Hyperthermia — the therapeutic elevation of tissue temperature to 40–43°C — is one of the most evidence-backed adjunct therapies in oncology, yet one of the most underutilized. Decades of randomized controlled trials and meta-analyses demonstrate that hyperthermia meaningfully improves outcomes when combined with radiotherapy and chemotherapy across multiple cancer types including breast, cervical, head and neck, soft tissue sarcoma, and bladder cancer. Its mechanisms are multi-target: it kills cancer cells directly through heat-induced protein denaturation and DNA repair inhibition; it sensitizes tumors to radiation and chemotherapy; it activates anti-tumor immune responses through heat shock protein release and immunogenic cell death; and it dramatically improves tumor perfusion and oxygenation. At Root Causes, hyperthermia is used in the SEED Program as a Tuesday/Thursday pairing with IV mistletoe — a scheduling that creates specific mechanistic synergy between heat-induced immune activation and mistletoe's NK cell stimulation. Hyperthermia's abandonment in much of mainstream oncology over the past several decades was driven primarily by logistical challenges, not clinical inefficacy. The evidence that justified its use was there — and is growing.
Hyperthermia in oncology encompasses a spectrum of temperature ranges, each with distinct mechanisms, applications, and evidence bases. Understanding this spectrum is essential for correctly interpreting the literature and positioning Root Causes' clinical approach.
| Type | Temperature | Clinical Role & Notes |
|---|---|---|
| Fever-range / Mild | 38.5–40.5°C | Systemic immune activation; enhances lymphocyte trafficking; anti-inflammatory resolution; synergistic with immunotherapy; used in whole-body hyperthermia protocols |
| Moderate (Therapeutic) | 40–43°C | Primary clinical range for radiosensitization, chemosensitization, immunogenic cell death; most RCT evidence base; direct tumor cell cytotoxicity begins; DNA repair inhibition active |
| Thermal Ablation | >45°C | Direct, non-selective tumor destruction; used in RFA and focused ultrasound; different mechanism and application from therapeutic hyperthermia; tissue damage nonselective at these temperatures |
Root Causes uses moderate therapeutic hyperthermia (40–43°C) in the SEED Program — the range that is the subject of the RCT evidence base for radiosensitization, chemosensitization, and immunogenic cell death. This is distinct from thermal ablation, which operates at higher temperatures with different goals and mechanisms.
Delivery modalities
Multiple technologies can deliver heat to target temperatures. The most clinically established include:
Whole-body hyperthermia (WBH) — elevates core body temperature systemically using infrared devices, water-filtered IR-A (wIRA), thermal chambers, or heating blankets; fever-range to moderate temperatures; used for systemic immune activation and chemotherapy potentiation
Regional hyperthermia — deep tissue or loco-regional heating of specific body regions via radiofrequency or microwave applicators; the modality behind most of the RCT evidence in cervical, bladder, and head and neck cancers
Local hyperthermia — focused heating of a specific tumor via external, interstitial, or intraluminal applicators; highest temperature precision
HOCATT / Ozone sauna-based hyperthermia — infrared and ozone-based whole-body system delivering fever-range to moderate hyperthermia with simultaneous ozone benefits; increasingly used in integrative oncology settings
Hyperthermia with radiotherapy was an active area of clinical investigation in the 1970s–1990s, with multiple randomized controlled trials demonstrating meaningful benefit. Yet it was largely abandoned in mainstream oncology — not because the evidence showed it didn't work, but because the technology of the era was logistically cumbersome, temperature monitoring was imprecise, and newer radiosensitizing drugs offered a more convenient alternative. The Cochrane reviewer Overgaard explicitly noted that HBOT (with a similar radiosensitization rationale) 'was abandoned before a measured evaluation was made of its true clinical impact.'
The same applies to hyperthermia. The clinical benefit was real. The infrastructure to deliver it reliably was the barrier. Modern hyperthermia equipment has substantially addressed the technical challenges that led to its abandonment, and the evidence base — including multiple systematic reviews and meta-analyses — has continued to accumulate in its favor.
At temperatures above 40°C, cancer cells undergo progressive cellular stress. Above 42°C, direct cytotoxic effects accelerate significantly. The mechanisms include:
Protein denaturation — heat disrupts the three-dimensional structure of proteins critical for cellular function — particularly those involved in DNA replication, repair, and cell cycle progression
DNA repair inhibition — hyperthermia at therapeutic temperatures inhibits homologous recombination and other DNA repair mechanisms; DNA strand breaks that would otherwise be repaired become lethal
Cell cycle arrest — heat disrupts spindle assembly and blocks cells in S-phase — a cell cycle stage particularly sensitive to hyperthermia — leading to apoptosis
Differential cancer cell vulnerability — cancer cells express significantly lower levels of heat shock proteins (HSPs) than normal cells at baseline, making them less able to mount the protective heat shock response; this selectivity is analogous to the antioxidant defense differential exploited by IV Vitamin C and ozone
Hyperthermia's most clinically validated mechanism — and the basis for its strongest RCT evidence — is sensitization of tumors to radiation and chemotherapy. Multiple complementary mechanisms drive this:
Hypoxic cell sensitization — hypoxic tumor cells are inherently radioresistant because oxygen is required to fix radiation-induced DNA damage; hyperthermia is preferentially cytotoxic to hypoxic cells (which are also thermally sensitive) and improves tumor perfusion, oxygenation, and radiation response in these previously resistant populations
DNA repair inhibition as radiosensitization — radiation creates DNA strand breaks; normal repair mechanisms can fix sublethal damage in the hours following irradiation; hyperthermia inhibits these repair pathways, preventing cancer cells from recovering from radiation damage
Chemotherapy sensitization — hyperthermia increases cellular membrane permeability (improving drug uptake), enhances drug-DNA interaction, and inhibits drug efflux pumps that cancer cells use to resist chemotherapy; platinum compounds, anthracyclines, alkylating agents, and taxanes all show enhanced activity in combination with hyperthermia
Improved drug delivery — mild hyperthermia at 40–41°C significantly increases tumor blood flow and vascular permeability, improving delivery of both chemotherapy and immune effector cells to tumor tissue
One of the most important mechanistic developments in hyperthermia research over the past decade is the understanding of its role in immunogenic cell death (ICD) and tumor immunophenotype conversion.
When cancer cells die under heat stress in the 41–43°C range, they undergo a specific form of cell death — distinct from silent apoptosis — that releases danger-associated molecular patterns (DAMPs) including extracellular heat shock proteins (HSP70, HSP90), HMGB1, calreticulin, and ATP. These act as 'danger signals' that activate dendritic cells, NK cells, and T lymphocytes. The result is an immune response directed specifically against the tumor antigens released by dying cancer cells — effectively turning the tumor's own cell death into an in situ vaccination event.
This mechanism converts immunologically 'cold' tumors (poorly infiltrated by immune cells, resistant to immunotherapy) into 'hot' tumors (immune cell-rich, responsive to checkpoint inhibitors and other immunotherapy approaches). HSPs released to the extracellular space bind tumor peptides and deliver them to antigen-presenting cells via CD91 receptors, stimulating CD8+ T-cell responses and NK cell activation.
The ICD mechanism positions hyperthermia as a powerful potentiator of immunotherapy. Checkpoint inhibitors (PD-1/PD-L1, CTLA-4) work by releasing brakes on pre-existing immune responses — but in cold tumors with minimal immune infiltration, there is little response to release. Hyperthermia-induced ICD creates the immune infiltration and antigen presentation that checkpoint inhibitors need to function. Emerging clinical data and multiple preclinical studies support the combination of hyperthermia with immune checkpoint inhibitors as one of the most promising directions in current oncology research.
Mild to moderate hyperthermia (40–42°C) substantially increases tumor blood flow and vascular perfusion. This has multiple downstream benefits: improved delivery of chemotherapy to hypoxic tumor regions, improved immune cell infiltration, increased tumor oxygenation (synergizing with HBOT and ozone in the SEED protocol), and enhanced lymphocyte trafficking through tumor vasculature. At moderate temperatures, tumor vasculature dilates and becomes more permeable — the opposite of the dysfunctional, collapsed tumor vasculature that characterizes hypoxic tumor regions.
Direct cytotoxicity, radiosensitization, and chemosensitization are all strongly supported mechanistically and clinically — these are the basis for the RCT evidence base. ICD and cold-to-hot tumor conversion are mechanistically well-established and supported by preclinical data, with growing clinical evidence particularly in combination with immunotherapy. The differential HSP expression vulnerability of cancer cells vs. normal cells has biological support but requires further clinical translation. Overall: hyperthermia has the most mechanistically mature and clinically validated evidence base of the six SEED therapies when used as a radiation and chemotherapy adjunct.
The same A–D evidence grade framework used throughout the SEED Evidence Series is applied here.
| Grade | Level | Description |
|---|---|---|
| A | Strong | Multiple RCTs or meta-analyses with consistent results |
| B | Moderate | Limited RCTs, prospective cohorts, or phase II trials with positive signal |
| C | Emerging | Phase I trials, uncontrolled studies, strong preclinical data; promising but not definitive |
| D | Limited | Case reports, mechanistic rationale only, or conflicting results |
| Study | Key Finding | Grade |
|---|---|---|
| International Collaborative Hyperthermia Group Meta-analysis Breast Cancer — Superficial / Recurrent HT + RT vs. RT alone | Complete response 59% with HT+RT vs. 41% with RT alone (OR = 2.3, 95% CI 1.4–3.8, p<0.001) in superficial localized breast cancer. Separate recurrent breast cancer meta-analysis: CR 60.2% with HT+RT vs. 38.1% with RT (OR = 2.64, 95% CI 1.66–4.18, p<0.0001). Level I evidence for HT as radiation sensitizer in breast cancer. | A |
| Datta et al. — Meta-analysis (2016) Head & Neck Cancer HT + RT vs. RT alone | 6 RCTs included. Overall complete response: 62.5% with thermoradiotherapy vs. 39.6% with RT alone (OR 2.92, 95% CI 1.58–5.42, p=0.001; RR 1.61, p<0.0001). Risk difference 0.25 in favor of combined treatment. Robust meta-analytic evidence across multiple institutions. | A |
| Minnaar et al. — Phase III RCT (2019/2022) Cervical Cancer (HIV+ and HIV-) Modulated Electro-HT + Chemoradiation | Phase III RCT of modulated electro-hyperthermia (mEHT) added to standard chemoradiotherapy in locally advanced cervical cancer. Improved local disease control and overall survival at 2 and 3 years in both HIV-positive and HIV-negative patients. One of the few Phase III RCTs of hyperthermia with survival as a primary endpoint. | A |
| Datta et al. — Meta-analysis (2016) Locoregional Recurrent Breast Cancer HT + Reirradiation | 779 patients reirradiated with mean additional dose of 36.7 Gy with hyperthermia. Complete response rate 66.6% — a clinically significant outcome in a notoriously treatment-resistant setting. Supports HT as enabling dose escalation through reirradiation. | A |
| Systematic Review — Clinical Trials Registered 2000–2020 All Cancer Types (Peeters et al., 2022) | Comprehensive systematic review of all oncological hyperthermia trials registered on ClinicalTrials.gov. Documented growing trial activity across cancer types including breast, cervical, bladder, soft tissue sarcoma, head and neck, and GI cancers. Confirms ongoing global clinical interest and expanding evidence base. | B |
| Frontiers Review — SWOT/TOWS Analysis (2020) Locoregional Hyperthermia Integration All Cancer Types | Comprehensive narrative review concluding hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding Level I evidence in systematic reviews and meta-analyses for various tumor sites. Articulates the logistical rather than clinical basis for underutilization. | A |
| Lukácsi, Munkácsy, Győrffy — Review (2024) Molecular, Cellular, and Immunological Effects HT + Immunotherapy Synergy | Comprehensive 2024 review of hyperthermia's molecular, cellular, and immunological effects. Confirms mild hyperthermia elevates blood flow, tumor perfusion, and oxygenation; heat shock impedes DNA repair; HSP release activates dendritic cells and T cells; ICD mechanism converts cold tumors to hot. Positions HT as an ideal immunotherapy potentiator. | B |
| From Cold to Hot — PMC Review (2025) Hyperthermia + Checkpoint Inhibitors Immunotherapy Synergy | HT influences both innate and adaptive immunity — NK cells, dendritic cells, macrophages, and T cells. Promotes ICD with DAMP release (HSPs, HMGB1, calreticulin, ATP). Converts immunologically cold tumors to hot. Amplifies efficacy of immune checkpoint inhibitors by improving immune cell infiltration and antigen presentation. Synergy with PD-1/PD-L1 inhibitors supported. | B |
Strongly supported (Level I): Hyperthermia as a radiation and chemotherapy sensitizer. Multiple meta-analyses across thousands of patients in RCTs demonstrate significantly improved complete response rates and, in some settings, survival benefit when HT is added to radiotherapy or chemoradiotherapy. This is the strongest evidence base of any SEED therapy for a specific measurable anti-tumor outcome.
Strongly supported: Safety profile in combination with standard treatment. Multiple systematic reviews confirm HT does not meaningfully increase normal tissue toxicity when added to RT or chemotherapy. The therapeutic ratio is improved, not compromised.
Moderately supported: ICD and immune activation. Mechanistically robust preclinical evidence; growing clinical evidence for immune infiltration and response, particularly in combination with immunotherapy.
Moderately supported: Whole-body hyperthermia for immune stimulation and chemotherapy potentiation. Less RCT evidence than locoregional approaches; growing body of prospective data from integrative oncology centers.
Emerging: Hyperthermia as an immunotherapy potentiator. The combination of HT with immune checkpoint inhibitors is one of the most active areas of current clinical investigation. Results from ongoing trials are expected to significantly strengthen this evidence base in the coming years.
Important caveat: The RCT evidence base is primarily for HT in combination with radiation or chemotherapy in specific cancer types and settings. The evidence for HT as standalone therapy, or HT in the integrative oncology context without concurrent conventional treatment, is less developed. Root Causes' use of HT in the SEED Program should be framed as consistent with the mechanistic rationale and supportive care evidence, not as a replication of the RCT conditions.
The honest summary: Hyperthermia has the strongest Level I evidence base of all six SEED therapies for specific anti-tumor outcomes in conventional treatment combination settings. The challenge is that this evidence was largely generated in locoregional and regional HT settings with concurrent radiation or chemotherapy — which is not the exact context of the SEED intensive. The mechanistic rationale for HT's inclusion in an integrative protocol is strong; the specific evidence base for HT as a standalone integrative adjunct (without concurrent radiation) is less developed but mechanistically coherent.
In the SEED 1-week intensive, hyperthermia is administered on Tuesday and Thursday — paired with IV mistletoe on both days. This pairing is mechanistically intentional and represents one of the most coherent synergistic pairings in the SEED protocol.
Both hyperthermia and mistletoe exert their most important clinical effects through immune activation — specifically through NK cell stimulation, ICD induction, and antigen presentation. When a tumor cell dies under heat stress, it releases HSPs, HMGB1, calreticulin, and ATP that act as danger signals and activate dendritic cells and NK cells. Mistletoe simultaneously activates those same NK cells and stimulates the production of IL-2, IFN-γ, and TNF-α needed for T-cell-mediated anti-tumor response.
The heat-induced tumor cell death creates the antigen presentation; mistletoe's immune activation provides the effector cells to respond to that presentation. The combination creates a more complete in situ vaccination effect than either therapy achieves alone. Additionally, hyperthermia increases tumor vascular permeability, which may enhance IV mistletoe's delivery to the tumor microenvironment — creating a pharmacokinetic benefit on top of the immunological synergy.
Temperature range — 40–43°C (therapeutic hyperthermia range); below ablation threshold
Duration — typically 30–90 minutes per session depending on modality and patient tolerance
Frequency in SEED — Tuesday and Thursday of the 1-week intensive
Modality — whole-body or local/regional hyperthermia depending on equipment and clinical indication; HOCATT or similar infrared-based systems for whole-body applications
Monitoring — core temperature monitoring throughout session; patient vital signs monitored
With HBOT (daily) — hyperthermia increases tumor perfusion and oxygenation on HT days; daily HBOT maintains the baseline oxygenated microenvironment in which hyperthermia's radiosensitization effects can operate
With IV mistletoe (same day) — complementary immune activation mechanisms converge — HT-induced HSP/DAMP release activates antigen-presenting cells; mistletoe activates NK cells and T cells; together they create a more complete anti-tumor immune response
With IV Vitamin C (alternate days) — IVC's pro-oxidant H₂O₂ generation in the tumor microenvironment is potentiated by improved tumor perfusion from HT days; the two therapies operate on alternate days, building a week-long oxidative and immune activation environment
With ozone (daily) — ozone-improved microcirculation and Nrf2 antioxidant priming on HT days protects normal tissue while the heat stress targets cancer cells
With terrain support medications (daily) — chemosensitization mechanism of hyperthermia — increased membrane permeability, improved drug delivery — is relevant to oral terrain support medication uptake and distribution
Hyperthermia addresses the cancer terrain at perhaps the most comprehensive level of any single SEED therapy. It simultaneously: modifies the tumor microenvironment through perfusion normalization and oxygenation improvement; activates innate and adaptive immune surveillance through ICD and HSP-mediated antigen presentation; sensitizes cancer cells to oxidative stress from companion therapies; exploits cancer cells' differential HSP vulnerability; and converts immunologically cold tumors into hot ones capable of mounting a sustained immune response. In the SEED framework, hyperthermia is the catalyst — the therapy that initiates the immune cascade that mistletoe, IVC, and ozone then sustain.
Hyperthermia at therapeutic temperatures (40–43°C) has a well-characterized safety profile with manageable adverse effects. The key principle is temperature control: staying within the therapeutic range and avoiding thermal doses that damage normal tissue.
| Consideration | Clinical Detail | Management |
|---|---|---|
| Thermal Burns / Tissue Damage | The primary local risk is thermal injury if temperatures exceed 44°C in normal tissue. Localized burns, blisters, and discomfort can occur with imprecise temperature delivery, particularly with interstitial or intraluminal modalities. | Temperature monitoring throughout session is mandatory. Stay within 40–43°C therapeutic range. Patient feedback and vital sign monitoring during session. Whole-body systems allow more conservative temperature management. |
| Dehydration and Electrolyte Imbalance | Significant heat exposure causes sweating and fluid loss. Electrolyte shifts can occur during prolonged WBH sessions, particularly in patients with compromised renal or cardiac function. | Ensure adequate hydration before and during sessions. Electrolyte monitoring recommended for patients with cardiac or renal compromise. Oral or IV hydration support as indicated. |
| Cardiovascular Stress | Hyperthermia increases heart rate and cardiac output and decreases systemic vascular resistance. Patients with significant cardiac compromise (severe CHF, recent MI, significant arrhythmia) require careful evaluation. | Cardiac clearance for patients with significant cardiac history before initiating hyperthermia. Continuous monitoring of heart rate and blood pressure during sessions. Moderate WBH (38.5–40°C) preferred over higher temperatures in cardiac patients. |
| CNS Sensitivity | The brain is particularly sensitive to heat. Whole-body hyperthermia that elevates core temperature significantly can cause neurological symptoms at higher temperature ranges (>40.5°C core). The NCI notes brain sensitivity as a consideration for WBH. | Stay within moderate WBH temperature range (38.5–40°C) for systemic protocols. Local or regional HT does not raise core temperature significantly. Monitor for neurological symptoms including headache, confusion, visual changes. |
| Thermotolerance | Repeated hyperthermia sessions at short intervals can induce thermotolerance — increased HSP expression that protects cancer cells against subsequent heat stress. This reduces efficacy with overly frequent scheduling. | Space hyperthermia sessions to allow thermotolerance to resolve — twice weekly scheduling (Tuesday/Thursday in SEED) is supported by the literature as an interval that limits thermotolerance accumulation while maintaining therapeutic effect. |
| Implanted Metal Devices | Metal implants (surgical hardware, pacemakers, some ports) can concentrate radiofrequency energy during regional HT, causing local heating at implant sites. Risk depends on device type and HT modality. | Review implant history before initiating HT. Infrared and WBH methods carry lower implant risk than RF-based regional HT. Verify specific device compatibility. |
| Active Hemorrhage / Severe Coagulopathy | Hyperthermia-induced vasodilation and increased cardiac output can worsen active hemorrhage. Not an issue in stable patients. | Defer HT in patients with active significant hemorrhage. Assess coagulation status in patients on anticoagulation. |
| Common Mild Effects | Fatigue, warmth, mild nausea, and temporary fatigue in the hours following sessions. Mild skin redness with surface heating. Generally manageable and transient. | Patient counseling on expected effects. Adequate rest after sessions. Hydration support. All effects typically resolve within hours. |
Hyperthermia earns its place in the SEED Program as the therapy with the strongest Level I evidence base among all six core therapies for specific anti-tumor outcomes:
Strongest RCT-level evidence in the SEED protocol — multiple meta-analyses demonstrating significantly improved complete response rates in breast, cervical, and head and neck cancers with HT added to standard treatment; this is Level I clinical evidence
ICD and in situ vaccination — heat-induced immunogenic cell death converts tumor-specific cell death into an immune activation event — releasing HSPs, HMGB1, calreticulin, and ATP that activate dendritic cells, NK cells, and T lymphocytes in a tumor-antigen-specific manner
Cold-to-hot tumor conversion — converts immunologically cold tumors into hot ones — a prerequisite for effective immune response and the necessary precondition for immunotherapy synergy
Tuesday/Thursday pairing with mistletoe — creates the most mechanistically coherent pairing in the SEED protocol: HT generates the antigen presentation and immune activation stimulus; mistletoe provides the NK cells and cytokines to respond; together they form a complete in situ vaccination cycle
Differential cancer cell vulnerability — cancer cells' reduced HSP expression makes them less able to mount the protective heat shock response, creating a therapeutic window that spares normal tissue
Synergy with all other SEED therapies — improved tumor perfusion potentiates drug delivery for terrain support medications; oxygenation improvement synergizes with HBOT and ozone; radiosensitization is relevant for patients receiving concurrent radiation
Vernon CC, Hand JW, Field SB, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35(4):731–744.
Datta NR, Puric E, Klingbiel D, Gomez S, Bodis S. Hyperthermia and radiation therapy in locoregional recurrent breast cancers: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2016;94(5):1073–1087.
Datta NR, Rogers S, Ordonez SG, Puric E, Bodis S. Hyperthermia and radiotherapy in the management of head and neck cancers: a systematic review and meta-analysis. Int J Hyperthermia. 2016;32(1):31–40.
Minnaar CA, Kotzen JA, Ayeni OA, et al. The effect of modulated electro-hyperthermia on local disease control in HIV-positive and -negative cervical cancer women in South Africa: early results from a phase III randomised controlled trial. PLoS One. 2019;14(6):e0217894.
Minnaar CA, Maposa I, Kotzen JA, Baeyens A. Effects of modulated electro-hyperthermia (mEHT) on two and three year survival of locally advanced cervical cancer patients. Cancers. 2022;14(3):656.
Peeters H, van Zwol EM, Brancato L, et al. Systematic review of the registered clinical trials for oncological hyperthermia treatment. Int J Hyperthermia. 2022;39(1):806–812.
Lukácsi S, Munkácsy G, Győrffy B. Harnessing hyperthermia: molecular, cellular, and immunological insights for enhanced anticancer therapies. Integr Cancer Ther. 2024;23:15347354241242094.
Jiang PS, Tsai HI, et al. From cold to hot: mechanisms of hyperthermia in modulating tumor immunology for enhanced immunotherapy. Front Immunol. 2025;16. PMC11906415.
Frontiers in Oncology. Integrating loco-regional hyperthermia into the current oncology practice: SWOT and TOWS analyses. Front Oncol. 2020;10:819.
National Cancer Institute. Hyperthermia to Treat Cancer. cancer.gov. Updated 2024.
Chia BSH, et al. Review of the current clinical evidence for loco-regional moderate hyperthermia in the adjunct management of cancers. Cancers. 2023;15:346.
Ademaj A, Veltsista DP, Ghadjar P, et al. Clinical evidence for thermometric parameters to guide hyperthermia treatment. Cancers. 2022;14(3):625.
Wust P, et al. Temperature-dependent effects of induced hyperthermia, including whole-body hyperthermia, on the hallmarks of cancer: a systematic review. Cancers. 2025;17(23):3824.
This white paper is prepared for clinical and provider education purposes as part of the Root Causes SEED Program Evidence Series. It summarizes published research and does not constitute medical advice. All clinical decisions should be individualized by a qualified provider. Evidence grades reflect the authors' assessment of the published literature at time of writing and will be updated as new research emerges.