Table 4.
Efficacy of hyperthermia in studies of the second level of evidence (single-arm studies and case series)
| Reference | Intervention, Duration of target temp. per session, Period of time of the study | Number of participants, Cancer type | Outcome | |
|---|---|---|---|---|
| Outcome: Tumour response | ||||
| Atmaca et al. [59] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Cycles repeated every 28 days up to a total of 6 cycles. Median cycles: 2.7 (range: 1–6). Period of time: May 1997-December 2002 |
n = 35. Ovarian carcinoma | CR: 11%, PR: 34%, SD: 26%, PD: 29%, RR (PR and CR): 45.7% | |
|
Bakhshandeh-Bath et al. [60] Bruns et al. [61] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Responding patients up to 2 additional cycles. Period of time: April 1999-February 2001 |
n = 25. Pleural mesothelioma |
Overall RR: 20% (95% CI 8.9–39.1%), CR: n = 0, PR: n = 5, MR: n = 3, SD: n = 11, PD: n = 6 | |
| Bakhshandeh-Bath et al. [62] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Patients received second cycle 4 weeks after first cycle. Period of time: March 2000-March 2003 |
n = 13. Pancreatic adenocarcinoma | PR: n = 3, SD: n = 5, RR (PR and CR): 23% | |
| Katschinski et al. [63] |
WBH (Aquatherm) + CTx, 41.8 °C for 60 min. Total of 53 cycles. Period of time: ni |
n = 17. Mixed cancer diagnosis | Comparison RR early versus late CTx-schedule: no significant difference (62 ± 6%) | |
| Richel et al. [64] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Total of 82 courses, median of 3 courses per patient (range: 1–6). Period of time: ni |
n = 21. Cervical cancer | CR: n = 1, PR: n = 6, RR (PR and CR): 33% (95%-CI: 13–53%), SD: n = 9, PD: n = 5 | |
| Westermann et al. [65] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Total of 44 combination treatments. Period of time: 1995–1999 |
n = 12. Ovarian carcinoma | CR: n = 1, PR: n = 4, SD: n = 4, PD: n = 3, RR (CR and PR): 35.7% (90%-CI: 15.3–60.9%) | |
| Westermann et al. [66] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Responding patients up to 2 additional cycles. Period of time: May 1995–December 2000 |
n = 95. Soft tissue sarcoma | CR: n = 4, PR: n = 23, SD: n = 31, PD: n = 37. RR (PR and CR, overall): 28.4% (95% CI: 19.8–38.5%). RR (no prior therapy): 36%, RR (pretreated patients): 24%. → Difference (RR pretreated vs. no prior therapy): not significant (p = 0.238) | |
| Robins et al. [67] |
WBH (Enthermics) alone, 39.5–41.8 °C for 35–140 min. Number of treatments at each level: 3–7. Total of 52 treatments. Period of time: ni |
n = 10. Mixed cancer diagnosis | SD: n = 5 (Median: 5 months), MR: n = 3, RR (PR and CR): 0% | |
| Robins et al. [68] |
WBH (Enthermics) + CTx, total of WBH-treatments: at 41.0 °C for 85 min: n (treatments) = 93, at 41.8 °C for 75 min: n = 105. Repetition due to escalation temperature scheme. Period of time: ni |
n = 23. Mixed cancer diagnosis |
Group A: no response: n = 3. Group B: PR: n = 2, improvement (less than PR): n = 1. Group C: CR: n = 1, improvement: n = 2, SD: n = 3, PD: n = 11. RR (overall PR and CR): 13% (Groups: different concentration of CTx) |
|
| Robins et al. [69] |
WBH (Enthermics) + RTx, 41.8 °C for 75 min. Total of 97 WBH-treatments. Period of time: November 1983–April 1987 |
n = 8. B-cell neoplasms | CR: n = 3 (n = 2 remain in a CR), PR: n = 4, improvement (a 48% decrease in tumour burden): n = 1, RR (PR and CR): 87.5% | |
| Robins et al. [70] |
WBH (Enthermics) + CTx, 41.8 ± 0.2 °C for 60 min WBH alone in week 1, WBH + CTx in week 2, CTx alone in week 5. Responding patients: WBH + CTx to maximum of further 5 cycles. Period of time: ni |
n = 30. Mixed cancer diagnosis | CR: n = 1 (neuroendocrine tumour → hormone marker-negative, TTP: 410 days), PR: n = 2 (TTP: 96 days, 208 days), SCR: n = 2 (TTP: > 9 months, 233 days), MR: n = 1 (TTP: 143 days), SD: n = 8, improvement after WBH + CTx, but progression after CTx alone: n = 2, RR (PR and CR): 10% | |
| Bull et al. [71] |
WBH (Heckel HT-2000) + CTx, 40 °C for 6 h. Cycle repeated up to 7 times. (range: 1–8). Period of time: January 2000–June 2004 |
n = 37. Mixed cancer diagnosis | CR: 3%, PR: 41%, SD: 19%, PD: 38%, RR: (CR + PR): 43% | |
| Kraybill et al. [72] | WBH (Heckel, HT-2000) alone, group A: 39–39.5 °C for 3 h, Group B: 39–39.5 °C for 6 h, Group C: 39.5–40 °C for 6 h. Period of time: ni | n = 9. Mixed cancer diagnosis | No clinical responses (anti-tumour effects of WBH) | |
| Barlogie et al. [73] |
WBH (water blankets, Cincinnati Sub-Zero) alone or WBH + CTx, 42 °C for 4 h. Frequency: Ø 3x. Period of time: June 1977–April 1978 |
n = 11. Mixed cancer diagnosis | CR: n = 0, PR: n = 0, SD: n = 7 (of them: n = 4 objective regression, less then PR, all apparent after WBH alone), progression: n = 4, RR (PR and CR): 0% | |
| Gerad et al. [74] |
WBH (nylon and vinyl mesh water perfused suit (Whittaker General Medical), heating blankets) + CTx, 41.8 °C–43.0 °C for 2 h, Total of 35 treatments, Period of time: ni |
n = 11. Soft tissue Sarcoma | RR (CR and PR): 36%, CR: n = 2, PR: n = 2. RR for soft tissue sarcoma (excluding patients with mesothelioma): 44% (90% CI: 17–71%) | |
| Koga et al. [75] | ECC-WBH (Parks and Smith) + CTx, 41.5 °C for 3–5 h, 4 times at intervals of 7–10 days (some patients received treatment only once). Period of time: ni | n = 17. Gastro-intestinal cancer | PR: n = 3, SD: n = 9, ST: not markedly prolonged (even in patients with PR). Not evaluable: n = 4 (died, probably ascribable to ECC-WBH). RR (PR and CR): 18% | |
| Wiedemann et al. [76] | ECC-WBH (Parks and Smith) + CTx, 41.8 °C for 1 h. Patients received 3 thermo-chemotherapy treatments every 3 weeks. Total of 49 treatments. Period of time: ni | n = 19. Sarcoma or malignant teratoma | PR: n = 7 (progression 5 months after therapy: n = 2), SD: n = 8, PD: n = 4, RR (PR and CR): 37% | |
| Wiedemann et al. [77] |
ECC-WBH (Level One) + CTx, 41.8 °C: 1 h. Period of time: ni |
n = 12. Sarcoma | CR: n = 0, PR: n = 7, SD: n = 3, PD: n = 2, RR (CR and PR): 58% (95%-CI: 28–85%.) | |
| Steinhart et al. [78] |
ECC-WBH (heated air blanket, Cincinnati Sub-Zero hyper-hypothermia machine) alone, 40 °C or 42 °C for 1 h. Period of time: ni |
n = 6. Kaposi’s sarcoma | Some improvement of KS lesions (lightening in colour and decrease in size): n = 6, KS-lesions regressed to pre-treatment status 2-weeks post-WBH: n = 5, size of KS-lesion continued to diminish: n = 1, progression of KS: n = 2 | |
| Douwes et al. [79] |
EH (Oncotherm EHY2000) + CTx, 60 min, temp. reached in tumour: 42–44 °C (measured non-invasive by energy absorption). Treatments repeated every 4 weeks until PD Number of treatments: mean: 3 (range: 1–9). Period of time: ni |
n = 30. Pancreas carcinoma | CR: n = 1, PR: n = 10, SD: n = 12, PD: n = 7, DCR (CR, PR, SD): n = 23 (77%), RR (PR and CR): 37% | |
| Gadaleta-Caldarola et al. [80] |
EH (Oncotherm EHY2000) + Sorafenib, 60 min. 3 times/week for 6 weeks, followed by 2 weeks without treatment. Period of time: February 2009–September 2010 |
n = 21. Hepatocellular carcinoma |
CR: n = 0, PR: n = 1, SD: n = 11, PD: n = 9, DCR (= CR, PR, SD): 45%, RR (PR and CR): 5% | |
| Wismeth et al. [81] |
EH (Oncotherm EHY2000) + CTx, 20–60 min. Median number of EH-sessions: 20 (range: 11–77). Period of time: January 2006–March 2008 |
n = 15, 20 lesions. Glioma WHO grade III or IV |
CR: n = 2 lesions, PR: n = 1 lesion, PD: n = 9 lesions, SD: n = 5 lesions, not evaluable: n = 3 lesions, RR (PR and CR of the lesions): 15% |
|
| Yoo et al. [82] |
EH (Oncotherm, EHY2000 + , Oncotherm), 2 sessions per week for 3 weeks, CTx before study. Temp: ni. Period of time: October 2008–March 2016 |
n = 19. Recurrent and progressive ovarian cancer |
SD: n = 1. N = 18 died with a median follow-up of 8.0 months (range 2–32 months). Time to death ranged from 2.5 to 32.0 months |
|
| Yu et al. [83] |
EH (Celsius42 +) + RTx, 60 min, Skin surface temp.: 36–37.5 °C, twice a week, at intervals of at least 72 h, for 5 total sessions. Period of time: November 2013–August 2014 |
n = 10. Colorectal cancer, hepatic metastasis | Metastasis response: PD: n = 2, PR: n = 3, at 2 months: hepatic PD: n = 3, PD-free 3 months after treatment: n = 3, RR (PR and CR): 30% | |
| Sahinbas et al. [84] |
EH (local electrohyperthermia) + CTx, 1 h, during first and second CTx-cycle three times a week. From third CTx-cycle two times a week. Mean: 2.25 cycles of CTx and hyperthermia. Period of time: ni |
n = 4. Colorectal cancer, hepatic metastases |
PR: n = 1, SD: n = 2, PD: n = 1, RR (PR and CR): 25% | |
| Outcome: Survival data | ||||
| Atmaca et al. [59] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Cycles repeated every 28 days up to a total of 6 cycles. Median: 2.7 (range: 1–6). Period of time: May 1997–December 2002 |
n = 35. Ovarian carcinoma | Median OS: 61.5 weeks (= 14.2 months, from start of treatment) (range: 5–292 weeks). Median TTP: 29 weeks (= 6.7 months, from start of treatment) (range: 14–172). Median response duration: 25 weeks (range: 9–112) | |
|
Bakhshandeh-Bath et al. [60] Bruns et al. [61] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Responding up to 2 additional cycles. Period of time: April 1999–February 2001 |
n = 27. Pleural mesothelioma | Median ST: 76.6 weeks (= 17.6 months, from start of treatment) (95%-CI: 65–87.8 weeks). Median ST: 83.8 weeks (= 19.3 months, from diagnosis) (95% CI 73.9–93.8 weeks). PFS: 29.6 weeks (= 6.8 months, from start of treatment) (95%-CI: 24.4–34.7 weeks). 1y OS: 68%, 2y OS: 20% | |
| Bahkshandeh-Bath et al. [62] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Patients received second cycle 4 weeks after first cycle. Period of time: March 2000–March 2003 |
n = 13. Pancreatic adenocarcinoma | Median PFS (all patients): 4.7 months. Median OS (all patients): 11.4 months. Median OS (patients with PR): 15.8 months. 1y OS (all patients): 38%. No information, if data from start of study or from diagnosis | |
| Richel et al. [64] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Total of 82 courses, median of 3 per patient (range: 1–6). Period of time: ni |
n = 21. Cervical cancer | Median PFS: 5.3 months (range: 0.5–43 + , from start of study). Median OS: 7.8 months (range: 1.3–43 + , from start of study) | |
| Westermann et al. [66] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Responding patients up to 2 additional cycles. Period of time: May 1995–December 2000 |
n = 95. Soft tissue sarcoma | Median OS: 327 days (= 10.7 months) (95%-CI: 393–496 days). Median TTF: 123 days (95%-CI: 77–164). Difference in OS, TTF depending on tumour response. OS: responders versus PD: significant (p = 0.04). OS: SD versus PD: significant (p = 0.07). TTF: responder versus SD: not significant (p = 0.31). No information, if data from start of study or from diagnosis | |
| Robins et al. [69] |
WBH (Enthermics) + RTx, 41.8 °C for 75 min. Period of time: ni |
n = 8. B-cell neoplasms | Median ST: 52.5 months. Median TTF: 9.4 months (90%-CI: 7–15.4 months). No information, if data from start of study or from diagnosis | |
| Bull et al. [71] |
WBH (Heckel HT-2000) + CTx, 40 °C for 6 h. Cycle repeated up to 7 times. (range: 1–8). Period of time: January 2000–June 2004 |
n = 37. Mixed cancer diagnosis | Mean time to disease progression: 5.5 months. Mean OS: 8.1 months. No information, if data from start of study or from diagnosis | |
| Wismeth et al. [81] |
EH (Oncotherm EHY2000) + CTx, 20–60 min. Median number of EHT sessions: 20 (range: 11–77). Period of time: January 2006–March 2008 |
n = 15, 20 lesions. Glioma WHO, grade III or IV | Median TTP: 14 weeks (= 3.2 months) (range: 6–40). Median OS (after start of study, patients diseased at time of study report): 26 weeks (= 5.9 months) (range 14–41). Median OS (after start of study, in total population): 30 weeks (= 6.9 months) (range 14–109 weeks). Median OS (from diagnosis, in patients diseased at time of study report): 59 weeks (range 43–106). Median OS (from diagnosis, in total population): 81 weeks (= 18.6 months) (range: 43–387 weeks) | |
| Douwes et al. [79] |
EH (Oncotherm EHY2000) + CTx, 60 min, temp. reached in tumour: 42–44 °C (measured non-invasive by energy absorption). Treatments repeated every 4 weeks until PD Number of treatments: mean: 3 (range: 1–9). Period of time: ni |
n = 30. Pancreas carcinoma | Median ST: 8 months: (range: 2–53, no information, if data from start of study or from diagnosis.), 1y OS: 31%, 2y OS: 24% | |
| Gadaleta-Caldarola et al. [80] |
EH (Oncotherm EHY2000) + Sorafenib, 60 min. 3 times/week for 6 weeks, followed by 2 weeks without treatment. Period of time: February 2009–September 2010 |
n = 21. Hepatocellular carcinoma |
PFS (at four months): 70%. Median TTP (initial treatment until PD): 5.2 months (95%-CI: 4.2–6.2). Median OS (initial treatment to mortality): 10.4 months (95%-CI: 10–11) | |
| Lee et al. [85] |
EH (Oncotherm EHY2000) + CTx, 38.5–42.5 °C. for 60 min, every second day. Period of time: April 2006–March 2012 |
n = 23. Small cell lung cancer | ST: range: 2–36 months. Died during treatment: n = 7. Survival > 3 years: n = 3. No information, if data from start of study or from diagnosis | |
| Yoo et al. [82] |
EH (Oncotherm, EHY2000 + , Oncotherm), 2 sessions per week for 3 weeks, CTx before study. Temp: ni. Period of time: October 2008–March 2016 |
n = 19. Recurrent and progressive ovarian cancer | Median overall survival: 8.0 months. Time to progression: ranged from 2.5 to 5.0 months. Time to death ranged from 2.5 to 32.0 months, 18 of 19 patients died | |
| Heo et al. [86] |
EH (Celsius42 +) + RTx, 40–43 °C for 60 min. 6 times (range: 3–12 times). Period of time: September 2010–July 2015 |
n = 20. Glioma | Median OS: 8.4 months (95%-CI: 6.9–9.9). 6-month survival: 67%, 12-month survival: 30%. Median PFS: 4.1 months (95%-CI 3.4–4.7). Median 6-month-PFS: 13%. Data from re-irradiation | |
| Yu et al. [83] |
EH (Celsius42 +) + RTx, 60 min, skin surface temp.: 36–37.5 °C, twice a week, at intervals of at least 72 h, for 5 total sessions. Period of time: November 2013–August 2014 |
n = 4. Colorectal cancer, hepatic metastasis | Local PFS at 3 months: 30%. Data from start of treatment | |
| Sahinbas et al. [84] | EH (local electrohyperthermia) + CTx, 1 h, during first and second CTx-cycle three times a week. From third CTx-cycle two times a week. Mean: 2.25 cycles of CTx and hyperthermia. Period of time: ni |
n = 4. Colorectal cancer, hepatic metastases |
Mean PFS: 5.2 months. Mean OS: 9.8 months. No information, if data from start of study or from diagnosis | |
| Outcome: Pain | ||||
| Bull et al. [71] |
WBH (Heckel HT-2000) + CTx, 40 °C for 6 h. Cycle repeated up to 7 times. (range: 1–8). Period of time: January 2000–June 2004 |
n = 37. Mixed cancer diagnosis | Pain prior to treatment: n = 28 → requiring narcotic drug control. Of them all patients with objective tumour response (n = 13) reported decrease of pain and pain medication. 8 of the 13 patients able to stop narcotic pain medication | |
| Koga et al. [75] | ECC-WBH (Parks and Smith) + CTx, 41.5 °C for 3–5 h, 4 times at intervals of 7–10 days (some patients received treatment only once). Period of time: ni | n = 17. Gastro-intestinal cancer | Reduction of abdominal cancer pain: n = 3 | |
| Wiedemann et al. [76] | ECC-WBH (Parks and Smith) + CTx, 41.8 °C for 1 h. Patients received 3 thermo-chemotherapy treatments every 3 weeks. Total of 49 treatments. Period of time: ni | n = 19. Sarcoma or malignant teratoma | Improvement after first WBH treatment: n = 4 | |
| Ariyafar et al. [87] |
EH (Celsius42 +) + RTx 60 min, 2 h after RTx (10 fractions over 2 weeks). Temp: ni. Period of time: December 2016–December 2017 |
n = 23. Bony metastases |
1. Median pain score: at T0: ranged from 6 to 8. At T1: significant reductions in the worst pain, least pain, average pain and current pain (p < 0.001 for all), maintained during T2–T4 Mean score of worst pain in a 24-h period: at BL: 8.39 (range: 6 to 10), significantly decreased at T1: 4.26 (range: 0 to 9), sustained at T2: 3.74, T3: 3.43 and T4: 3.61 (range: 0 to 9 for all). Similar results observed for least pain, average pain and current pain 2. Pain response (CR: pain score 0 at the worst pain in the preceding 24 h. PR: ≥ 2 drop of the worst pain compared to BL during the preceding 24 h. Stable pain: no change in the score or only pain reduction of 1 score compared to BL at the worst pain during the preceding 24 h over three-months): At T4: CR or PR: n = 18 (78%, 95%CI: 61%–95%), refractory to the treatments and stable pain: n = 4, variable between stable or partial response: n = 2 3. Pain relief medications: Number of patients using pain relief medications: at T0: 74% (n = 17), at T1: 52% (n = 12), at T4: 48% (n = 11) (T0: at BL, T1: treatment completed, T2: 1 month-, T3: 2 months-, T4: 3 months- post-treatment (n = 23)) |
|
| Yu et al. [83] |
EH (Celsius42 +) + RTx, 60 min, Skin surface temp.: 36–37.5 °C, twice a week, at intervals of at least 72 h, for 5 total sessions. Period of time: November 2013–August 2014 |
1. T1: n = 10, T3: n = 4 2. T0: n = 10, T1: n = 5, T2: n = 4, T3: n = 4. Colorectal cancer, hepatic metastasis |
1. Pain response according to IBMCG criteria: at 1 month: PR: n = 4 with SD. At 2 months: PR converted to CR: n = 1, PR: n = 2, SD: n = 1. At 3 months: no change in pain. Pain-PFS: at 3 months: 58.3% 2. Median VAS score: at T0: 4.0 (range: 0–10), at T1: 3.5 (range: 0–7), at T2: 3.0 (range: 0–7), at T3: 0 (range: 0–9) (T0: BL, T1: at 1 month, T2: at 2 months, T3: at 3 months) |
|
| Outcome Quality of life: | ||||
| Steinhart et al. [78] |
ECC-WBH (heated air blanket, Cincinnati Sub-Zero hyper-hypothermia machine) alone, 40 °C or 42 °C for 1 h. Period of time: ni |
n = 6. Kaposi’s sarcoma | 40 °C group: no change after WBH, 42 °C group: felt better after WBH | |
| Bruns et al. [61] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Responding up to 2 additional cycles. Period of time: April 1999–February 2001 |
n = 22. Pleural mesothelioma | Assessment QoL: + 1,41. Part of the modified Brunner-Score | |
| Bull et al. [71] |
WBH (Heckel HT-2000) + CTx, 40 °C for 6 h. Cycle repeated up to 7 times (range: 1–8). Period of time: January 2000–June 2004 |
n = 37. Mixed cancer diagnosis | Clear changes in responding patient | |
| Ariyafar et al. [87] |
EH (Celsius42 +) + RTx, 60 min, 2 h after RTx (10 fractions over 2 weeks). Temp.: ni. Period of time: December 2016–December 2017 |
n = 23. Bony metastases |
QLQ-C30: during T0 to T4: improvement in all functional scale and symptom scales, except for nausea and vomiting (p = 0.455), appetite loss (p = 0.764), diarrhoea (p = 0.092) and financial difficulties (p = 0.055) Compared to T0: physical (p = 0.002) and role (p = 0.001) functioning, fatigue (p < 0.001) and pain (p < 0.001) symptoms along with global health status (p < 0.001) improved significantly at T4. Emotional (p = 0.002) and social (p = 0.004) functioning scales improved within T2 and T3 For cognitive functioning (p = 0.016), dyspnea (p = 0.031), insomnia (p = 0.012) and constipation (p = 0.031): improvement observed at T2 (T0: at BL, T1: treatment complete, T2: 1 month-, T3: 2 months-, T4: 3 months- post-treatment) |
|
| Yu et al. [83] |
EH (Celsius42 +) + RTx, 60 min, Skin surface temp.: 36–37.5 °C, twice a week, at intervals of at least 72 h, for 5 total sessions. Period of time: November 2013–August 2014 |
T0: n = 10, T1: n = 5, T2: n = 4, T3: n = 4. Colorectal cancer, hepatic metastasis |
HRQoL (EORTC QLQ-C30 and FACT-Hep): no significant differences (T0–T3) (T0: BL, T1: at 1 month, T2: at 2 months, T3: at 3 months) |
|
| Yoo et al. [82] |
EH (Oncotherm, EHY2000 +), two sessions per week for 3 weeks, CTx before study. Temp: ni. Period of time: October 2008–March 2016 |
n = 7. Ovarian cancer |
Fact-O QOL survey: At T1: composite scores and subscale scores decreased in all 16 patients, but no significant change in scores At T2: physical well-being scores significant decreased in n = 7 (p = 0.044). Social, emotional and functional well-being scores not significantly changed (T0: at BL: n = 19, T1: after 3 cycles: n = 16, T2: after 6 cycles: n = 7) |
|
| Outcome: Haemodynamic parameters: | ||||
| Robins et al. [68] |
WBH (Enthermics) + CTx, total of WBH-treatments. at 41.0 °C for 85 min: n = 93, at 41.8 °C for 75 min: n = 105. Repetition due to escalation temperature scheme. Period of time: ni |
n = 23. Mixed cancer diagnosis | Episodes of hypotension (within first 6 h post-WBH (systolic blood pressure > 60–80): n = 7. Atypical BP response (> 160/110 mmHg): n = 1 | |
| Robins et al. [67] |
WBH (Enthermics) alone, 39.5–41.8 °C for 35–140 min, Number of treatments at each level: 3–7, Total of 52 treatments. Period of time: ni |
n = 8. Mixed cancer diagnosis | Increase in cardiac output and heart rate. Stroke volume remained relatively constant | |
| Robins et al. [70] |
WBH (Enthermics) + CTx, 41.8 ± 0.2 °C for 60 min WBH alone in week 1, WBH + CTx in week 2, CTx alone in week 5. Responding patients: WBH + CTx to maximum of further 5 cycles. Period of time: ni |
n = 30. Mixed cancer diagnosis | Asymptomatic hypotension post-WBH (systolic blood pressure: 80–90 mmHg): n = 2 | |
| Barlogie et al. [73] |
WBH (water blankets, Cincinnati Sub-Zero) alone or WBH + CTx, 42 °C for 4 h. Frequency: Ø 3x. Period of time: June 1977–April 1978 |
n = 12. Mixed cancer diagnosis | HR: increased significantly from average: 91/min to 131/min during heating (p = 0.001), rapid return to pre-treatment conditions within 12 h. SBP: no significantly change during WBH. DBP: dropped significantly, average of 73 mmHg prior to a mean of 60 mmHg during WBH (p < 0.01), rapid return to pre-treatment values within 12 h | |
| Bull et al. [88] | WBH (highflow, heated-water perfusion suit enclosed in insulated cover, Webb Associates) alone, 39.5–41.8 °C for 1–4 h. N = 4 repeated exposures at 2 to 3-week intervals at 41.8 °C for 4 h for 6–26 procedures. Period of time: ni | n = 14. Mixed cancer diagnosis |
1. HR (beats/min): T0: 88.0 ± 4.0, T1: 160.0 ± 9.0. MAP (mm Hg): T0: 89.0 ± 7.0, T1: 69.0 ± 4.0 (T0: BL, T1: at 41.8 °C, T2: 24 h after WBH procedure). Pulmonary capillary wedge pressure (mmHg) T0: 9.0 ± 1.0, T1: 5.0 ± 1.0. CaI (litre/min-m2): T0: 3.3 ± 0.2, T1: 7.2 ± 0.3. SBP: 70–90 mmHg for 30 min 3 h post-treatment: n = 5 2. Exposure at 41.8°: 2 h versus 1 h: cardiovascular variables: no difference |
|
| Gerad et al. [74] |
WBH (nylon and vinyl mesh water perfused suit (Whittaker General Medical), heating blankets) + CTx, 41.8–43.0 °C for 2 h, Total of 35 treatments, Period of time: ni |
n = 11. Soft tissue Sarcoma | Significant mean changes: HR and respiratory rate: rise, DBP: decline. Once temperature max. (Tmax) reached, only minor changes → cooling to 37 °C significant reduction of levels observed at Tmax. All parameters returned to near BL levels by 24 h | |
| Locker et al. [89] |
ECC-WBH (Rota-Flow) alone, 41.8 ± 0.2C° for 120 min. Number of cycles for each patient: range: 1–4. Period of time: ni |
n = 6. Soft tissue Sarcoma | HR, CaI, stroke volume index: significantly increased (p < 0.05). BP, pulmonary vascular RI: significantly decreased (p < 0.05). Fluid balance: 5822 ± 1766 mL per heating period. Low doses of norepinephrine required to maintain MAP > 60 mmHg, rapidly tapered reaching normothermia | |
| Wiedemann et al. [76] | ECC-WBH (Parks and Smith) + CTx, 41.8 °C for 1 h. Patients received 3 thermo-chemotherapy treatments every 3 weeks. Total of 49 treatments. Period of time: ni | n = 19. Sarcoma or malignant teratoma | HR and cardiac output: increased with rising core temperature, HR rose more than the stroke volume. Stable MAP achieved by fluid substitution and catecholamines | |
| Wiedemann et al. [77] | ECC-WBH (Parks and Smith) + CTx, 41.8 °C for 1 h. Period of time: ni | n = 12. Sarcoma | HR and cardiac output: increased with rising core temperature, HR rose more than the stroke volume. Stable MAP achieved by fluid substitution and catecholamines. MAP pre-treatment: 116.4 ± 10.7 mmHg, at 41.8 °C: 82.4 ± 8.6 mmHg | |
| Steinhart et al. [78] |
ECC-WBH (heated air blanket, Cincinnati Sub-Zero hyper-hypothermia machine) alone, 40 °C or 42 °C for 1 h. Period of time: ni |
n = 6. Kaposi’s sarcoma | MAP: decreased modestly at 40 °C group and decreased markedly at 42 °C group. CaI: increased modestly at 40 °C, rose 100% or more in 42 °C group. End-diastolic index increased during warming phase in both groups, during hyperthermia increased in response to fluid challenge more predictable than capillary wedge pressure | |
| Lee et al. [90] | EH (Oncotherm EHY2000) alone, 38.5 ± 0.8 °C for 60 min. Period of time: ni | n = 20. Cervical carcinoma |
1. S/D ratio (mean ± SD) with BC-p-values, comparison with BL: T0: 1.65 ± 0.20, T1: 1.40 ± 0.13, T2: 1.22 ± 0.09, T3: 1.40 ± 0.16. T1: p < 0.001, at T2: p < 0.001, at T3: p < 0.001 2. RI (mean ± SD) with BC-p-values, comparison with BL: T0: 0.40 ± 0.12, T1: 0.29 ± 0.11, T2: 0.19 ± 0.06, T3: 0.30 ± 0.10. T1: p < 0.01, T2: p < 0.001, T3: p < 0.05 (T0: 30 min before EH, T1: 30 min during EH, T2: 60 min during EH, T3: 30 min after EH) |
|
| Outcome: Haematological and serum chemistry profiles | ||||
| Katschinski et al. [63] |
WBH (Aquatherm) + CTx, 41.8 °C for 60 min. Total of 53 cycles. Period of time: ni |
n = 17. B-cell neoplasms | Comparison clinical parameters early versus late CTx-schedule: Late CTx-schedule significant (p < 0.05) clinical advantage. Delay in CTx secondary to thrombocytopenia and neutropenia: late schedule: 22 days versus early schedule: 95 days, (Chi2: 0.15 versus 1.3). Incidence of plated transfusions: late schedule: 5 transfusions versus early schedule: 40 transfusions (Chi2: 0.3 vs. 1.5). Unanticipated hospitalization secondary to thrombocytopenia: late schedule: 4 hospital days versus early schedule: 56 hospital days | |
| Robins et al. [67] |
WBH (Enthermics) alone, 39.5–41.8 °C for 35–140 min. Number of treatments at each level: 3–7. Total of 52 treatments. Period of time: ni |
n = 12. Mixed cancer diagnosis | Mean values post-therapy ( and normal range, within 1 SMD of pretreatment mean value. Liver status (LDH, AP, GOT): no changes: n = 7, transient elevation: n = 3, tumour lysis syndrome with increased LDH: n = 1, hepatic change (LDH levels with increase of 60%) and tumour lysis syndrome: n = 1. CPK: significant elevation after WBH: n = 1 with no clinical symptoms. WBC count: no trends as WBH dose escalated. WBC did not change post-WBH. Platelet count: no trends as WBH dose escalated. Fibrinogen levels, prothrombin time, partial thromboplastin time, fibrin split products: clinically normal range during and after treatment | |
| Robins et al. [68] |
WBH (Enthermics) + CTx, total of WBH-treatments. at 41.0 °C for 85 min: n = 93, at 41.8 °C for 75 min: n = 105. Repetition due to escalation temperature scheme. Period of time: ni |
n = 23. Mixed cancer diagnosis | Course of haematological and chemistry profiles (blood count, WBC, prothrombin- and partial thromboplastin time, liver function tests, electrolytes, , and CPK) pre-treatment, 24 h and 48 h post-WBH: only slight changes | |
| Robins et al. [69] |
WBH (Enthermics) + RTx, 41.8 °C for 75 min, total of 97 WBH-treatments. Period of time: November 1983–April 1987 |
n = 8. B-cell neoplasms |
24 h and 48 h post-WBH/RTx: creatinine, liver function, bilirubin, electrolytes, haematocrit, prothrombin- and partial thromboplastin time: no significant changes. No substantial immediate effects on WBC counts, platelet counts, or differential counts after the administration of WBH + RTx (T0: BL, T1: at peak temperature, T2: 24 h after treatment) |
|
| Robins et al. [70] |
WBH (Enthermics) + CTx, 41.8 ± 0.2 °C for 60 min WBH alone in week 1, WBH + CTx in week 2, CTx alone in week 5. Responding patients: WBH + CTx to maximum of further 5 cycles. Period of time: ni |
n = 30. Mixed cancer diagnosis | Difference WBC- and platelet nadirs: WBH + CTx versus CTx alone: not significant (WBC: p < 0.74, platelet: p < 0.75). Percent change in platelet count correlated well with AUC for ultra-filterable platinum (r = 0.86, p < 0.001). Total clearance of platinum correlated well with the creatinine clearance (r = 0.790, p < 0.001) | |
| Kraybill et al. [72] | WBH (Heckel, HT-2000) alone, group A: 39–39.5 °C for 3 h, group B: 39–39.5 °C for 6 h, group C: 39.5–40 °C for 6 h. Period of time: ni | n = 9. Mixed cancer diagnosis | WBH no impact on red cell mass or platelets. Patients heated for 6 h: increases in total numbers of WBC directly following WBH treatment. Increases in granulocytes and monocytes. Majority of patients: transient decreases in T-lymphocytes and L-selectin positive lymphocytes | |
| Barlogie et al. [73] |
WBH (water blankets, Cincinnati Sub-Zero) alone or WBH + CTx, 42 °C for 4 h. Frequency: Ø 3x. Period of time: June 1977–April 1978 |
n = 12. Mixed cancer diagnosis |
WBH-associated significant changes: (mean ± SD): platelets (× 103/litre): T0: 243 ± 65, T1: 224 ± 91, T2: 147 ± 75 → most patients recovered from thrombocytopenia within 1 week. Prolongation in prothrombin time (average of 4 s) and partial thromboplastin (average of 6 s) during initial 24 h after WBH. CPK (units/litre): T0: 50 ± 60, T1: 80 ± 92, T2: 399 ± 621 (excluding n = 1 with severe rhabdomyolysis, CPK: 40,000 units/litre). Subsequent courses associated with progressively smaller CPK elevations (p = 0.001). Glucose (mg/dl): T0: 109 ± 27, T1: 223 ± 98, T2: 160 ± 98 → normoglycaemia within 48 h after WBH. Significant alterations in electrolytes: hypocalcaemia: minimum average of 8.5 mEq/litre at T1, hypomagnesemia: 1.3 mEq/litre at T2, hypophosphatemia of 1.8 mEq/litre at T1 and hypokalemia with mean potassium concentration of 3.2 mEq/litre at T2. No significant elevations of GOT and LDH (T0: pre-treatment, T1: during WBH, T2: after 24 h) |
|
| Bull et al. [88] |
WBH (highflow, heated-water perfusion suit enclosed in insulated cover, Webb Associates) alone, 39.5–41.8 °C for 1–4 h. N = 4 repeated exposures at 2 to 3-week intervals at 41.8 °C for 4 h for 6–26 procedures. Period of time: ni |
n = 14. Mixed cancer diagnosis |
Serum-CPK: elevated at T2 in comparison with T0. Creatinine and creatinine clearance, sodium, potassium, chloride, bicarbonate, BUN, serum protein, albumin, bilirubin, LDH, AP: no significantly change during T0-T2. Serum phosphate: T0 median: 3.5 mg/dl (range: 2.3–4.0 mg/dl) at the end of treatment: 1.0 mg/dl (range: 0.6–1.5 mg/dl). Values returned to normal levels by 36 h. Magnesium: T0 median: 1.7 meq/litre at end of treatment: 1.3 meq/litre, returned to normal range by 24 h. Phosphate and magnesium changes: due to respiratory alkalosis. Transient elevation of GOT (T0: 27 U/litre. T2: 68 U/litre) and GPT (T0: 26 U/litre. T2: 97 U/litre): n = 5, in normal range within 6 days. Leucocyte count: median at T0: 7.8 × 103, at T1: elevated to median: 11.5 × 103 cells (range: 7.5–32.5). Granulocyte count median at T0: 6.5 × 103, at T1: elevated to: median 10.9 × 103 cells (range: 6.0–28.7). Lymphocyte count: insignificant fall from: median 1.2 × 103 cells to 0.9 × 103 cells (range: 0.3–1.4) →counts returned toward normal values at 24 h. Coagulation parameters: no significant alteration during T0–T2. No significant changes of haemoglobin level or platelet count (T0: BL, T1: at 41.8 °C, T2: 24 h after WBH procedure) |
|
| Gerad et al. [74] |
WBH (nylon and vinyl mesh water perfused suit (Whittaker General Medical), heating blankets) + CTx, 41.8–43.0 °C for 2 h. Total of 35 treatments. Period of time: ni |
n = 11. Soft tissue Sarcoma |
At 41.8 °C: significant (p < 0.05) shift in: sodium, chloride, bicarbonate, BUN, glucose, creatinine, total bilirubin, calcium, phosphorus and CPK compared to BL. Liver enzymes significant delayed change 24 h post-treatment (GOT, GPT, LDH: increase, AP: decrease) Follow-up: return to BL or normal range for all values. No significant change in prothrombin- and partial thromboplastin time, thrombin time, or fibrinogen levels. No evidence of disseminated intravascular coagulation Mean WBC nadirs: 1620 µl ± 305 (18 euthermic treatments) versus 1590 µl ± 235 (32 WBH treatments): no significantly difference. Platelet count nadirs (mean ± SD): at BL: 285.6 103/µl ± 21.4, 24 h after WBH: 177.9 103/µl ± 12.7: significant decrease (p = 0.0001). Fall in haemoglobin between 1 or 2 g/dl in all patients over first 48 h post-WBH due to dilution, blood sampling, and possibly heat. Leucocyte differentials: immediate leucocytosis resolved over 2–3 days |
|
| Locker et al. [89] |
ECC-WBH (Rota-Flow) alone, 41.8 ± 0.2 °C for 120 min. Number of cycles for each patient: range: 1–4. Period of time: ni |
n = 6, 12 treatments. Soft tissue sarcoma | Hypocalcemia: (grade 1): 8%, (grade 2): 42%. Hypophosphatemia: (grade 2): 25%, (grade 3): 50%. Hypomagnesemia: (grade 1): 33%. Hypopotassemia: (grade 1): 42%. Hypermagnesemia: (grade 1): 33%. Hyperchloremia: (grade 1): 8%. Hypernatremia: (grade 1): 8%. Hyperbilirubinemia: (grade 1): 33%, (grade 2): 17%, (grade 3): 25%. Hypoalbuminemia: (grade 1): 50%. Elevated lipase: (grade 1): 8%, (grade 2): 8%, (grade 3): 17%. AST elevation: (grade 1): 33%, (grade 2): 25%, (grade 3): 17%, (grade 4): 17%. ALT elevation: (grade 1): 33%, (grade 2): 8%, (grade 3): 25% (grade 4): 17%. GGT elevation: (grade 1): 17%, (grade 2): 8%. Elevated phosphatase: (grade 1): 17%. Amylase elevation: (grade 3): 33%. Hypoglycaemia: (grade 1): 8%. Hyperglycaemia: (grade 1): 8%. Creatinine elevation: (grade 1): 8%. CPK elevation: (grade 1): 33%, (grade 2): 25%, (grade 4): 8%. Troponin T elevation: (grade 2): 8%. Anaemia: (grade 1): 42%. Thrombocytopenia: (grade 1): 25% (grade 2): 17%, (grade 3): 33%, (grade 4): 25%. Thrombocytes significantly decreased with a nadir at 24 h after ECC-WBH (p < 0.05), but spontaneously resolved during the following days. Leucopenia: (grade 1): 25%, (grade 2): 8%. Neutropenia: (grade 1): 8%. Haemolysis: (grade 1): 33%. PTT prolongation: (grade 1): 25% | |
| Worel et al. [91] |
ECC-WBH (Rota-Flow) alone, 41.8 ± 0.2 °C for 120 min. Number of cycles for each patient: range: 1–4. Period of time: ni |
Included: n = 6, analysed: 12 treatments. Soft tissue sarcoma |
T1 versus T0: coagulation alterations most likely due to anticoagulation. (70 U/kg of UFH (unfractionated heparin)) →significant increase of aPTT (> 60 s). PT, fibrinogen, D-dimers, platelet counts and liver enzymes remained stable T2 versus T1: Effect of initially applied UFH declined (aPTT: 46.3 ± 2.9 s). Mild but significant signs of coagulation activation: increase of D-dimers. Thrombocytopenia (platelet counts: slightly but significant decrease, within normal range (173 ± 24 g/l)). Liver enzymes (AST, ALT, bilirubin): significant increase, but not clinically relevant T3 versus T2: D-dimer: significantly increased. Platelet counts: significantly decreased (58 ± 34 g/l, in 50% of treatments: platelets < 50 g/l). AST, ALT, bilirubin: significant increase (p < 0.05), AP remained within normal range T4 versus T2: PT, fibrinogen, and AT III (anti-thrombin III). Significantly increased (p < 0.05, exceeded BL values). D-Dimer decreased, but remained above normal range. AST and bilirubin: decreased to nearly normal values. ALT and AP: further increase. ALT remained above normal range. Platelet counts exceeded BL counts (T4: 287 ± 61 vs. BL: 195 ± 21 g/l. p < 0.05) (T0: BL, T1: after 30 min on normothermic ECC, T2: end of heating period, T3: 24 h after ECC-WBH, T4: 8 days after ECC-WBH) Changes in platelet counts and liver enzymes tended to correlate, but not significant. (AST vs. platelets R2 = 0.49) |
|
| Koga et al. [75] | ECC-WBH (Parks and Smith) + CTx, 41.5 °C for 3–5 h, 4 times at intervals of 7–10 days (some patients received treatment only once). Period of time: ni | n = 17. Gastro-intestinal cancer | Thrombocytopenia (7 × 1 /mm3): n = 13 (76.5%), between 1–3 days after ECC-WBH. Leucocytopenia (< 3 × 103/mm): n = 8 (47.1%), time to leucocyte count nadirs not uniform. Serum GOT, GPT, LDH and AP levels little elevated. Pretreatment serum total bilirubin level (0.9 ± 0.3 mg/dl) significantly elevated only on the third day after ECC-WBH (1.4 ± 0.5 mg/dl. p < 0.05), but declined to pretreatment level after the fifth day. Creatinine and urea nitrogen levels little affected and marked urine abnormalities not shown. Pre-treatment serum CPK level (32 ± 41 mU/ml) significantly elevated on first day after ECC-WBH (164 ± 143 mU/ml. p < 0.05), but decreased gradually | |
| Wiedemann et al. [76] |
ECC-WBH (Parks and Smith) + CTx, 41.8 °C for 1 h. Patients received 3 thermo-chemotherapy treatments every 3 weeks. Total of 49 treatments. Period of time: ni |
n = 19. Sarcoma or malignant teratoma | CTx without ECC-WBH: WBC nadir: 2.2 ± 0.37 k/ml (range: 1.6–3.9), platelet nadir: 67 ± 19 k/ml (range: 29–122). CTx with ECC-WBH: WBC nadir: 2.6 ± 0.41 k/ml (range: 1.7–4.9), platelet nadir 58 ± 17 k/ml (range: 27–130) →differences not statistically significant → bone marrow toxicity of given CTx not increased by WBH. Liver parameters (LDH, AP, AST): no change after WBH: n = 5. transient LDH elevation without rise of AP and AST: n = 11. LDH twice pretreatment value, returned to pre-WBH values 3 days after last thermo-chemotherapy: n = 1 | |
| Steinhart et al. [78] |
ECC-WBH (heated air blanket, Cincinnati Sub-Zero hyper-hypothermia machine) alone, 40 °C or 42 °C for 1 h. period of time: ni |
n = 6. Kaposi’s sarcoma | 40 °C group: no significant changes. 42 °C group: modest increase in CPK, GOT, GPT and bilirubin. Serum phosphate levels fell slightly at end of WBH. Platelet count fell and bicarbonate, prothrombin time and free haemoglobin increased in 42 °C group. None of changes associated with clinical symptoms and all normalized by end of follow-up period | |
| Yu et al. [83] |
EH (Celsius42 +) + RTx, 60 min, skin surface temp.: 36–37.5 °C, twice a week, at intervals of at least 72 h, for 5 total sessions. Period of time: November 2013–August 2014 |
at 1 month: n = 10, at 3 months: n = 4. Colorectal cancer, hepatic metastasis |
Haemoglobin, platelet, AST, ALT, albumin, total bilirubin, creatinine: of them significant changes at 1-, 2-, 3-month-follow up: platelets: (cells/μL) BL: 232 (range: 132–560), at 1 month: 121 (range: 40–227) (p = 0.008), at 3 months: 241 (range: 115–329). Creatinine (mg/dl): BL: 0.72 (range: 0.59–1.09), at 1 month: 0.65 (range: 0.46–0.97) (p = 0.002), at 3 months: 0.71 (range: 0.57–0.85) | |
| Outcome: Pharmacokinetics of CTx | ||||
| Robins et al. [68] |
WBH (Enthermics) + CTx, total of WBH-treatments. at 41.0 °C for 85 min: n = 93, at 41.8 °C for 75 min: n = 105. Repetition due to escalation temperature scheme. Period of time: ni |
n = 23. Mixed cancer diagnosis | Difference lonidamine-serum levels: before versus after WBH: No significant difference → WBH no significant effect on pharmacokinetics of lonidamine | |
| Robins et al. [70] |
WBH (Enthermics) + CTx, 41.8 ± 0.2 °C for 60 min |
n = 30. Mixed cancer diagnosis | Analysis of platinum in plasma ultrafiltrate and urine: WBH no significant effect on pharmacokinetics and renal excretion of platinum | |
| Wiedemann et al. [76] | ECC-WBH (Parks and Smith) + CTx, 41.8 °C for 1 h. Patients received 3 thermo-chemotherapy treatments every 3 weeks. Total of 49 treatments. Period of time: ni | n = 19. Sarcoma or malignant teratoma | Area under the curve of CTx: 37 °C versus 41.8 °C: significantly different (p < 0.001) →one-third reduction of 4-Hydroxyifosfamide (activated intermediate metabolite of Ifosfamide and Carboplatin), due to loss by haemodialysis. But increase of Chloroacetaldehyde (Ifosfamide metabolite) | |
| Outcome: Course of tumour marker | ||||
| Atmaca et al. [59] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Cycles repeated every 28 days up to a total of 6 cycles. Median: 2.7 (range: 1–6). Period of time: May 1997–December 2002 |
n = 30. Ovarian carcinoma | CA 125: response (serum CA 125 decrease > = 50% of BL): n = 18, biochemical progress: n = 7, no change: n = 5 | |
| Richel et al. [64] |
WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Total of 82 courses, median of 3 per patient (range: 1–6). Period of time: ni |
n = 9 (stable patients analysed). Cervical cancer | CA 125, SCC-Ag: Substantial marker decrease (> 50%): n = 5, increase (> 50%): n = 1 | |
| Outcome: modified Brunner-Score: (integrates: PFS, change of physical performance, quality of life self-assessment, toxicity) | ||||
| Bruns et al. [61] | WBH (Aquatherm) + CTx, 41.8 °C for 1 h. Responding up to 2 additional cycles. Period of time: April 1999–February 2001 | n = 22. Pleural mesothelioma | MBS for overall study group: 4.21 points (range: − 4.43–16.45), 16 of 22 patient achieved positive score. Subgroups of MBS: improvement of performance index: + 0.29, QoL: + 1.41 | |
| Outcome: Body weight | ||||
| Steinhart et al. [78] | ECC-WBH (heated air blanket, Cincinnati Sub-Zero hyper-hypothermia machine) alone, 40 °C or 42 °C for 1 h. Period of time: ni | n = 6. Kaposi’s sarcoma | 40 °C group: no change, 42 °C group: gained weight | |
| Bull et al. [71] | WBH (Heckel HT-2000) + CTx, 40 °C for 6 h. Cycle repeated up to 7 times (range: 1–8). Period of time: January 2000-–June 2004 | n = 37. Mixed cancer diagnosis | n = 29 reported weight loss of 5–35 pounds prior to treatment. 14 of the 16 responding patients with weight loss regained weight (range: 45–100%, median: 76%) | |
| Outcome: Heat dose tolerance | ||||
| Bull et al. [88] |
WBH (highflow, heated-water perfusion suit enclosed in insulated cover, Webb Associates) alone, 39.5–41.8 °C for 1–4 h. 4 repeated exposures at 2 to 3-week intervals at 41.8 °C for 4 h for 6–26 procedures. Period of time: ni |
n = 14. Mixed cancer diagnosis |
1. Heat escalation over weeks versus initial heat exposure over 1 h at 41.8 °C: no difference in tolerance 2. Exposure at 41.8 °C: 2 h versus 1 h: increased fatigue treated 2 h |
|
| Robins et al. [67] |
WBH (Enthermics) alone, 39.5–41.8 °C for 35–140 min, number of treatments at each level: 3–7. Total of 52 treatments. Period of time: ni |
n = 12. Mixed cancer diagnosis |
At core temperature (41.8 °C): average maximum skin temperature: 42.66 ± 0.58 °C Temperatures in bladder: close to rectal temperatures but differed from concurrent esophageal temperatures. Axillary profiles of 3 patients treated at 41.8 °C: temperature of 41.8 °C in pulmonary artery achieved → patient covered with blankets and a vapour barrier and removed from apparatus → rectal temperature of 41.8 °C achieved about 10 min later, after plateau phase → coverings removed: pulmonary artery temperature decreased immediately, drop in blood temperature precedes fall in rectal temperature |
|
| Lee et al. [90] | EH (Oncotherm EHY2000) alone, 38.5 ± 0.8 °C for 60 min. Period of time: ni | n = 20. Cervical carcinoma |
Peri-tumour temperature (mean ± SD) with BC-p-values, comparison with BL: T0: 36.7 ± 0.2 °C, T1: 37.5 ± 0.5 °C, T2: 38.5 ± 0.8 °C, T3: 37.1 ± 0.3 °C. T1: p < 0.001, T2: p < 0.001, T3: p < 0.05 (T0: 30 min before EH, T1: 30 min during EH, T2: 60 min during EH, T3: 30 min after EH) |
|
| Outcome: Fatigue | ||||
| Bull et al. [71] |
WBH (Heckel HT-2000) + CTx, 40 °C for 6 h. Cycle repeated up to 7 times (range: 1–8). Period of time: January 2000–June 2004 |
n = 37. Mixed cancer diagnosis | N = 34 reported grade 1–2 fatigue, with n = 1 reporting grade 3 fatigue prior to treatment. All 16 patients with objective tumour response reported increased energy, improved sense of well-being and 15 resumed normal activities, including n = 7 resuming former employment | |
| Outcome: Respiratory parameters | ||||
| Robins et al. [67] |
WBH (Enthermics) alone, 39.5–41.8 °C for 35–140 min. Number of treatments at each level: 3–7. Total of 52 treatments. Period of time: ni |
n = 12. Mixed cancer diagnosis | pH: BL: mean pH value: 7.42 ± 0.02, treated at 39.5–40.5 °C: mean 7.38 ± 0.05, treated at 41.5–41.8 °C mean: 7.38 ± 0.06. Arterial CO2-tension: normal during WBH. Serum lactate at plateau: 2.53 ± 0.08 mmol/l. At core temperature: rise in oxygen consumption. Arterial and venous oxygen saturation: normal, even in patients not receiving nasal oxygen | |
| Barlogie et al. [73] |
WBH (water blankets, Cincinnati Sub-Zero) alone or WBH + CTx, 42 °C for 4 h. Frequency: Ø 3x. Period of time: June 1977–April 1978 |
n = 12. Mixed cancer diagnosis | No significant changes in pH and base deficit (pre-treatment to 24 h after treatment) | |
| Bull et al. [88] | WBH (highflow, heated-water perfusion suit enclosed in insulated cover, Webb Associates) alone, 39.5–41.8 °C for 1–4 h. N = 4 repeated exposures at 2 to 3-week intervals at 41.8 °C for 4 h for 6–26 procedures. Period of time: ni | n = 14. Mixed cancer diagnosis | Thermally induced hyperventilation → respiratory alkalosis with median arterial pH: 7.5 ± 0.05 and arterial PaCO2: range 18–20 mmHg. Respiratory rate: increased from median of 11 ± 3 to 38 ± 5 at 41.8 °C. Arterial oxygen saturation remained unchanged throughout treatment | |
| Locker et al. [89] |
ECC-WBH (Rota-Flow) alone, 41.8 ± 0.2 °C for 120 min. Number of cycles for each patient: range: 1–4. Period of time: ni |
n = 6. Soft tissue sarcoma |
Oxygen delivery and consumption: significantly increased during ECC-WBH (p < 0.03). Respiratory rate: initially dropped, but then significantly increased during heating (p < 0.05), remained elevated during heating period. Arterial pH: significant changes over time (increase), but within normal range. PaCO2: moderate increase on normothermic ECC, significantly decrease during plateau phase (p < 0.05). Standard bicarbonate and base excess: continuously decreased (p < 0.05) until end of WBH. Lactate level: significant elevation up to .6 mmol· (p < 0.05) | |
y OS 1 year-overall-survival; 2y OS 2 year-overall-survival. ALT alanine transaminase. Anal. Analysed; AP alkaline phosphatase; APr arterial pressure; aPTT activated partial thromboplastin time; ARDS acute respiratory distress syndrome; AST aspartate aminotransferase; AUC area under the curve; AV atrioventricular; BC Bonferroni-corrected; BL baseline; BP blood pressure; BUN blood urea nitrogen; CaI cardiac Index; CI confidence-interval; CPK creatine phosphokinase; CR: complete response CTCAE common terminology criteria for adverse events version; CTx chemotherapy; DBP diastolic blood pressure; DCR disease control rate; DIC disseminated intravascular coagulation; ECC-WBH extracorporeal-circulation-WBH; ECOGEastern Cooperative Oncology Group. EEG electroencephalogram. EORTC European Organization for Research and Treatment of cancer; EH electro hyperthermia; FACT-Hep Functional Assessment of Cancer Therapy-hepatobiliary; GFR glomerular filtration rate; GGT gamma-glutamyl transferase; GOT glutamic oxaloacetic transaminase; GPT glutamic pyruvic transaminase; h hours; HR heart rate; HRQoL health-related quality of life; IBMCG International Bone Metastases Consensus Group (IBMCG); Iv Intra-venous; Incl included; KS Kaposi’s sarcoma; LDH lactic dehydrogenase; MAP mean-arterial blood pressure; MBS modified Brunner Score; MCP Metoclopramid; min minutes; MR minor response; MTD maximum tolerated dose; n number of patients; NC no change; NCICTC National Cancer Institute Common Toxicity Criteria; ni no information; ORR objective response rate; OS overall survival; PD progressive disease; PFS progression free survival; PR partial response; PTT partial thromboplastin time; QLQ-C30 European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; QoL quality of Life; RI resistance index; RR response rate; RTx radiotherapy; S/D ratio peak systolic velocity/end-diastolic velocity ratio; SBP systolic blood pressure; Scc-Ag squamous cell carcinoma antigen; SCR serologic complete response; SD stable disease; SIRS systemic inflammatory response syndrome; SMD standardized mean deviation; ST survival time; Tmax maximum temperature; TTF time to treatment failure; TTP time to progression; UFH unfractionated heparin; VAS visual analogue scale; vs versus; WBC white blood cell count; WBH whole-body hyperthermia