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Yagawa et al. Cancer immunity and hyperthermia

surface at around 43 °C while irrigating the drug solution. squamous cell carcinoma of the thoracic esophagus
was disclosed. Patients underwent neoadjuvant
Adjuvant chemotherapy is often given after surgery for chemoradiotherapy with or without radiofrequency
certain types of cancer, such as pancreatic, colorectal, wave local hyperthermia, and the 3-year survival rate
and breast cancer, to improve prognosis by reducing was 24.2% and 50.4%, respectively. There were no
the potential for recurrence and metastasis [96-99] . procedural complications [105] . Additionally, in 2010, the
However, in some cancers, including intrahepatic results of a randomized phase III trial of patients with
cholangiocarcinoma (ICC), the prognosis of patients high-risk soft-tissue sarcoma were reported. Patients
is extremely poor because the recurrence rate underwent neoadjuvant chemotherapy consisting of
after curative operation is very high and there is no etoposide, ifosfamide, and doxorubicin with or without
standard adjuvant setting. We reported previously that local hyperthermia. The treatment response rate in the
postoperative adjuvant immunotherapy with intradermal group that received regional hyperthermia was 28.8%,
administration of a DC vaccine and intravenous compared with 12.7% in the group with chemotherapy
administration of activated T-cells would be a feasible alone (P = 0.002) [106] .
and effective treatment for preventing recurrence and
achieving long-term survival in patients with ICC. In During the postoperative period, immunity is suppressed
this study, the median 5-year progression-free survival by operative invasion [107] and the administration of
and overall survival were 18.3 and 31.9 months in anesthetic drugs such as opioids [108] , and it results in the
the patients receiving adjuvant immunotherapy, and encouragement of postoperative cancer metastasis [109] .
7.7 and 17.4 months in the group with surgery alone Concerning the biological effect, preoperative fever-
(P = 0.005 and 0.022, respectively). Additionally, range whole-body hyperthermia was reported to
patients whose skin reactions at the vaccine site augment postoperative cancer immunity by increasing
were ≥ 3 cm showed dramatically better prognosis the blood level of TNFα and HSP60 [77] . Thus,
in patients receiving adjuvant immunotherapy [100] . hyperthermia increased the benefit of neoadjuvant
As has been explained above, hyperthermia can therapy.
elicit early skin reactions when used in conjunction
with immunotherapy including with DC vaccines and Adverse effects of hyperthermia
activated T-cell transfer [76] . Hyperthermia can also Adverse effects of acute or chronic periods of
augment the efficacy of adoptive immunotherapy by regional hyperthermia do not develop often and are
up-regulating IFN-γ secretion to stimulate naïve T-cells, usually minor, owing to a recent development of
and enhancing homing of DCs and T-cells [75] . For the heating techniques and thermometry, or treatment
reasons stated above, hyperthermia is considered to schedule [110] . Adverse effects of hyperthermia include
be useful for adjuvant settings. skin burns and skin pain, but these events usually heal
spontaneously [111] . In terms of combination therapies
Neoadjuvant chemotherapy and chemoradiotherapy with hyperthermia, radiation toxicity is not increased, but
have become well established, especially for toxicity of chemotherapy might be enhanced depends
esophageal cancer patients [101] . These neoadjuvant on the increase in drug efficacy [110] . In rare settings of
therapies improved the long-term survival rate, but combination therapy with chemotherapy, the formation
the therapeutic benefit was sometimes countered of severe subcutaneous fat or muscle necrosis that
by a significant increase in adverse effects [102] . In required surgery to cure was reported. Adverse effects
addition, postoperative complications, including cardiac of regional hyperthermia vary with the type of targeted
diseases and pulmonary diseases, are much more organ or heating device and techniques. Whole body
severe after chemoradiotherapy [103,104] . Preoperative hyperthermia is a slightly more invasive hyperthermal
radiotherapy increases the risk of postoperative method accompanied by a feeling of heat, tiredness,
anastomosis leakage, an unfavorable complication. and loss of sweat due to a rapid elevation of the core
As has been mentioned above, hyperthermia has body temperature. Dehydration, heat illness, cardiac
the potential to augment the effects of chemotherapy disease, or thrombosis might appear depending on
or radiotherapy. Combination use of hyperthermia underlying disease or physical condition. In addition,
with chemotherapy or radiotherapy may be useful whole body hyperthermia has a risk for toxicity to the
even in the neoadjuvant setting to suppress the peripheral nervous system. Hence, this method is
possibility and seriousness of adverse effects and contraindicated for patients with neurodegenerative
complications by reducing the dose of chemotherapy or diseases, such as multiple sclerosis [112] .
radiotherapy required while maintaining or increasing
its anticancer effects. Indeed, in 1995, the result of a On the other hand, no reports that describe hyperthermia
randomized phase III study for patients with resectable having a positive impact on cancer progression in
226 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ October 31, 2017