Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses

Abstract

Moderate hyperthermia at temperatures between 40 and 44°C is a multifaceted therapeutic modality. It is a potent radiosensitizer, interacts favorably with a host of chemotherapeutic agents, and, in combination with radiotherapy, enforces immunomodulation akin to "in situ tumor vaccination." By sensitizing hypoxic tumor cells and inhibiting repair of radiotherapy-induced DNA damage, the properties of hyperthermia delivered together with photons might provide a tumor-selective therapeutic advantage analogous to high linear energy transfer (LET) neutrons, but with less normal tissue toxicity. Furthermore, the high LET attributes of hyperthermia thermoradiobiologically are likely to enhance low LET protons; thus, proton thermoradiotherapy would mimic ¹²C ion therapy. Hyperthermia with radiotherapy and/or chemotherapy substantially improves therapeutic outcomes without enhancing normal tissue morbidities, yielding level I evidence reported in several randomized clinical trials, systematic reviews, and meta-analyses for various tumor sites. Technological advancements in hyperthermia delivery, advancements in hyperthermia treatment planning, online invasive and non-invasive MR-guided thermometry, and adherence to quality assurance guidelines have ensured safe and effective delivery of hyperthermia to the target region. Novel biological modeling permits integration of hyperthermia and radiotherapy treatment plans. Further, hyperthermia along with immune checkpoint inhibitors and DNA damage repair inhibitors could further augment the therapeutic efficacy resulting in synthetic lethality. Additionally, hyperthermia induced by magnetic nanoparticles coupled to selective payloads, namely, tumor-specific radiotheranostics (for both tumor imaging and radionuclide therapy), chemotherapeutic drugs, immunotherapeutic agents, and gene silencing, could provide a comprehensive tumor-specific theranostic modality akin to "magic (nano)bullets." To get a realistic overview of the strength (S), weakness (W), opportunities (O), and threats (T) of hyperthermia, a SWOT analysis has been undertaken. Additionally, a TOWS analysis categorizes future strategies to facilitate further integration of hyperthermia with the current treatment modalities. These could gainfully accomplish a safe, versatile, and cost-effective enhancement of the existing therapeutic armamentarium to improve outcomes in clinical oncology.

Keywords: SWOT analysis; chemotherapy; clinical trials; hyperthermia; hyperthermia treatment planning; immunotherapy; radiation therapy; radiosensitizer.

Figure 1

Multifaceted action of clinical hyperthermia at 39–45°C with its effects as a potent radiosensitizer; independent, additive, and synergistic action with chemotherapeutic agents; a tumor immunomodulator with potential as an in situ tumor vaccinator; and its prospects using magnetic nanoparticles with payloads. Reproduced with permission from Datta et al. (12).

Figure 2

(A) Radiotherapy-induced immunomodulation: Immunomodulation induced by radiotherapy is known to be mediated via the sequence of events initiated by activation of dendritic cells, which take up tumor antigens released from cancer cells following radiation-induced cell death. Activated dendritic cells activate T cells leading to a cascade of events resulting in stimulation of cytotoxic CD8⁺ T cells. These cells are further promoted by radiation-induced chemokines to kill tumor cells that are finally scavenged by macrophages. (B) Immunomodulation following hyperthermia and radiotherapy: The differential observation of increased CD68⁺ macrophage infiltration in the part treated by combined hyperthermia + radiotherapy could be the result of accelerated immunomodulation secondary to hyperthermia. Hyperthermia along with radiotherapy is known to release heat shock proteins by tumor cells, which may act as additional “danger signals” that may further promote immune responses. Heat shock proteins and antigen-containing exosomes could contribute to dendritic cell recruitment leading to enhanced immunomodulatory effects in this part. This may speed up radiation-induced immunomodulation, as suggested by increased CD68⁺ macrophage infiltration in this part. These interpretations are based on the observation that the tumor specimen taken at 6 weeks showed CD4⁺ T cell infiltration in the part treated by radiotherapy alone, likely representing a first set of events of radiation-induced immunomodulation. In turn, a higher number of CD68⁺ macrophages were found in the part treated by thermoradiotherapy (207).

Figure 3

Primary elements of the SWOT analysis for hyperthermia. MMNs, multifunctional nanoparticles; PARP1, poly (ADP-ribose) polymerase-1; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; HSP, heat shock proteins.

Figure 4

Upper panel: Moderate hyperthermia, with its ability to inhibit radiotherapy-induced DNA repair and its radiosensitizing effects on hypoxic tumor cells, has features akin to high linear energy transfer (LET) radiations. Following hyperthermia, the normal tissues exhibit a “heat-sink” effect resulting in the washing off the delivered heat due to heat-induced vasodilation and thus spared from thermal radiosensitization. On the other hand, tumors with its altered vasculature would fail to vasodilate and thus retain heat leading to a “heat-trap” effect. As the physical dose profiles of photons/X-rays are similar to those of neutrons in the irradiated volume, thermoradiobiologically photon beam thermoradiotherapy would have differential effects on tumors and normal tissues. This would be analogous to high LET neutrons for tumor owing to their selective thermal radiosensitization, whereas the normothermic normal tissues would be irradiated with low LET photons/X-rays. Middle panel: Protons radiobiologically have low LET radiation features but share similar physical dose profiles with those of high LET ¹²C ions. Thus, hyperthermia with its thermoradiological similarities to high LET radiations when delivered along with protons could mimic C¹² ion therapy. Lower panel: Conceptual illustration of multifunctional magnetic nanoparticles with appropriate payloads of radioisotopes for radiotheranostics (both tumor imaging and radiotherapy) and chemotherapeutic and immunotherapeutic agents and siRNA and miRNA for therapeutic gene silencing. These magnetic nanoparticles in the presence of alternating magnetic field could deliver local hyperthermia and with additional payloads could act as “nanobullets.” The figure has been reproduced and modified with permission from Datta et al. (212, 213).

Figure 5

Flowchart depicting the hyperthermia treatment planning process, including SAR and temperature optimization, delivery, and online adaptive optimization. In addition, the hyperthermia and radiation therapy treatment plans are integrated in a joint platform using biological modeling with temperature-dependent linear-quadratic parameters α and β. RT, radiotherapy; HTP, hyperthermia treatment planning; HTRT, thermoradiotherapy; SAR, specific absorption rate. The images of HTP, RT, and HTRT plans have been modified and reproduced with permissions from Kok et al. (261) and van Leeuwen et al. (262).

Figure 6

An illustrative example of a patient with locally advanced pancreatic cancer being treated with hyperthermia and radiotherapy as per the HEATPAC protocol (264). Multisensor thermometry probes are guided through the endoscope and placed in the duodenum. Hyperthermia treatment plan is obtained using HYPERPLAN, and the online temperature monitoring is carried out during the hyperthermia. The tumor shows metabolic complete remission on PET obtained at 6 months following the treatment with hyperthermia, radiotherapy, and chemotherapy (HTCTRT).

Figure 7

Forest plot showing the risk difference of complete local tumor control in patients from various disease sites treated with thermoradiotherapy (HTRT) vs. radiotherapy (RT) alone. Plot generated using data from Datta et al. (12).

Figure 8

A TOWS analysis to identify key strategies to take advantage of the strength and opportunities while overcoming the weakness and reducing the threats. This could enable integrate hyperthermia in the present clinical armamentarium of oncology care. MMNs, multifunctional magnetic nanoparticles.

Figure 9

Integration of hyperthermia in clinical practice along with other treatment modalities is supported by its thermobiological rationale and clinical evidences reported from various phase III randomized trials and meta-analysis of various tumors sites. ReRT, reirradiation; HT, hyperthermia; RT, radiotherapy; HTRT, thermoradiotherapy; CTRT, chemoradiotherapy; NACT, neoadjuvant chemotherapy; PRFS, proton resonance frequency shift. The images of RT, HT, and HTRT plans have been modified and reproduced with permission from van Leeuwen et al. (262).