FIGURE 1 Prisma flow diagram. HT = hyperthermia; SR = systematic review.
Ellen Conte,1,2 Athanasios Psihogios,1,2 and Dugald Seely1,2
ABSTRACT
Introduction: Hyperthermia (HT) in cancer management refers to the external application of heat to raise intratumoural temperature to between 39°C and 45°C. Locoregional hyperthermia (LRHT) is the most used and studied type of HT in cancer care. A literature search was conducted to produce a monograph to help clinicians and patients make informed choices in considering the application of this therapy.
Methods: A search was performed in Medline and Cochrane library for LRHT and cancer in May 2020. Eligible studies were English-language clinical studies reporting on efficacy, quality of life (QoL), safety, or feasibility. Additional cursory literature scoping was performed to identify missing papers and background information. Papers were independently screened by two reviewers. Following development of a full monograph, a condensed version suitable for publication was created and is presented here.
Results: A total of 980 articles were identified and 166 met inclusion criteria. Most were single-arm or observational. However, among the 166, there were 7 systematic reviews (including 37 RCTs) and 18 additional RCTs identified. Several mechanisms of action have been proposed for HT in cancer care including physiological changes, direct cytotoxic effects, chemosensitization and radiosensitization, and immune modulation. Locoregional HT is used primarily as an adjunct to chemotherapy and radiotherapy due to its possible synergistic effects. Various studies demonstrated improved outcomes for patients treated with LRHT and chemo-and/or-radiotherapy. The best evidence for improved disease control and survival is seen for breast cancer (locally recurrent), cervical cancer, esophageal and gastric cancers, head and neck squamous cell carcinoma, and high-risk soft tissue sarcoma. Research related to quality of life (QoL) is limited and often focuses on pain. Hyperthermia with modern technology and treatment planning is generally well tolerated; the most common side effects are discomfort, mild pain, local erythema, skin burns, and, less commonly, subcutaneous burns. Trial heterogeneity and methodological concerns limit the strength of conclusions.
Conclusions: Locoregional HT is a promising adjunct treatment to chemotherapy and radiotherapy for a variety of cancer types. To determine in what situations this therapy could be best applied, more high-quality well-controlled studies are needed.
Key Words Locoregional Hyperthermia, Oncothermia, Oncology, Integrative Oncology, Naturopathic Oncology
Hyperthermia (HT) for cancer involves heating cells and tissue to temperatures above the normally maintained range via exogenous means to selectively affect tumours. It is usually used in combination with conventional care.1 Several types of HT exist: local (LHT), regional (RHT), interstitial and endocavitary, whole-body, hyperthermic isolated limb perfusion,2 hyperthermic intraperitoneal chemotherapy (HIPEC), and hyperthermic intravesical chemotherapy (HIVEC).3 Local and regional hyperthermia (locoregional hyperthermia; LRHT) is available in a few Canadian naturopathic practices. Local HT increases the temperature of superficial tumours using applicators or antennae over skin with a contact medium.3 In RHT, deep tumours and body regions are heated by arrays of antennas; often arranged in a ring around the patient.2 The applicators typically emit microwaves or radio waves to heat the tumour.2 Locoregional HT aims to increase intratumoural temperature to 39–45°C, although 41–43°C is considered optimal.4,5
Despite many LRHT studies for cancer care, no comprehensive resource outlining clinical evidence exists. Therefore, a detailed and structured literature search was performed to evaluate the clinical efficacy of LRHT in cancer care, from which a comprehensive monograph was developed, and its adapted condensed review presented here.
Medline and Cochrane Library were searched in May 2020 without date restrictions. Search terms included the neoplasm medical subject headings (MeSH) terms, and terms related to LRHT, including: local hyperthermia, locoregional hyperthermia, regional hyperthermia, modulated electrohyperthermia, external hyperthermia, part-body hyperthermia, and oncothermia. Scoping and reference reviews were performed to identify additional papers. Titles and abstracts were screened in duplicate, followed by single-review of full-text publications (Figure 1).
FIGURE 1 Prisma flow diagram. HT = hyperthermia; SR = systematic review.
Inclusion criteria included English-language studies of human populations with cancer receiving external LRHT. Studies could investigate outcomes related to clinical effectiveness (e.g., survival, recurrence, response), quality of life (QoL), safety, adverse events (AEs) and feasibility. Eligible study designs included systematic reviews and meta-analyses, clinical trials, and observational studies. Exclusion criteria included preclinical trials, narrative reviews, case studies, other types of HT, and/or technical studies on HT instrumentation. Studies accounted for in systematic reviews or meta-analyses were excluded to not be described twice.
This literature review is a condensed version derived from the full monograph for LRHT and cancer care. The cancers with the most available evidence are the focus of this condensed literature review. Studies of patients with mixed cancer types were omitted due to space limitations and heterogeneous participant samples, designs, and quality. Complete details can be found in the full monograph by contacting the corresponding author.
A total of 1,000 articles were identified. Scoping and reference review identified an additional 25 papers. After deduplication, 980 articles were screened, and 166 were included in the monograph (Figure 1). This condensed literature review, which does not discuss mixed cancer types, includes 126 papers.
Cancer types with the most rigorous research are described henceforth in detail. Systematic reviews and meta-analyses are described in Table 1, and randomized controlled trials (RCTs) in Table 2. Full discussion of all data identified in the original literature search can be found in the healthcare provider monograph; please contact the corresponding author for more information and access details.
TABLE 1 Systematic reviews and meta-analyses of locoregional hyperthermia (LRHT) for cancer
TABLE 2 Randomized controlled trials of locoregional hyperthermia (LRHT) for cancer
One meta-analysis (31 articles reporting on 34 studies)11 and two single-arm trials31,32 were identified. The meta-analysis included five RCTs, three non-randomized controlled trials, and 26 single-arm trials, all of which investigated LRHT combined with radiation (RT) for locally recurrent breast cancer.11 Based on controlled trials (both randomized and non-randomized) from the meta-analysis, the complete response (CR) rate was 60.2% in the combination group and 38.1% in the control group (odds ratio [OR]: 2.64; 95% confidence interval [CI]: 1.66–4.18, p < 0.0001). Based on single-arm trials, the CR rate was 63.4%. Mean acute and late grade III/IV toxicities were higher in the hyperthermia group compared with the control (14.4% vs 5.2%). As publication dates spanned 34 years, no uniform toxicity scoring criteria or review could be presented.
Two single-arm studies not included in the meta-analysis were identified.31,32 The first reported jointly on two phase I studies including 29 patients with chest-wall recurrences, all of whom had received prior standard treatments.31 Locoregional HT delivered within 30 to 60 minutes of doxorubicin resulted in a response rate of 48.3%, with 17.2% having CR. All adverse events (AEs) were reported as chemotherapy-related. The second single-arm trial (n = 7) applied chemotherapy and LRHT simultaneously for patients with recurrent, inoperable breast cancer who had received prior conventional care.32 All participants experienced an objective response (OBJR), with four CR and three partial responses (PR). Median time to recurrence was six months.
Two systematic reviews with meta-analysis7,8 (reporting on seven RCTs), five publications on three RCTs,19,20,28,29,33 and six single-arm trials were included.34–39
The latest systematic review, which performed two separate analyses (conventional and network meta-analysis) of LRHT for patients with locally advanced cervical cancer, was published in 2016.7 In the conventional meta-analysis conducted (6 RCTs, n = 427), HT with radiotherapy (HTRT) was found to outperform RT for CR (OR 2.67, 95% CI 1.57–4.54, p < 0.001) and long-term locoregional control (OR 2.61, 95% CI: 1.55–4.39, p < 0.001). Overall survival (OS) was superior in the HTRT group compared with RT (OR 1.94, 95% CI 1.10–3.40, p = 0.021). However, risk difference was not significant (8.4% difference, p = 0.299). In the network meta-analysis conducted (7 RCTs, n = 1,160), HT combined with chemotherapy and radiation (HTCTRT) was superior to chemotherapy combined with radiation (CRT) (OR 2.91, 95% CI 1.97–4.31), and RT (OR 4.52, 95% CI 1.93–11.78) for CR. The OS in the HTCTRT group was superior to chemoradiotherapy (CRT) (OR 2.65, 95% CI 1.51–4.87) and RT (OR 5.57, 95% CI 1.22–23.42). A 2010 Cochrane review found similar results.8
Three controlled trials yielded five publications since the last systematic review.19,20,28,29,33 One multicentre RCT (n = 101) that included treatment-naive patients with locally advanced cervical cancer reported that the addition of LRHT to CRT did not improve overall five-year survival (adjusted hazard ratio [HR]: 0.485, 95% CI: 0.217–1.082, p = 0.077), disease-free survival (DFS) (adjusted HR: 0.517, 95% CI: 0.251–1.065, p = 0.073), local relapse-free survival (LRFS) (p > 0.05) or CR (p > 0.05) compared with CRT alone.20
Three papers published data from an ongoing phase III RCT investigating modulated electro-hyperthermia (mEHT) with CRT, compared with CRT alone, for patients with stage IIB–IIIB cervical cancer.19,28,29 Patients from a low-resource African setting were treated with mEHT twice weekly before RT in addition to cisplatin-chemotherapy. The first publication reported early results.19 At six months, the local disease control and local DFS were superior in the mEHT group than in the control (45.5% vs 24.1%, p = 0.003; 38.6% vs 19.8%, p = 0.003, respectively). The second publication found no significant difference in treatment toxicity between study arms, and AEs attributed to mEHT were minor.29 There was some evidence of QoL improvement, specifically for cognitive function, post-treatment fatigue, and social and emotional functioning in the HT arm. The third publication evaluated the abscopal effect in a subgroup of patients with involved lymph nodes outside of the treatment field.28 Participants in the LRHT arm experienced significantly higher complete metabolic response (abscopal effect marker) than the control (24.1% vs 5.6%, p = 0.013).
Lastly, a controlled clinical trial in patients with recurrent, previously irradiated cervical cancer administered platinum-based chemotherapy with (n = 18) or without (n = 20) mEHT.33 Objective response rates were superior in the mEHT group than in the control (p = 0.046). However, there was no significant OS difference.
Six phase I and II studies were identified.34–39 Four phase I/II studies evaluated LRHT administered with cisplatin in patients with pelvic recurrences.34,36,38,39 The first study found that LRHT alongside six-weekly cisplatin treatments in 19 patients produced an overall response rate of 53% with no dose-limiting toxicities.34 An additional 28 people were enrolled and the full dataset of 47 people was published separately.38 The OBJR rate from that publication was 58%, with a median OS of eight months. In patients with pain, 74% achieved palliation. A phase II study administered LRHT simultaneously with cisplatin in 23 patients.36 The response rate was 52%, median duration of response 9.5 months, mean OS 8 months, and one-year survival 42%. Another phase I/II study in patients with treatment-naive stage IIB–IVA cervical cancer published early39 and late results.37 Sixty-eight people were treated with RT, weekly cisplatin, and four weekly-whole pelvis LRHT treatments. Complete response was observed in 90% of patients. Two-year DFS and OS were 71.6% and 78.5%, respectively, and five-year DFS and OS were 57.5% and 66.1%, respectively. Lastly, a phase II study administered LRHT to 18 patients with advanced cervical cancer receiving 28-fractions of RT.35 Thirteen patients had a CR, four patients a partial response, and there was a local control rate of 48% at two years.
One meta-analysis (19 RCTs),6 two single-arm trials,40,41 and one observational trial42 were identified. The meta-analysis (n = 1,519) published in 2017 compared HTCTRT with CRT and RT.6 Compared with CRT, HTCTRT significantly improved one-year survival (OR 1.79, 95% CI 1.12–2.84, p = 0.01), three-, five-, and seven-year survival, but not two-year survival. In terms of response rate, HTCTRT significantly improved the rate compared with CRT alone (OR 2.00, 95% CI 1.49–2.69, p < 0.00001) but did not significantly alter recurrence or distant metastasis rates. HTCTRT decreased several adverse effects of CRT, including gastrointestinal reactions, leukocytopenia, and esophagitis. When comparing HTCTRT with RT, HTCTRT significantly improved one-year survival (OR 3.2, 95% CI 2.07–4.95, p < 0.00001) and survival at two, three, and five years. Quality of the individual RCTs was generally low.
Two single-arm studies40,41 and one observational study42 were also reviewed. The phase I/II study evaluated feasibility and toxicity of combined chemotherapy and LRHT for patients with esophageal cancer.41 Locoregional HT administered on day 1 of neoadjuvant chemotherapy was feasible with acceptable toxicity. Another phase II study enrolled 28 people with resectable esophageal cancer and applied neoadjuvant CRT with LRHT.40 The response rate was 74%, with 19% having a CR. After a median follow-up of 37 months, locoregional disease control was 100%, one-year, two-year, and three-year survival were 79%, 57%, and 54%, respectively. Lastly, one retrospective observational study evaluated combined radiotherapy and LRHT with or without cisplatin to patients with supraclavicular lymph node metastasis.42 The three-year progression-free survival (PFS) and OS were 34.9% and 42.5%, respectively.
Two RCTs,16,23 one single-arm study,43 and two observational studies44,45 were identified.
A phase II RCT (n = 118) enrolled patients with advanced gastric cancer who received chemotherapy with or without LRHT twice per week.16 For the HCT group compared with the chemotherapy group, the disease control rate (CR/PR/Stable Disease) was 70.9% vs 46.0% (p = 0.006), mean OS was 23.5 months vs 14 months (p = 0.01), and the three-year survival rate was 11.4% vs 0% (p = 0.018). There were no group differences in grade III/IV AEs.
Another large (n = 293) three-armed RCT randomized patients with newly diagnosed non-metastatic gastric cancer to surgery alone, preoperative RT, or preoperative HTRT.23 Compared with surgery alone, HTRT significantly improved three-year survival (57.6% ± 6.3 vs 35.5% ± 4.9, p < 0.05) and five-year survival (51.4% ± 6.6 vs 30.1 % ± 4.7, p < 0.05). Radiotherapy alone did not significantly improve survival compared with surgery alone. There was no significant difference between survival for the RT group and the HTRT group, indicating no advantage of adding HT.23
The small single-arm study evaluated LRHT in 25 patients with unresectable, recurrent gastric cancer.43 Amongst nine patients who had peritoneal carcinomatosis treated with LRHT, the survival outcomes were superior to a historical comparator (12.8±8.6 months vs 6.4±5.0 months, p < 0.01), but poor design and reporting limit generalizability.
One of the observational studies (retrospective) administered regional abdominal LRHT during intraperitoneal cisplatin for patients with stage IIA–IIIC surgically resected gastric cancer who were also receiving IV 5FU and leucovorin.44 After 58 months, 68.2% recurred and 45.5% had died. Lastly, the other retrospective study evaluated a multimodal intervention of chemotherapy, ketogenic diet, insulin induced hypoglycemia, hyperbaric oxygen therapy (HBOT), and mEHS in patients (n = 25) with stage III/IV gastric cancer.45 The treatment was administered in a three-week cycle of chemotherapy with HT and HBOT given sequentially for 60 minutes each on the day of, or day after, chemotherapy. The CR rate was 88%, mean OS 39.5 months (95% CI 28.1–51.0), and mean PFS was 36.5 months (95% CI: 25.7–47.2). There were no AEs attributed to the ketogenic diet, mEHT, or HBOT.
One systematic review and meta-analysis10 (six controlled trials), one non-randomized controlled trial,46 five single-arm clinical trials,47–51 and three observational studies52–54 were identified. The 2016 systematic review and meta-analysis of LRHT with RT for primarily locally-advanced head and neck cancer (HNC) reviewed six studies (five RCTs).10 One study used intracavitary HT, which is outside the scope of this review. However, it does not appear that the findings would significantly skew the results. The CR rate of RT alone was 39.6% compared with 62.5% with HTRT (OR 2.92, 95% CI 1.58–5.42, p = 0.001). The risk difference was 0.25 (95% CI 0.12–0.39, p < 0.0001). Funnel plots indicated no publication bias. However, there were a small number of studies included. Rates of grade III/IV toxicities were similar between groups.
Two single-arm studies evaluated LRHT with RT for HNC. One of the phase I/II studies delivered LRHT and RT to 27 patients with cervical lymph node metastasis.47 The response rate was 92%, and the five-year nodal control and survival were 64.5% ± 19%, and 24% ± 10%, respectively. The other phase I/II single-arm trial48 included 13 participants with parotid cancer and administered HTRT. Complete response was observed in 16/20 lesions and PR in the remaining four.
Three single-arm trials and one observational study evaluated combined LRHT and CRT.49,50,52,55 All three trials administered radiation five times per week with weekly chemotherapy and twice weekly LRHT. In one study, 53 patients with HNC with N2 or N3 metastatic cervical lymph nodes were treated.49 The local CR rate was 82% and the PR rate 9%; the nodal CR rate was 85% and the PR rate 9%. At two years, the OS and DFS were 51% ± 9% and 54% ± 8%. Treatment toxicity was deemed acceptable. In the second study, 20 patients with previously treated recurrent metastatic cervical LNs were included.50 Symptom palliation (pain, bleeding, difficulty breathing, difficulty swallowing, difficulty speaking) occurred in 19/20 patients. Response rates included 8/20 with a CR and 11/21 with a PR. The one-year OS was 39% ± 11%, with three patients alive at three years. Adverse events were generally grade 1 to 2 hematological and skin toxicity. A retrospective analysis of 40 patients with advanced HNC given seven weeks of radiation and once weekly LRHT and chemotherapy reported CR and PR rates of 76.23% and 23.68%, respectively, and one-year and two-year OS of 75.69% and 63.08%, respectively.52
Three small studies evaluated LRHT with chemotherapy.46,51,54 A non-randomized controlled trial administered chemotherapy alone or with LRHT for patients with nodal-metastatic HNC.46 The overall tumour response rate was 36% in the control group, compared with 100% in the intervention group (no statistics presented). In another study (pilot), eight patients with advanced or recurrent disease were treated with carboplatin plus LRHT once every four weeks for 1 to 3 rounds.51 There was one CR and two PRs. Six patients died within 4 to 13 months, with two long-term survivors. The last study (n = 31) included patients with local squamous cell carcinoma (SCC) of the lip treated with twice weekly IV bleomycin and methotrexate, followed by HT for 4.5 to 7.5 weeks, reporting a CR and PR rate of 93.55% and 6.45%, respectively.54 Among those experiencing CR, during a five-year follow-up there was one local recurrence and one death. Authors noted good cosmetic results.
Lastly, a small retrospective analysis evaluated LRHT with radiation and cetuximab.53 Six patients with locally advanced SCC were treated with radiation for six to seven weeks, with once weekly cetuximab and LRHT. All patients experienced a CR; side effects included mucositis and acneiform rash.
One RCT (yielding three publications),13–15 five observational studies56–60, and seven single-arm trials61–67 were identified. Additionally, one single-arm trial68 included deep seated sarcomas, and one observational study mixed soft tissue tumours.69
The RCT (multicentre), which included patients with localized, high-risk soft-tissue sarcoma (STS), found the addition of regional HT enhanced the effect of chemotherapy.13 Participants (n = 341) were randomized to receive four three-week cycles of chemotherapy with or without HT (days 1 and 4). Following surgery and/or radiation, patients received another four cycles of their allocated treatment. The first publication from this trial reported that after a 34-month median follow-up, the HT arm had superior PFS (HR 0.58, 95% CI 0.41–0.83, p = 0.003) and an absolute difference in PFS of 15% at two years (CI 6%–26%). Disease-free survival (HR 0.70, 95% CI 0.54–0.92), treatment response rate (28.8% vs 12.7%, p = 0.002), and OS (HR 0.66, 95% CI 0.45–0.98) were also improved in the regional HT arm compared with the control arm. Grade III/IV leukopenia was greater in the regional HT arm (77.6%, vs 63%, p = 0.005). Hyperthermia-related AEs included pain, bolus pressure, and skin burn. In 2018, a long-term analysis of the same study was published.15 After a median follow-up of 11.3 years, the RHT arm experienced a significantly improved local PFS (HR: 0.65; CI: 0.49–0.86, p = 0.002). Combination treatment resulted in significantly prolonged survival rates compared with the control (HR: 0.73, 95% CI: 0.54–0.98, p = 0.04). This trial produced one additional publication with a sub-group analysis of patients with abdominal or retroperitoneal high-risk STS.14 The regional HT plus chemotherapy arm had improved five-year PFS (56% vs 45%, p = 0.044) and DFS (34% vs 27%, p = 0.040), but no difference in OS (57% vs 55%, p = 0.82).
Three controlled observational studies were identified; one used a Bone and Soft Tissue Tumor (BSTT) registry for comparison purposes,56 and the others compared results with RT or CRT alone.59,60 The BSTT registry comparison study reported that patients who received LRHT during chemotherapy (post-radiotherapy) did not experience a significant five-year OS benefit (78.3% vs 81.2%, p = 0.33). In the LRHT arm, the local-control rate at five years was significantly better (97.7% vs 85.1%, p = 0.017), and negative surgical margins were significantly higher (p < 0.0001). The other two controlled studies59,60 both reported no significant benefit from LRHT, including local control (p = 0.39), DFS (p = 0.69), and response (p = 0.67). One of them59 reported that cancer-specific mortality was significantly better compared with the control (p = 0.03), while the other60 showed no significant benefit for two-year OS, local-control survival, or distant metastasis-free survival.
Two uncontrolled observational studies were identified. One included 64 participants with recurrent or residual STS who received LRHT with CRT.57 Five-year survival was 86.4% (± 7.3%) and the local control rate was 86.7% (± 7.1%). The other study included 110 participants with locally advanced high-risk STS receiving combined chemotherapy and LRHT.58 Disease control occurred in 59% of non-metastatic cases and 47% in those with metastases, with a median OS of 26 and 12 months, respectively.
Seven single-arm trials evaluated LRHT in combination with various treatments. Two of them applied LRHT with chemotherapy alone, with one61 delivering LRHT in patients with high-grade STS on days 1 and 4 of neoadjuvant chemotherapy. After four cycles, mean tumour volume reduction was 49% (5% to 91%, SD: 27%). The other trial included patients with doxorubicin/ifosfamide-refractory STS receiving chemotherapy, seven of whom received LRHT.62 Two of the seven patients experienced a PR.
Five single-arm trials explored LRHT specifically added to standard peri-operative care.63–67 In one, 13 patients received LRHT and radiation, with five participants receiving pre-operative chemotherapy and seven post-operative chemotherapy.65 Limb salvation was possible for 12 of 13 patients; there was no local recurrence; the five-year survival was 40.4%, and DFS was 30.1%. Mean tumour volume reduction was 68.2%, with no participants experiencing CR, seven PR, three no change, and three progressing. Another study (n = 58) explored the use of combined LRHT with chemotherapy in both the neoadjuvant and post-treatment phase.66 The overall OBJR rate (based on 40 evaluable patients) was 13%. Radiological response was 33%, and of the 30 who underwent treatment, six experienced pathological CR (23%). Median time to local relapse or progression was 21 months, with a median five-year OS of 31 months. One publication combined data from two phase II trials, exploring the use of neoadjuvant CRT and LRHT, surgery, and adjuvant CRT (without LRHT).64 The OBJR rate (evaluable in 39 participants) was 21% with a median OS of 105 months. Five-year OS was 57%, with a five-year local recurrence-free survival of 48%. A similar single-arm phase II trial applied LRHT pre-operatively alongside chemotherapy, followed by post-operative radiation when indicated. Responders received additional chemotherapy and LRHT after surgery. The OBJR rate was 17%, median survival was 52 months, and five-year OS was 49%. The combination of pre-operative chemotherapy and LRHT, with radiation applied post-operatively, was further explored in another single-arm trial (n = 59).63 The OBJR rate was 17%, with one CR and eight PR. Out of the total group, 49 were eligible for surgery. The overall five-year rate of local relapse-free survival was 40% and the median survival was 52 months, with a five-year OS of 49%. One final study delivered LRHT in combination with neoadjuvant chemotherapy for patients with poorly resected, non-metastatic, STS.67 The overall OBJR rate was 16%, of which all were partial. Median time to local relapse or progression was 21 months, median OS was 33 months, and the four-year OS rate was 40%.
Two studies included patients with malignancies other than STS. One single-arm trial included a mix of different deep-seated, advanced sarcomas.68 In addition to standard supportive care, participants received LRHT with chemotherapy. Based on 61 evaluable participants, overall OBJR was 34%, and 13 patients who were initially deemed to have unresectable disease were eligible for surgery. One observational study included patients with unresectable and/or recurrent mixed soft-tissue tumours, applying a combination of LRHT and radiation.69 This produced a CR in 42% of tumours treated, with a five-year survival of 32%.
The original literature review identified and described studies of LRHT for cancers of the bladder,12,70–72 brain,73–75 colon/rectum76–92 and anus,93 hepatobiliary,94–97 lymphatic system (Hodgkin’s lymphoma)98, lung21,22,27,99–109, skin (melanoma),17,18, 110–113 ovary,114–120 pancreas,9, 121–129 prostate,130–133 and vagina and vulva,134 as well as studies including mixed cancer types. Detailed descriptions for each cancer can be found in the complete monograph.
Relatively few studies included QoL endpoints,27,29,38,50,79,90,91,105,106,115 and many were single-arm trials, making interpretation challenging. Two RCTs reported improvements in QoL; in patients with cervical cancer, fatigue, cognitive, and social functioning improved,29 and in patients with non-small cell lung cancer (NSCLC), physical, emotional, and global QoL as well as symptoms of pain, fatigue, nausea, shortness of breath, and appetite loss significantly improved.27 Three single-arm trials38,79,90 and one chart review106 reported reductions in pain. However, one retrospective study reported increases.105 Two studies found no change in QoL.91,115 Ultimately, based on limited data, QoL support is not a primary or recommended indication for use.
Locoregional HT is generally safe and well tolerated,135,136 especially with contemporary technology.5 Toxicity in patients receiving chemo- and/or RT, with or without LRHT, is typically comparable.135 Technology advances, treatment planning, and guideline availibility137–140 have improved tolerability.5 Thus, safety and toxicity concerns from older studies should be interpreted judiciously. The following AEs have been attributed to HT in recent years (post-2000): discomfort during treatment,60,63,78,79 mild pain,25,62,123,135 local erythema,32,62,66,67 skin/superficial burn (mild-moderate; grade 1–2),29,13,56,135 and, less commonly, subcutaneous thermal injury/adipose burns.9,133,30
There are several cardiorespiratory effects specifically observed with deep regional HT that may affect safety. Changes include slightly increased core temperature (38.2±1.4 vs 36.6±0.8, p < 0.001), tachycardia (104±15 vs 85±16 bpm, p < 0.05), decreased respiratory rate (23±3 vs 21±3/min, p < 0.05), transient orthostatic hypotension after completion of treatment, reduced oxygen saturation (95±2% vs. 97±1%, p < 0.05), and fluid loss through sweating when compared with baseline.141
Locoregional HT is considered a chemosensitizer and radiosensitizer5 and is regularly used with chemotherapy and radiation as reviewed above. There is insufficient evidence for the combined use of HT with targeted therapies including monoclonal antibodies and small molecule inhibitors, or endocrine therapies.
Locoregional HT should be used cautiously with medications that can alter a patient’s consciousness, pain perception, or ability to communicate.
No reports of negative interactions for LRHT and other CAM treatments were found.
Common contraindications include:142,143
Patients with implanted/worn/carried medical devices, implants, or any foreign objects
Inability to feel or respond to pain, including sedation, loss of consciousness, and severe neuropathy
Systemic fever > 38°C140
Severe pulmonary disease (Forced Expiratory Volume (FEV) < 50%)
Cardiovascular high-risk patients
Severe cerebrovascular disease
Treatment delivered to areas of prior irradiation
Known decreased circulation in heated area
Patients prone to hemorrhage, presence of an open wound
Patients with organ transplant
Children (due to lack of evidence)
Locoregional HT for cancer care can be found in a few North American complementary health clinics, most often offered by naturopathic doctors. Despite the rich research landscape of HT, a comprehensive review of all cancer types was not identified. This review describes the cancers with the strongest evidence for benefit with adjunctive LRHT. There is some encouraging evidence for improvements in OBJR rates, and conceivably survival, for patients with certain cancer types, while in other areas the evidence is preliminary and/or too heterogeneous to form conclusions.
For patients with locally recurrent breast cancer receiving radiotherapy, the addition of HT likely improves CR rates and disease control based on results of a meta-analysis.11 Less is known about the use and effects of LRHT for patients with different breast cancer presentations (e.g., metastatic disease). For cervical cancer, there is consistent and strong evidence that the addition of LRHT to radiation therapy and chemoradiation for patients with stage II–IVa disease is beneficial. Further studies are needed to determine the magnitude of effect and impact on unique subgroups of patients who may benefit. For patients with esophageal cancer, results are suggestive of benefit for response rate and survival outcomes when combined with neoadjuvant conventional care. Although results were consistent across studies, the quality of the RCTs was generally low. Locoregional HT is a promising treatment to improve survival in advanced gastric cancer and as a neoadjuvant treatment for operable gastric cancer. Combined with RT, HT may improve response rates in patients with locally advanced HNC based on controlled trials, and further research is warranted for combination with CRT. Evidence demonstrates a benefit for PFS and OS in patients with localized, high-risk STS treated with neoadjuvant and adjuvant LRHT with chemotherapy compared with chemotherapy alone. The evidence for the use of HT in other settings with sarcomas or other soft-tissue tumours is unclear.
Treatment methods including timing of LRHT in relation to conventional treatment, frequency, and duration are important clinical considerations. Quality assurance guidelines for HT state that chemotherapy is to be given just before or simultaneous to HT, and radiation be given ideally within one hour of HT (but up to four hours is acceptable).138 This guideline is consistent with the methods used by almost all studies. The target tumour temperature ranges for LRHT are 39°C to 45°C, however 41°C to 43°C is considered optimal.4,5 Based on RCTs (Table 2), LRHT is most commonly administered once or twice weekly for the duration of conventional treatment, with each session typically lasting 60 to 90 minutes.140
Multiple theories of mechanism of action exist for HT, including mitigating hypoxia and inflammation via perfusion and oxygenation changes,3 damaging tumour vasculature,3 and denaturing structural proteins.144 Synergistic effects with chemotherapy include increasing cell membrane permeability and drug uptake by malignant cells3 and enhancing chemotherapeutic cytotoxicity.145 When combined with radiation, HT may offset hypoxia-associated radioresistance,136 suppress cancerous DNA damage repair,136 and augment advantageous proapoptotic effects3 and reactive oxygen species.136
The studies included in this review have several limitations. First, most of the studies were single-arm or observational. These studies have a greater risk of bias as they lack controls and blinding, making it difficult to determine the effect of the LRHT compared with the other treatments. Many of the studies had small samples sizes, in some cases fewer than 10 people. Again, this weakens the strength of the conclusions and often leaves the studies underpowered to detect clinical outcome changes. Technology has significantly changed in the past two decades, with studies published prior to 2000 often reporting higher AE rates and not always having proper treatment planning or the ability to achieve target temperature and duration.4,5 In addition, changes to conventional care within contemporary settings may not reflect the standards of care provided in some older trials, rendering them not comparable/relevant.
There are several limitations to this review. First, a rigorous evaluation and quality assessment including risk of bias using a validated tool was not performed. Although some qualitative description of trial quality was provided, without a standardized approach, some poorer-quality studies may have been overrepresented and, alternatively, higher-quality studies not given sufficient attention. Second, the quality and types of studies included have a high degree of population and co-treatment heterogeneity, making interpretation and comparison of results challenging. Lastly, due to the sheer number of studies included, a full description of the trials and outcomes could not be practically provided. In addition, the heterogeneity and scope of the work performed did not allow for meta-analysis.
Moving forward, high-quality RCTs are necessary for most cancer types to assess the efficacy and magnitude of the effect of LRHT and create changes to practice. Future studies should be sufficiently powered with a large enough sample size to enable the clinical effect to be observed, low risk of bias with proper randomization including allocation concealment, and the appropriate population type, as well as proper quality assurance of treatment application. Additionally, studies using LRHT alongside newer cancer treatments, including immunotherapy, monoclonal antibodies, and tyrosine kinase inhibitors, are needed as these therapies are being increasingly used in oncology.146,147
Additional information, including access to the complete monograph, is available upon request. Please contact Dugald Seely, ND, MSc at dseely@thechi.ca.
1Centre for Health Innovation, Ottawa, ON, Canada
2Patterson Institute for Integrative Oncology Research, Canadian College of Naturopathic Medicine, Toronto, ON, Canada
The authors appreciate the generous support from an anonymous donor in support of this work and the creation of the full monograph.
We have read and understood the CAND Journal’s policy on conflicts of interest disclosure and declare that we have none.
Ottawa Integrative Cancer Centre (OICC) Foundation.
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Correspondence to: Ellen Conte, The Centre for Health Innovation - 429 MacLaren Street, Ottawa, Ontario K2P 0M7, Canada. E-mail: i.econte@thechi.ca
To cite: Conte E, Psihogios A, Seely D. Hyperthermia in cancer care: A literature review. CAND Journal. 2021;28(3):14-30.
Received: 20 May 2021; Accepted: 25 June 2021; Published: 30 September 2021
© 2021 Canadian Association of Naturopathic Doctors. For permissions, please contact candj@cand.ca.
CAND Journal | Volume 28, No. 3, September 2021