete analysis response as endpoint		Cox proportional hazard using 2-year local control as endpoint
Variable	p-Value	Relative risk	p-Value	Relative risk
Hyperthermia (rad + heat vs. rad alone)	0.0015	4.01 (1.77–9.08)†	0.023	1.73 (1.07–2.78)†
Tumour size
(largest diameter in cm)	0.0048	0.77 (0.65–0.91)	0.050	0.91 (0.85–0.99)
Radiation dose
(27 vs. 24 Gy)	0.049	2.31 (1.03–5.16)	0.049	1.17 (1.01–1.36)
Sex (female)	0.018	2.81 (1.23–6.41)	0.15	not estimated
Time to recurrence (months)	0.41	not estimated	0.24	not estimated
Tumour localization
(node vs. cutaneous)	0.56	not estimated	0.79	not estimated
No. of tumours
(multiple vs. single)	0.65	not estimated	0.63	not estimated
Age (years)	0.65	not estimated

†95% confidence limits.

Figure 2. Tumour control probability after treatment with radiation alone or combined with hyperthermia.

Figure 3. Response in comparable paired tumours from same patient. The tumours were selected to belong to same size strata (above or below 4 cm) and was given same radiotherapy (24 or 27 Gy), but with or without hyperthermia. The correlation is highly significant (p = 0.014; McNemar's test).

Table V.  Acute and late radiation reaction in skin.

	Rad alone (%)	Rad + heat (%)	All tumours (%)
Acute (93 fields)
None/slight	51	42	46
Moderateisevere	49	58	54
Late (57 fields)
None/slight	72	63	67
Moderate/severe	28	37	33

Figure 4. Relationship between the T_max, T_min and T_norm, showing the quality and ability of the hyperthermic therapy.

Figure 5. Relationship between the T_max and T_min in 168 heat treatments. The correlation is highly significant (p < 0.0001, Spearman). The dashed lines separates between treatments above or below 60 min Eq. 43 C, and indicate the number of sufficient and insufficient heat treatments.

Table VI.  Spearman rank correlation and statistical analysis of 168 heat treatments.

Parameter	Tmax	Tnorm	No. probes	Treatment number	Tumour size (diameter)	Tumour depth under skin
Tmin	ρ = 0.450	ρ = 0.178	ρ = −0.382	ρ = 0.033	ρ = −0.176	ρ = −0.217
	p < 0.0001	p = 0.092	p < 0.0001	p = 0.662	p = 0.022	p = 0.005
Tmax		ρ = 0.1918	ρ = 0.054	ρ = −0.053	ρ = 0.041	ρ = 0.014
		P = 0.070	p = 0.488	p = 0.489	p = 0.563	p = 0.854

Figure 6. Effect of heating quality. Tumour control probability after treatment with radiation alone or combined with high or low dose hyperthermia above or below the median value of Av-T_max. Data from 65 non-heated and 54 heated tumours where sufficient temperature data were available.

Table VII.  Prognostic importance of various temperature parameters describing the heating quality. Univariate and final multivariate levels of significance are given for data analysed by stepwise logistic regression analysis using CR as endpoint and by Cox proportional hazard analysis using 2-years local control probability.

	Logistic regression		Cox proportional hazard
Variable	p-Value Univariate	p-Value Multivariate	p-Value Univariate	p-Value Multivariate
Tmax/any, continuous	0.027	0.29	0.026	0.12
Tmax.any, median	0.018	0.84	0.06	0.98
Av-Tmax continuous	0.08	0.21	0.047	0.21
Av-Tmax median	0.018	0.009	0.050	0.026
Tmin/any, continuous	0.27	0.65	0.12	0.43
Tmin/any, median	0.019	0.94	0.08	0.96
Av-Tmin, continuous	0.25	0.64	0.11	0.40
Av-Tmin, median	0012	0.77	0.054	0.66

Figure 7. The values and relationship between T_max/any and T_max/any (top) and between Av-T_max and Av-T_min (bottom) for 54 heated tumours with evaluable data. The dashed lines separate between treatments above or below 60 min Eq. 43°C, and indicate the number of sufficient and insufficient heat treatments.

Figure 8. Probability of crude survival in all patients with evaluable tumours (top left); in patients with or without persistent control of all known disease at the time of treatment (top right); as a function of number of recurrent or metastatic tumours (bottom left); and related to sex (bottom right).

Table VIII.  Cox proportional hazard analysis of 68 patients using death as endpoint.

Variable	p-Value	Relative risk
Local control of all lesions
(yes vs. no)	0.006	0.42 (0.22–0.81)†
Female sex	0.019	0.51 (0.30–0.89)
No. of tumours
(Multiple vs. single)	0.035	1.94 (1.10–3.42)
Tumour localization
(Node vs. cutaneous)	0.17	not estimated
Time to recurrence	0.51	not estimated
Age (years)	0.66	not estimated

^†95% confidence limits.