We analyzed the response evaluation of pleural effusions between the two groups after a median of 3.5 cycles (range 2–6) treatment. In the HCT group, four patients (25.0%) had CR status, nine patients (56.3%) had PR status, and two patients (12.5%) had SD status, and one patient (6.3%) experienced a PD. The ORR was 81.2%. In the CT group, no patients achieved CR status, four patients (40.0%) achieved PR status, and four patients (40.0%) achieved SD status, and two patients (20.0%) had PD status. The ORR was 40.0%. There was a significant difference between the two groups (P = 0.046) [Table 4].
The malignant pleural effusion often occurs in the advanced NSCLC, weakening the pulmonary function, and diminishing the quality of life due to symptoms like dyspnea, pain, cough, etc. In this study, we discovered that the regional hyperthermia combined with interleukin-2 intrapleural injections was one of the effective means for managing pleural effusion, with an ORR of 81.2% in HCT group compared to 40% in CT group. No major complications, such as respiratory events and fever, were encountered. There were no minor complications, except the pain at the chest tube insertion sites. It might be due to that the alignment of these two could strongly induce expression of heat-shock protein 70, CD8-positive and CD4-positive T cells, promoting tumor cells apoptosis and necrosis and then reducing the formation of malignant pleural effusion. Hyperthermia could also promote permeation of chemotherapeutics into the pleural cavity.
This work was supported by the grants from the Scientific Research Foundation of Shanxi Province Healthy Commission (No. 2017068), and Shanxi Province Science Foundation for Youths (No. 201801D221259).
1. Chen W, Zheng R, Zhang S, Zeng H, Xia C, Zuo T, et al. Cancer incidence and mortality in China, 2013. Cancer Lett
2017; 401:63–71. doi: 10.1016/j.canlet.2017.04.024.
2. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin
2012; 62:220–241. doi: 10.3322/caac.21149.
3. Oei AL, Vriend LE, Crezee J, Franken NA, Krawczyk PM. Effects of hyperthermia
on DNA repair pathways: one treatment to inhibit them all. Radiat Oncol (London, England)
2015; 10:165doi: 10.1186/s13014-015-0462-0.
4. Liu Z. Clinical effects of high frequency hyperthermia
-assisted irinotecan chemotherapy
on patients with middle and advanced colorectal cancer and its safety assessment. Oncol Lett
2019; 17:215–220. doi: 10.3892/ol.2018.9574.
5. Gao S, Zheng M, Ren X, Tang Y, Liang X. Local hyperthermia
in head and neck cancer: mechanism, application and advance. Oncotarget
2016; 7:57367–57378. doi: 10.18632/oncotarget.10350.
6. Verduijn GM, de Wee EM, Rijnen Z, Togni P, Hardillo JAU, Ten Hove I, et al. Deep hyperthermia
with the HYPERcollar system combined with irradiation for advanced head and neck carcinoma - a feasibility study. Int J Hyperthermia
2018; 34:994–1001. doi: 10.1080/02656736.2018.1454610.
7. Kalapurakal JA, Mittal BB, Sathiaseelan V. Re-irradiation and external hyperthermia
in locally advanced, radiation recurrent, hormone refractory prostate cancer: a preliminary report. British J Radiol
2001; 74:745–751. doi: 10.1259/bjr.74.884.740745.
8. Cohen J, Anvari A, Samanta S, Poirier Y, Soman S, Alexander A, et al. Mild hyperthermia
as a localized radiosensitizer for deep-seated tumors: Investigation in an orthotopic prostate cancer model in mice. Br J Radiol
2019; 92:20180759doi: 10.1259/bjr.20180759.
9. Li Z, Sun Q, Huang X, Zhang J, Hao J, Li Y, et al. The efficacy of radiofrequency hyperthermia
combined with chemotherapy
in the treatment of advanced ovarian cancer. Open Med (Warsaw, Poland)
2018; 13:83–89. doi: 10.1515/med-2018-0013.
10. Sugimachi K, Kitamura K, Baba K, Ikebe M, Morita M, Matsuda H, et al. Hyperthermia
combined with chemotherapy
and irradiation for patients with carcinoma of the oesophagus--a prospective randomized trial. Int J Hyperthermia
1992; 8:289–295. doi: 10.3109/02656739209021783.
11. Ohguri T, Imada H, Yahara K, Moon SD, Yamaguchi S, Yatera K, et al. Re-irradiation plus regional hyperthermia
for recurrent non-small cell lung cancer: a potential modality for inducing long-term survival in selected patients. Lung Cancer(Amsterdam, Netherlands)
2012; 77:140–145. doi: 10.1016/j.lungcan.2012.02.018.
12. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy
regimens for advanced non-small-cell lung cancer. New Engl J Med
2002; 346:92–98. doi: 10.1056/NEJMoa011954.
13. Zhang T, Pan Q, Xiao S, Li L, Xue M. Docetaxel combined with intraperitoneal hyperthermic perfusion chemotherapy
in the treatment of advanced ovarian cancer. Oncol Lett
2016; 11:3287–3292. doi: 10.3892/ol.2016.4414.
14. Fujimoto S, Takahashi M, Endoh F, Shrestha RD, Kokubun M, Takai M, et al. A clinical pilot study combining surgery with intraoperative pelvic hyperthermochemotherapy to prevent the local recurrence of rectal cancer. Ann Surg
15. Schlemmer M, Wendtner CM, Lindner L, Abdel-Rahman S, Hiddemann W, Issels RD. Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS). Int J Hyperthermia
2010; 26:127–135. doi: 10.3109/02656730903335995.
16. Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, et al. Effect of neoadjuvant chemotherapy
plus regional hyperthermia
on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 randomized clinical trial. JAMA Oncol
2018; 4:483–492. doi: 10.1001/jamaoncol.2017.4996.
17. Raoof M, Zhu C, Cisneros BT, Liu H, Corr SJ, Wilson LJ, et al. Hyperthermia
inhibits recombination repair of gemcitabine-stalled replication forks. JNCI: J Natl Cancer Inst
2014; 106:dju183doi: 10.1093/jnci/dju183.
18. Mohamed F, Marchettini P, Stuart OA, Urano M, Sugarbaker PH. Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia
. Ann Surg Oncol
2003; 10:463–468. doi: 10.1245/ASO.2003.08.006.
19. Maehara Y, Sakaguchi Y, Takahashi I, Yoshida M, Kusumoto H, Masuda H, et al. 5-Fluorouracil's cytotoxicity is enhanced both in vitro and in vivo by concomitant treatment with hyperthermia
and dipyridamole. Cancer Chemother Pharmacol
1992; 29:257–260. doi: 10.1007/BF00685941.
20. Raaphorst GP, Yang DP. The evaluation of thermal cisplatin sensitization in normal and XP human cells using mild hyperthermia
at 40 and 41 degrees C. Anticancer Res
21. Takemoto M, Kuroda M, Urano M, Nishimura Y, Kawasaki S, Kato H, et al. The effect of various chemotherapeutic agents given with mild hyperthermia
on different types of tumours. Int J Hyperthermia
2003; 19:193–203. doi: 10.1080/0265673021000035235.
22. Raaphorst GP, Li LF, Yang DP, LeBlanc JM. Cisplatin sensitization by concurrent mild hyperthermia
in parental and mutant cell lines deficient in homologous recombination and non-homologous endjoining repair. Oncol Rep
23. Wiedemann G, Roszinski S, Biersack A, Weiss C, Wagner T. Local hyperthermia
enhances cyclophosphamide, ifosfamide and cis-diamminedichloroplatinum cytotoxicity on human-derived breast carcinoma and sarcoma xenografts in nude mice. J Cancer Res Clin Oncol
1992; 118:129–135. doi: 10.1007/BF01187501.
24. Gerad H, van Echo DA, Whitacre M, Ashman M, Helrich M, Foy J, et al. Doxorubicin, cyclophosphamide, and whole body hyperthermia
for treatment of advanced soft tissue sarcoma. Cancer
1984; 53:2585–2591. doi: 10.1002/1097-0142(19840615)53:12<2585::AID-CNCR2820531203>3.0.CO;2-2.
25. Urano M, Ling CC. Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro. Int J Hyperthermia
2002; 18:307–315. doi: 10.1080/02656730210123534.
26. Orlandi L, Zaffaroni N, Bearzatto A, Costa A, Supino R, Vaglini M, et al. Effect of melphalan and hyperthermia
on cell cycle progression and cyclin B1 expression in human melanoma cells. Cell Prolif
1995; 28:617–630. doi: 10.1111/j.2040-1124.2010.00046.
27. Ng CE, Bussey AM, Raaphorst GP. Sequence of treatment is important in the modification of camptothecin induced cell killing by hyperthermia
. Int J Hyperthermia
1996; 12:663–678. discussion 679-680. doi: 10.3109/02656739609027674.
28. Krawczyk PM, Eppink B, Essers J, Stap J, Rodermond H, Odijk H, et al. Mild hyperthermia
inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc Natl Acad Sci U S A
2011; 108:9851–9856. doi: 10.1073/pnas.1101053108.
29. Eppink B, Krawczyk PM, Stap J, Kanaar R. Hyperthermia
-induced DNA repair deficiency suggests novel therapeutic anti-cancer strategies. Int J Hyperthermia
2012; 28:509–517. doi: 10.3109/02656736.2012.695427.
30. Park HJ, Choi EK, Choi J, Ahn KJ, Kim EJ, Ji IM, et al. Heat-induced up-regulation of NAD(P)H:quinone oxidoreductase potentiates anticancer effects of beta-lapachone. Clin Cancer Res
2005; 11:8866–8871. doi: 10.1158/1078-0432.ccr-05-0818.
31. Ihara M, Takeshita S, Okaichi K, Okumura Y, Ohnishi T. Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repair. Int J Hyperthermia
2014; 30:102–109. doi: 10.3109/02656736.2014.887793.
32. Ohguri T, Imada H, Yahara K, Morioka T, Nakano K, Terashima H, et al. Radiotherapy with 8-MHz radiofrequency-capacitive regional hyperthermia
for stage III non-small-cell lung cancer: the radiofrequency-output power correlates with the intraesophageal temperature and clinical outcomes. Int J Radiat Oncol Biol Phys
2009; 73:128–135. doi: 10.1016/j.ijrobp.2008.03.059.
33. Augusto AC, Miguel F, Mendonca S, Pedrazzoli J Jr, Gurgueira SA. Oxidative stress expression status associated to Helicobacter pylori virulence in gastric diseases. Clin Biochem
2007; 40:615–622. doi: 10.1016/j.clinbiochem.2007.03.014.
34. Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, et al. Neo-adjuvant chemotherapy
alone or with regional hyperthermia
for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol
2010; 11:561–570. doi: 10.1016/s1470-2045(10)70071-1.
35. Klodzinska A, Chojnacka-Wojcik E. Hyperthermia
induced by m-trifluoromethylphenylpiperazine (TFMPP) or m-chlorophenylpiperazine (m-CPP) in heat-adapted rats. Psychopharmacology
1992; 109:466–472. doi: 10.1007/BF02247725.
36. Thomas JM, Musani AI. Malignant pleural effusions: a review. Clin Chest Med
2013; 34:459–471. doi: 10.1016/j.ccm.2013.05.004.
37. Hu R, Ma S, Ke X, Jiang H, Wei D, Wang W. Effect of interleukin-2 treatment combined with magnetic fluid hyperthermia
on Lewis lung cancer-bearing mice. Biomed Rep
2016; 4:59–62. doi: 10.3892/br.2015.540.