Hypofractionated re-irradiation of large-sized recurrent breast cancer with thermography-controlled, contact-free water-filtered infra-red-A hyperthermia: a retrospective study of 73 patients

Figures & data

Table 1. Baseline patient and breast cancer characteristics at the time of first diagnosis.

Characteristic	Median (range)	No. of patients
Year of primary diagnosis
≤1990		3
1991–1994		9
1995–1999		5
>2000		56
Age (years)	54 (31–88)	73
Menopausal status:
Pre-menopausal		17
Peri-menopausal		12
Post-menopausal		43
Male		1
T-stage
T1		19
T2		25
T3		14
T4		14
T4 bilateral		1
Lymph node involvement
N0		15
N1		28
N2		19
N3		9
Unknown		2
Histological grading
G1		9
G2		28
G3		36
Resection status
R0		65
R1		8
Oestrogen receptor expression
Positive		41
Negative		15
Progesterone receptor expression
Positive		41
Negative		15
Her2/neu expression
Amplified		18
Missing		24
Unknown		14
Triple negative		17

Table 2. Patient and tumour characteristics at the onset of HT combined with re-RT.

	Median (range)	No. of patients
Total number of patients		73
No. of tumour regions treated		103
Patient age (years)	64 (36–91)	73
Interval from initial breast cancer to  first relapse (months)	36 (0–255)
Interval from initial RT to re-RT (months)	42 (0–348)
Presence of distant metastases		33
No. of previous recurrences	2 (1–8)
Anatomic site at the time of recurrence
Breast		4
Chest wall		51
Regional lymph nodes		11
Regional lymph nodes and chest wall		7
Tumour extension
Microscopic residual (R1/R2)		9
Macroscopic disease		64
Gross tumour volume (cm^3)	27 (3–64)	14
Tumour size (cm^2)	480 (12–4200)	50
Lymphangiosis carcinomatosa
No		18
Yes		46
Previous RT-dose (Gy)	56 (20–132.5)
Re-irradiation dose (Gy)
8		2
12		2
16		2
20		63
24		3
28		1
No. of previous lines of chemotherapy
None		13
1		8
≥2		52
No. of previous lines of hormonal therapy
None		33
1		13
≥2		27
No. of previous surgical procedures at  the same location
None		4
1		33
≥2		36
Tissue transfers
None		53
Meshgraft/skin transplant/reconstruction		20

Table 3. Evaluation of tumour response upon termination of combined HT + re-RT treatment.

No. of patients	73
Evaluation method
Clinical	46
Clinical + PET-CT	19
Clinical + MRI/CT	3
Clinical + PET-CT + MRI/CT	5

Table 4. Clinical outcome of combined HT + re-RT treatment.

	All	Macroscopic disease	Microscopic disease	Lymphangiosis
(a) Tumour response
No. of patients	73 (100%)	64 (100%)	9 (100%)	46 (100%)
Initial response
CR	48 (66%)	39 (61%)	9 (100%)	24 (52%)
PR	21 (29%)	21 (33%)		19 (41%)
NC	3 (4%)	3 (5%)		2 (5%)
PD	1 (1%)	1 (1%)		1 (2%)
No. of regions treated	103 (100%)	94 (100%)	9 (100%)	76 (100%)
Initial response
CR	71 (69%)	62 (66%)	9 (100%)	47 (62%)
PR	25 (24%)	25 (27%)		23 (30%)
NC	5 (5%)	5 (5%)		4 (5%)
PD	2 (2%)	2 (2%)		2 (3%)
(b) Local control and re-recurrences after CR
No. of patients	48 (100%)	39 (100%)	9 (100%)	24 (100%)
Local control (lifetime)	32 (67%)	23 (59%)	9 (100%)	8 (33%)
Re-recurrences	16 (33%)	16 (41%)	0	16 (66%)
(c) Analysis of re-recurrences (16 patients after CR)
No. of re-recurrences	27 (100%)	27 (100%)		27 (100%)
Infield	3 (11%)	3 (11%)		3 (11%)
Border	12 (44.5%)	12 (44.5%)		12 (44.5%)
Outside	12 (44.5%)	12 (44.5%)		12 (44.5%)
(d) Metastasis and secondary tumours
Without metastasis		28 (38%)
With metastasis		45 (62%)
Before		16 (22%)
New		12 (17%)
Before and new		17 (23%)
Secondary tumour (lung, rectum)		2 (3%)

Figure 1. Relative spectral irradiance of a halogen lamp (correlated colour temperature CCT =3000 K) as a function of wavelength, before (curve 1) and after passing a water-filter and a cut-off filter (BTE, Elsoff, Germany) (curve 2). Measurements by using a double monochromator spectroradiometer (Spectro 320 D, Instrument Systems, Munich, Germany) in the spectral range 0.4–1.7 μm) and calculation of data according to Planck’s law of radiation in the spectral range 1.7–4.5 μm. VIS: visible light spectrum

Figure 2. Measurement of surface temperature with contact electrodes (type PT100). Placement of sensor (upper left panel), fixation (upper right panel) and absolute temperature reading (lower left panel). Corresponding thermography (lower right panel).

Figure 3. Thermographic control of wIRA-hyperthermia in a patient with inflammatory breast cancer recurrence. Before start of heating: (a) visible inflammatory disease, (b) scar of the former tumourectomy, (c) field-mark for RT, (d) subcutaneous venous drainage, and (e) sebaceous retention cyst. Immediately after start of hyperthermia and within 19 s the venous drainage increases and transports heat away (cooling effect). After a few minutes this effect is clearly visible, then a breakdown of blood flow can be seen (after 2.5 min). These latter effects disappear after 3 min. Inflammatory recurrence and/or scarred tissue are heated up to 43 °C after 2.5 min and stay at this higher temperature level during the whole treatment period (see the bottom line at 20 and 45 min).

Figure 4. Inflammatory recurrent breast cancer in a 51-years old patient. Former conservative therapy for triple negative breast cancer consisting in tumourectomy, sentinel lymphadenectomy, adjuvant chemotherapy and radiotherapy with 50 Gy whole breast and boost up to 60 Gy. First recurrence treated with salvage surgery, chemotherapy followed by breast reconstruction. Top: Situation before start of re-RT and wIRA-HT (21.6.2011, patient in treatment position). Several biopsies on both breasts confirmed the inflammatory recurrence. Middle: First thermographically controlled wIRA-HT of both chest wall regions. Bottom: 4 years after completion of hypofractionated re-RT with 5 × 4 Gy and wIRA-HT (NED, 21.9.2015, patient in sitting position). Teleangiectasias are evident especially in the décolleté and the former irradiated region

Figure 5. Mean temperature profiles within tissues during wIRA-exposure under steady state conditions. Curve 1: Calculated by averaging measured data in normal tissues (Hellige in Ref. [11], open squares), tumour tissues (Seegenschmiedt et al. [31], circles) and in recurrent breast cancers (Notter et al., current report, red triangles). Curve 2: temperature profile in untreated skin and subcutis, i.e., no wIRA exposure (Hellige in Ref. [11], filled squares).

Figure 6. Top left: Overall survival of 73 patients with locally recurrent breast cancer treated with re-irradiation and wIRA-hyperthermia. Top right: Overall survival of 64 patients (macroscopic disease) with locally recurrent breast cancer treated with re-irradiation and wIRA-hyperthermia. Middle left: Influence of local control on survival after CR. 32 patients had local control throughout life time (upper curve), 16 patients presented with re-recurrences (lower curve). Difference is statistically significant (log rank test p = .03). Middle right: Influence of lymphangiosis carcinomatosa on survival. Forty-six patients had lymphangiosis carcinomatosa (lower curve), 18 patients presented with macroscopic disease without lymphangiosis (upper curve). Difference is statistically significant (log rank test p < .001). Bottom left: Local progression-free survival until re-recurrence after CR (n = 48). Bottom right: Local progression-free survival until re-recurrence or patient death after CR (n = 48).

Table 5. Side effects upon HT + re-RT of recurrent breast cancers.

No. of patients evaluated	73 (100%)
No acute side effects observed	60 (82%)
Acute side effects	13 (18%)
G1: erythema	9 (12%)
Hyperpigmentation	9 (12%)
Scurfs	6 (8%)
No chronic side effects observed	50 (68%)
Chronic side effects	23 (32%)
G1: hyperpigmentation	21 (29%)
G2: new teleangiectasia (moderate)	3 (4%)

Table 6. Combination of RT and HT in pre-irradiated, recurrent breast cancer: Review of available data.

				CR (%)			Re-irradiation			Hyperthermia
Authors	Year	N	n	RT + HT	RT	Pre-irradiationTotal dose, Gy (range)	Dose/fraction (Gy)	Total dose (Gy)	No. fractions/wk	Technique (MHz)	Duration (min)	Total no.	No. fractions	Sequence, time lag	HT-related skin toxicity≥ G2^8 (%)
A. Randomised trials
Vernon et al. ESHO [34]	1996	56		78	38	na	4	32	2	100–1000	60	8^2 (3–8)	2/wk	RT-HT, 30–60 min	23
Jones et al. [35]^3	2005	39		68	24	na	1.8–2	30–66	5	433	(60 –120)^4	≤ 10	2/wk	na	21^4
B. Non-randomised trials/retrospective analyses
Li et al. [36]^3	1990	20		80		40–65	2–2.5	47^1 (20–80)^4	4–5	915, 2450	40	11.6^1.4	2/wk	RT-HT, 15–30 min	na
DuBois et al. [37]^3	1990	34		65		50–60	3.5–4.5	(8.5–41)^4	2–3	2450	45	na	2–3/wk	RT-HT, “immediately”	12^4
Phromratanapongse et al. [38]	1991	44		41		59.7^1 (35–66.2)	2–5	29.4^1 (16–56)	2–5	300–1000	60	5^1 (2–9)	2/wk	RT-HT, “immediately”	24
Engin et al. [5]^3	1994	17	64	94		60^2 (50–75)	4^2 (1.75–5.2)	40^2 (8–68)	na	915	60	5^2 (1–14)	“patchwork”	RT-HT, 15–30 min	50^4
Lindholm et al. [30]	1995	54	69	71		48^2 (14–75)	2.3–3	34.5^2 (20.7–36.8)	5	434, 915, 2450	45	4^2 (3–6)	1–2/wk	RT-HT, 85^2 min	32
van der Zee et al. [39]	1999	119		71		45^2 (15–66)	4	32^9	2	433, 2450	60	8^9	2/wk	RT-HT, 40^1 min	37
Feyerabend et al. [26]^3^,^5	2001	18		22		57.2^2 (50–65)	1.2–2	40.2^2 (36–60)	5–9	na	60	4^2 (1–8)	1/wk	RT-HT, 30 min	na^6
Kouloulias et al. [40]^5	2002	15		20		≤60	1.8	30.6^9	5	433	60	6^9	1/mth	CT-HT, 32^2 hrs	7
Ben-Yosef et al. [41]^3	2004	14	23	39		na	1.8–2	30^2 (30–50)	5	915	45	4^2 (2–7)	na	RT-HT, 10 min	26
Li et al. [42]^3	2004		41	56		58^1 (45–100)	1.8–4	43^na	2–5	8, 13.56, 430, 2450, (US)	30–60	4.5^1 (2–9)^4	1–2x/wk	RT-HT, 30–60 min	na^6
Wahl et al. [43]	2008	54		67	39	60^2 (19.6–82)	na	48^2 (14–73)^4	na	multi-institutional review, no details					na^6
Gabriele et al. [44]^3	2009	23	44	66		(45–63)^4	1.8–2	31.8^1 (20–60)^4	5	434	35	5^1 (1–8)	2/wk	RT-HT, “asap”	22^4
Linthorst et al. [45]	2015	248		70		49^1 (18–70)	4	32^9	2	433	60	4^9	1/wk	RT-HT, na	23
Datta et al. [27]	2015	24		67		54^2 (30–70)	2.07^2 (1.8–4)	36.8^1 (20–50)	2–5	915	60	7^1 (2–11)	1–2/wk	HT-RT, 30 min	na^6
Oldenborg et al. [28]^7	2015	414		58		50^2 (17.2–66)	3–4	32^2 (24–40)	2–4	434	60	na	1–2/wk	RT-HT, 60 min	13
Notter et al., this report	2016	73	103	66		56^2 (20–132.5)	4	20^9	1	wIRA	45–60	5^9	1/wk	HT-RT, 1–4 min	0

N is the number of patients, n is the number of lesions/fields. RT: radiotherapy; HT: hyperthermia; CT: chemotherapy; CR: complete response rate; na: data not available/not specified; US: ultrasound; wIRA: water-filtered infra-red-A.

¹ Mean.

² Median.

³ Patients with re-RT + HT selected out of larger reported study population.

⁴ Related to unselected study population.

⁵ Treatment schedule included chemotherapy as well.

⁶ Skin toxicity data are reported, but do not allow specification of HT-relationship and grading ≥ grade 2.

⁷ 1982–2006, re-RT data related to 89% of the patients.

⁸ Blisters, ulcers, necrosis.

⁹ Data refer to treatment protocol.

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