Table 3.
Efficacy and side effects of hyperthermia in studies of the first level of evidence (SR, RCTs, CTs and cohort studies)
| Reference | Intervention | Endpoints | Outcomes | Side effects |
|---|---|---|---|---|
| Lassche et al. [45] | WBH + optional other treatment modalities |
1. RR (CR and PR) 2. Serious toxicity (grade 3 or 4) |
1. Over all trials: RR: 12–89% Recurrent or platinum resistant epithelial ovarian cancer: WBH + CTx, RR: 38–45% (Atmaca 2009 (n = 35), Douwes 2004 (n = 21), Westermann 2001 (n = 12)) Metastatic colorectal cancer: WBH + CTx, RR: 20% and 27%. (Hegewisch-Becker 2002 (n = 41), Hildebrandt 2004 (n = 10)) Small cell lung carcinoma: WBH + CTx, both published in 1982, lack description of pre-treatments, RR: 86–89% (Engelhardt (n = 15), Neumann (n = 18)) Sarcoma: WBH + CTx, RR: 12–58%. (Bull 1992 (n = 17), Westermann 2003 (n = 95), Wiedemann 1996 (n = 12)) Cervical cancer: WBH + CTx, RR: 34% (Richel 2004 (n = 21)) Melanoma: WBH + CTx, RR: 20% (Engelhardt 1990 (n = 15)) Pleural mesothelioma: WBH + CTx, RR: 20% (Bakhshandeh-Bath 2003 (n = 20)) |
2. Serious toxicity in almost all studies (oldest studies did not report any (serious) toxicity or did not grade it). According to CTCAE: Most frequently grade 3 and 4 toxicities in studies using WBH + CTx: myelosuppression (anaemia 5–49%, leucopenia 14–100%, thrombocytopenia 5–65%) Related to WBH: (grade 3 and 4) Ventricular cardiac arrhythmias, dermal complications, kidney failure All studies combined: 966 cycles of WBH + CTx in n = 350 evaluable patients: n = 4 died of treatment related complications, due to infectious complications (Bakhshandeh-Bath 2003, Hegewisch-Becker 2002, Westermann 2003) |
| Sulyok et al. [46] |
Arm A: WBH (Heckel HT 3000) + surgery (n = 9) Arm B: only surgery (n = 9) Type of cancer: Colorectal Cancer Duration target temp. per session: 39.0 °C for 2 h Period of time: ni |
1. Quality of Recovery: (QoR)-40 questionnaire at 24 h after intervention. (Score: 40–200, higher values: better quality of recovery) 2. Immunological markers |
1. No significant difference, global QoR-40 score of (mean (SD)) 167 (15) in arm A and 159 (16) in arm B. No significant differences for the individual dimensions (p = 0.81) 2. HSPs: increased in WBH group after treatment. HSP60 (in %) at T4: 143 (arm A) versus 89 (arm B) (p = 0.04). HSP90 (in %) at T2: 111 (arm A) versus 64 (arm B) (p = 0.04). HSP70: no significant difference (p = 0.40). TNF α-levels (in %) at T3: significant elevated in arm B. In arm A near BL: 73 (arm A) versus 151 (arm B) (p = 0.04). PCT at T3: increased in both groups, increase significantly higher in arm B (p = 0.02). No significant differences between the groups for IL-6, IL-10, HLA-DR, or LBP (p values for area under the level/time curve. T0: before treatment, T1: after treatment, T2: after surgery, T3: 24 h after surgery, T4: 48 h after surgery, T5: 5 days after surgery) |
Related to WBH: (n = 9) Transient erythema on chest: 60% Two round, thermal lesions appeared after WBH (combustion grade 2, 1.5 cm in diameter on both lower breasts): n = 1 According to the authors: no sedation related side-effects in either group, and no subject reported hyperthermia related stress |
| Robins et al. [47] |
WBH (Aquatherm) + CTx WBH alone during week 1→ randomized to receive either Melphalan alone on week 2 and Melphalan + WBH on week 5, or reverse sequence (n = 16) Type of cancer: Mixed cancer diagnosis Duration target temp. per session: 41.8 °C for 1 h Total of 49 WBH treatments Period of time: May 1992-May 1995 |
1. Tumour response 2. Myelosuppression 3. Nausea/vomiting 4. CTx-pharmacokinetics |
1. CR: n = 1, PR: n = 2, SD: n = 1, PD: n = 10, not measurable: n = 1. Reduction of tumour marker: n = 1 2. Average (across all CTx-levels): Mean nadir WBC count: Melphalan + WBH 35% lower than Melphalan alone (p = 0.006) At 17.5 mg/m2 Melphalan: mean WBC nadir: Melphalan alone: 3.8 ± 0.4 103/µl, Melphalan + WBH: 2.89 ± 0.8 103/µl. Mean nadir platelet count: Melphalan + WBH 20% lower than for Melphalan alone (p = 0.04). Mean platelet count nadirs: Melphalan alone: 168 ± 24 103/µl, Melphalan + WBH: 132 ± 21 103/µl 3. Nausea or vomiting: controlled with antiemetics. WBH alone: 19%, Melphalan alone: 44% and WBH + Melphalan: 31% 4. WBH: no significant alteration in clearance or distribution of Melphalan. Terminal half-life slightly prolonged in combination courses |
According to NCICTC (n = 16) Related to WBH: Low-grade fever (< 24 h posttreatment): n = 3 Oral herpes simplex (grade 1): n = 7 Transient increase in liver function tests (grade 2): n = 3 Urinary tract infection (grade 1): n = 1 No haematological toxicity associated with WBH alone Related to WBH + CTx: Myelosuppression at Melphalan: 17.5 mg (n = 6): Melphalan alone: thrombocytopenia (grade 1): n = 1, neutropenia (grade 1): n = 1. Melphalan + WBH: neutropenia (grade 2): n = 1, (grade 3): n = 1, (grade 4): n = 1, thrombocytopenia (grade 1): n = 1 No instances of bacterial infection, bleeding, or neutropenic fevers. All patients: recovery of blood counts after completion of therapy |
| Hegewisch-Becker et al. [48] |
All patients in weekly changing regime: CTx + WBH (Enthermics, RHS 7500) (= arm A), CTx without WBH (= arm B) (n = 44) Type of cancer: Adenocarcinoma of colon or rectum Duration target temp. per session: 41.8 °C for 60 min Overall number of cycles: 273 (130 with and 143 without WBH) Period of time: January 1999- January 2001 |
1. Tumour-response 2. TTP and OS from beginning CTx-treatment until disease progression or death 3. 1y OS (Kaplan–Meier -estimated probability) |
1. CR: n = 2, PR: n = 6, SD: n = 23, PD: n = 9, Death: n = 1, due to sepsis and tumour lysis. RR: (CR and PR): n = 8 (20%), (95% CI: 9–35%) 2. Median TTP, from begin of treatment: 21 weeks (95% CI: 17–25 weeks). Median OS, from begin of treatment: 50 weeks (95% CI: 39–61 weeks) 3. 46% |
According to WHO (n = 44) Related to WBH: Mucosal herpes infections: n = 17, responsive to acyclovir Pressure scores (grade 1 and 2): n = 3 Transient cardiac arrhythmias with ECG signs of myocardial ischaemia (grade 3): n = 5 Comparison Group A and B: Haematological toxicity: In cycles with WBH: grade 0: 91.7%, grade 1: 2.6%, grade 2: 4.4%, grade 3: 1.2% In cycles without WBH: grade 0: 93.7%, grade 1: 1.6%, grade 2: 2.8%, grade 3: 1.9% Gastrointestinal toxicity: In cycles with WBH: grade 0: 82.6%, grade 1: 11%, grade 2: 4.9%, grade 3: 1.5% In cycles without WBH: grade 0: 85.5%, grade 1: 9.6%, grade 2: 3.7%, grade 3: 1.2% Peripheral neurotoxicity: In cycle with WBH: grade 0: 39.2%, grade 1: 40.8%, grade 2: 18.5%, grade 3: 1.5% In cycle without WBH: grade 0: 49.0%, grade 1: 35.0%, grade 2: 14.7%, grade 3: 1.4% Fatigue syndrome: In cycle with WBH: grade 3: 20%, grade 4: 5% In cycle without WBH: grade 3: 6%, grade 4: 3% Related to Oxaliplatin: Most frequent: mild neurosensory toxicities: 68% Severe sensory neuropathy with functional impairment due to loss of sensitivity in fingertips and soles of feet towards end of therapy: n = 1 Almost all patients reported neurotoxicity to be less pronounced in cycles combined with WBH |
| Gerke et al. [49] |
Arm A: ECC-WBH (Level One) + CTx (n = 9) Arm B: rWBH (Aquatherm) + CTx (n = 18) Arm C: CTx alone (n = 16) Type of cancer: Sarcoma Duration target temp. per session: 41.8 °C for 1 h Number of treatments: 4–6 courses Period of time: January–December 1995 |
1. Serum creatinine, GFR, marker proteins (albumin, IgG, α1-microblobulin): comparison between three groups at T3 2. Serum creatinine, GFR, marker proteins: comparison between three groups at T4 (T0:1 day before ICE, T3: day 3 of ICE, T4: 21 days after T0) |
1. GFR: decreased more profoundly in the WBH treated patients than in patients treated with CTx alone (ICE vs. ICE + ECC-WBH: p = 0.016, ICE versus ICE + rWBH: p = 0.037) between ECC-WBH and rWBH no significant difference (p = 0.364) Creatinine: no significant difference between WBH + ICE groups and sole ICE group (ICE vs. ICE + ECC-WBH: p = 0.111, ICE versus ICE + rWBH: p = 0.227), no significant difference between ECC-WBH und rWBH (p = 0.364) Marker-Proteins: increased significantly more profoundly in WBH-treated patients than in patients treated with CTx alone (p < 0.05). Increase not significant different between ECC-WBH and rWBH (p > 0.05) 2. GFR: no significant difference between WBH + ICE group and sole ICE group (ICE vs. ICE + ECC-WBH: p = 0.631, ICE versaus ICE + rWBH: p = 0.763), no significant difference between ECC-WBH und rWBH (p = 0.688) Creatinine: no significant difference between WBH + ICE group and sole ICE group (ICE vs. ICE + ECC-WBH: p = 0.873, ICE versus ICE + rWBH: p = 0.921), no significant difference between ECC-WBH und rWBH (p = 0.841) Marker-proteins: no significant difference between ICE and ICE + rWBH. In ECC-WBH group: all 3 marker-proteins significantly pathological elevated in comparison with T0 (p < 0.05). Intergroup-comparison: ICE alone versus ICE + ECC-WBH and ICE + ECC-WBH versus ICE + rWBH: significant higher albumin and α1-microglobulin-values in ICE + ECC-WBH group. (p < 0.05) |
Except of analysed nephrotoxicity no further information |
| Reuter et al. [50] |
WBH (Iratherm 1000) + induced therapeutic fever Group A1: bacterial extracts: Se + Stp and Ps + Stp without preceding hyperthermia (135 applications, n = 44) Group A2: bacterial extracts (Se + Stp and Ps + Stp) preceded by 30 min WBH (215 applications, n = 62) Group B: combinations of approved drugs (Colibiogen, Iscador, Picibanil, Polyvaccinum, Strovac) preceded by WBH (100 applications, n = 25) Type of cancer: Mixed cancer diagnosis and other diseases Duration target temp. per session: 39–40 °C, no further description Period of time: ni |
1. Effect of preceding WBH | 1. Side reactions and difference between Se and Ps drastically reduced |
Related to combination therapy (no further distinction): Nausea/vomiting: group A1: Ps 15%, Se 24.9%, group A2: Ps 6.1%, Se 8.2%, group B: 26% Headache: group A1: Ps 12%, Se 19.3%, group A2: Ps 5.5%, Se 6.1% group B: 25% Back pain: group A1: Ps 5.4%, Se 7.4%, group A2: Ps 2.4%, Se 2.3%, group B: 12% Circulatory reactions: group A1: Ps 7.7%, Se 10.9%, group A2: Ps 3.1%, Se 3.2%, group B: 0.5% Weakness next day: group A1: Ps 17.7%, Se 21.2%, group A2: Ps 13.1%, Se 16.1%, group B: 0.5% |
| Minnaar et al. [51] |
Arm A: EH (EHY2000 + , Oncotherm, 2 treatments per week) + CTx + RTx (n = 104) Arm B: (CTx + RTx) (n = 106) Duration target temp. per session: 42.5 °C for a minimum of 55 min Treatment duration: ni, planned 10 treatments Period of time: January 2014–August 2018 |
1. 6-month LDFS (local disease-free survival) arm A: n = 101, arm B: n = 101 2. LDC (local disease control) censored for survival (arm A: n = 88, arm B: n = 83) 3. Tumour response (arm A: n = 85, arm B: n = 73) |
1. Arm A: n = 39 (38.6%), arm B: n = 20 (19.8%) (p = 0.003) 2. Arm A: n = 40 (45%), arm B: n = 20 (24%) (p = 0.003) 3. CMR (complete metabolic response): arm A: n = 49 (57.6%), arm B: n = 26 (35.6%) (p = 0.005) PMR (partial metabolic response): arm A: n = 33 (38.8%), arm B n = 44 (60.3%), SMD (stable metabolic disease): arm A: n = 1 (1.2%), arm B: n = 3 (4.1%), PMD (progressed metabolic response): arm A: n = 2 (2.4%), arm B: n = 0 |
Related to EH (according to CTCAE, n = 104): 91.4% participants received ≥ 8 of planned 10 EH treatments. Reasons for not receiving ≥ 8 EH: adipose burns (n = 2), 1 cm blister (n = 1), progressed on treatment (n = 1), moist desquamation resulting in RT and EH delay (n = 2), bleeding resulting in RTx and EH delay (n = 1), did not arrive for RTx or EH (n = 1), deceased on treatment (n = 1) Adipose tissue burns (grade 1–2): n = 10, (9.5%) Surface burns (grade 1): n = 2 (2.0%) Pain: n = 9 (8.6%) |
| Minnaar et al. [52] | Same study as Minnaar (2019), other endpoint |
1. QoL: C30 and Cx24 (EORTC) T1: 6 weeks post-treatment, T2: 3 months post-treatment |
1. At BL: no statistically significant differences in QLQ scores between two arms T1: mean change in cognitive function: arm A significantly higher than arm B (p = 0.031) T2: arm A compared to arm B: significant improvement in social functioning (p = 0.049), emotional functioning (p = 0.017), fatigue (p = 0.037) and pain (p = 0.007) Mean improvement in social, emotional and physical function at T1 significantly higher in patients with CR |
Others related to EH: HIV status, increased BMI and average energy not significant predictors of adverse events associated with EH |
| Minnaar et al. [53] | Same study as Minnaar (2019), other endpoint |
1. Abscopal response: all disease (primary tumour, lymph nodes within and outside radiation field) showing a CMR (complete metabolic response) at T1 in 18-FDG PET/CT (fluorodeoxyglucose-positron-emission tomography) |
1. Higher in arm A n = 13 (24.1%) compared to arm B: n = 3 (5.6%) (p = 0.013) | |
| Loboda et al. [54] |
Arm A: EH (MagTherm system Radmir, Ukraine, 27.12 ± 0.16 MHz) + neoadjuvant CTx (n = 103) Arm B: only neoadjuvant CTx (n = 97) Type of cancer: Locally advanced breast cancer Duration target temp. per session: 37–38.8 °C for 30 min Treatment duration: ni Period of time: 2008–2017 |
1. Blood flow of the breast 2. Tumour response 3. Survival |
1. Arm A: blood flow increased from 44.58 cm/s to 192.78 cm/s after EH. Mean values for systolic blood flow 3.5 times as high as those prior to EH, mean diastolic blood flow raised after EH 2. CR: arm A: n = 9, arm B: n = 6 (p = 0.68) PR: arm A: n = 51, arm B: n = 35 (p = 0.076) SD: arm A: n = 37, arm B: n = 49 (p = 0.052) PD: arm A: n = 6, arm B: n = 7 (p = 0.91) 3. 10-year OS significantly higher in arm A (p < 0.009) |
Comparison arm A to arm B: Haematologic, gastrointestinal toxicities, liver, and kidney function: no significant difference |
| Mahdavi et al. [55] |
Arm A: EH (Celsius 42 +) + CTx + RTx, n = 19 Arm B: CTx + RTx, n = 19 Type of cancer: Glioblastoma Duration target temp. per session: About 41 °C for 1 h, 2 times a week Number of treatments: 10–12 courses Period of time: ni |
1. OS, after 18 months (means ± SD) 2. Karnofsky Performance Status Scale (KPS), T0: at BL, T1: after treatment, T2: after 3 months (mean values) 3. Tumor volumes, measured by MRI (mean ± SD, in cm3), T0: at BL, T1: 3 months after treatment, T2: 6 months after treatment |
1. Arm A: 15.47 ± 4.6 months, arm B: 14.57 ± 4.5 months, no significant difference between arms (p = 0.55) 2. Arm A: T0: 86.31, T1: 88.95, T2: 85.26, arm B: T0: 84.73, T1: 84.21, T2: 78.94 no significant differences between T0–T3 3. Arm A: T0: 104.14 ± 58.4, arm B: T0: 135.42 ± 92.5, difference not statistically significant (p = 0.2) arm A: T1: 68.08 ± 59.64, T2: 68.41 ± 62.14 arm B: T1: 137.63 ± 113.93, T2: 151.42 ± 117.10, difference statistically significant (p < 0.05) |
Related to EH: (based on questionnaire): Mild headache, no necessity for any additional medication |
| Fiorentini et al. [56] |
Type of cancer n = 111 glioblastoma multiforme (GBM), n = 38 astrocytoma (AST) Arm A: n = 52 (n = 28: GBM, n = 24: AST): EH (EHY-2000 + , Oncotherm, 13.56 MHz), in arm A no CTx Arm B: n = 97 (n = 83 GBM, n = 14 AST): BSC (best supportive care: dexamethasone, glycerol, mannitol, holistic therapy, psychosocial support) In arm B: n = 28 (all GBM) received additionally CTx Duration target temp. per session: 40–42.5 °C for 20–60 min Treatment duration: 3 times per week for 8 weeks. Median number of EH treatments/patient: 22 (range: 11–62) Period of time: April 2003–January 2018 |
1. Tumor response at 3 months 2. Median OS 3. Quality of life |
1. Arm A: AST patients: CR: n = 2 (9%), PR: n = 8 (36%), SD: n = 6 (27%) Overall positive response of AST (CR + PR + SD): arm A: 72%, significantly higher than in arm B: 37% (p < 0.005) PD: arm A: n = 4 (18%) patients, arm B: n = 9 (56%) Arm A: GBM patients: CR: n = 1 (4%), PR: n = 6 (21%), SD: n = 8 (29%), Overall positive response of GBM (CR + PR + SD): arm A: 54% significantly higher than in arm B: 19% (p < 0.05) PD: arm A: n = 13 (46%), arm B: n = 62 (75%) 2. Median OS AST patients: arm A: 16 months (range: 3–156), arm B: 16.5 months (range: 3–120 months) (p = 0.0065) 5-year OS AST patients: arm A: 83%, arm B: 25% Median OS GBM patients: arm A: 14 months (range: 2–108 months), arm B: 9 months (range: 2–84 months), (p = 0.047) 3. Most patients reported better QoL (evaluated by subjective responses as during follow-up visits) in arm A |
Related to EH: (according to CTCAE, n = 50) Headache: n = 1 (2%) Scalp burn n = 1 (2%) Seizures n = 5 (10%) (all patients experienced this symptom from the beginning of disease. Seizure during EH in n = 1) |
| Kim et al. [57] |
Arm A: EH (EHY2000, Oncotherm) + conventional cancer treatment (after PSM: n = 35, at BL: n = 32) Arm B: Conventional cancer treatment alone (after PSM: n = 175, at BL: n = 83) Type of cancer: Lung cancer Duration target temp. per session: 39–42 °C for 60 min Numbers of treatment sessions: 1–47 (mean: 19.3) Treatment durations: 1–42 weeks (mean: 10.3 weeks) Period of time: 2010–2013 |
1. Pain intensity (PI): (numeric scale: 0–10) 2. Opioid analgesic dose (M) 3. Effective analgesic score (EAS): PI [1 + (M/10)]: increase in EAS: indication for problem with adequate analgesia 4. EAS-changes over time (T0: BL: days -30–0, T1: days 1–60, T2: days 61–120, T3: days 121–180) |
1. No significant differences between arms at any time 2. Significant higher M in arm A at T1 (means ± SD): in arm A: 479.29 mg ± 685.01 mg, in arm B: 243.60 mg ± 403.06 mg (p = 0.022) 3. No significant differences between arms at any time 4. EAS: significant interaction treatment x time: p = 0.038, significant interaction with T1, with higher (so worse) values for arm A compared to arm B. SMD: 101.76 points, standard error: 46.22 points, 95% CI: 10.20–193.32 points (p = 0.03) |
Related to EH: Pain due to EH particularly during early stages of treatment |
| Kim et al. [58] |
Arm A: EH (EHY2000, Oncotherm) additional during neoadjuvant RTx and CTx (n = 62) Arm B: only neoadjuvant RTx and CTx (n = 58) 6–8 weeks after neoadjuvant treatment: surgery Type of cancer: Locally advanced rectal cancer Duration target temp. per session: 60 min, n = 59 more than 8 session, temp: ni Treatment durations: ni Period of time: May 2012–December 2017 |
1. Pathologic outcome (pathologic T stage, T-downstaging rate pathologic N stage, N-downstaging rate, downstaging rate, TRG (tumor regression grade)) 2. Survival (n = 113 of 120) |
1. No significant differences between arms. (except: TRG 3 (near total regression) + TRG 4 (total regression) only for tumours with initial primary tumor volume > 65 ml: arm A: n = 6 (31.6%), arm B: n = 0 (0%) (p = 0.024) 2. Median follow-up period: arm A: 45 months (range: 7–71 months), arm B: 58 months (range: 6–95 months) 2-year OS: arm A: 100%, arm B: 96% no significant difference 2-year DFS: arm A: 96%, arm B: 76% (p = 0.054) 2-year LRRFS (locoregional recurrence free survival): arm A: 98%, arm B: 94% (p = 0.09) 2-year DMFS (distant metastases free survival): arm A: 94%, arm B: 79% (p = 0.083) |
Related to EH (according to Berlin scoring system, n = 62): Hot spot: n = 1 Fat necrosis: n = 1 Heat-related (no further information) grade 0: n = 45, grade 1: n = 15, grade 2: n = 0, grade 3: n = 2 Comparison arm A to arm B (according to NCICTC, n = 120): Incidence of leucopenia, neutropenia, and genitourinary toxicities similar between the two arms. (leucopenia: p = 0.219, neutropenia: p = 0.802, genitourinary: p = 0.362) Gastrointestinal toxicity: arm A: 64.5% (grade 0: n = 22, grade 1: n = 21, grade 3: n = 19), arm B: 87.9% (grade 0: n = 7, grade 1: n = 25, grade 2: n = 26) (p = 0.01) |
1y-OS 1 year-overall-survival; AST astrocytoma; BL baseline; BMI body mass index; CI confidence Interval; CR complete response; CTx chemotherapy; EAS effective analgesic score; EAS (PI [1 + (M/10)]: 1: anti-inflammatory drug at a regular dosage; M the weekly dose (mg) in oral morphine equivalents; n number of patients; PI the pain intensity on a 1–10 scale); ECC-WBH extracorporeal-circulation-WBH; ECG electrocardiographic; EH electro hyperthermia; GBM glioblastoma multiforme; GFR glomerular filtration rate; HLA-DR human leucocyte antigen of class DR; HSP heat-shock protein; ICE CTx of Ifosfamide, carboplatin and etoposide; IL interleukin; LBP lipopolysaccharide binding protein; MV mean value; NCICTC NCI common terminology criteria for adverse events; ni no information; OS overall survival; PCT procalcitonin; PI pain intensity; PR partial response; Ps Pseudomonas aeruginosa; PSM propensity score matching; QoR quality of recovery; RR response rate; rWBH radiant heat induced WBH; Se Serratia marcescens; SD stable disease; SMD standardized mean deviation; ST survival time; Stp Streptococcus pyogenes; TNF-α tumour-necrosis factor-α; TRG tumour regression grade; TTP time to progression; vs versus; WBH whole-body-hyperthermia; WHO: World-Health-Organization; WBC white blood cells