Long-Term Feasibility of 13.56 MHz Modulated Electro-Hyperthermia-Based Preoperative Thermoradiochemotherapy in Locally Advanced Rectal Cancer

Yohan Lee, Sunghyun Kim, Hyejung Cha, Jae Hun Han, Hyun Joon Choi, Eun Go, Sei Hwan You, Yohan Lee, Sunghyun Kim, Hyejung Cha, Jae Hun Han, Hyun Joon Choi, Eun Go, Sei Hwan You

Abstract

We evaluated the effect of 13.56 MHz modulated electro-hyperthermia (mEHT) boost in neoadjuvant treatment for cT3-4- or cN-positive rectal cancer. Sixty patients who completed the mEHT feasibility trial (ClinicalTrials.gov Identifier: NCT02546596) were analyzed. Whole pelvis radiotherapy of 40 Gy, mEHT boost twice a week during radiotherapy, and surgical resection 6-8 weeks following radiotherapy were performed. The median age was 59. The median follow-up period was 58 (6-85) months. Total/near total tumor regression was observed in 20 patients (33.3%), including nine cases of complete response. T- and N-downstaging was identified in 40 (66.6%) and 53 (88.3%) patients, respectively. The 5-year overall and disease-free survival were 94.0% and 77.1%, respectively. mEHT energy of ≥3800 kJ potentially increased the overall survival (p = 0.039). The ypN-stage and perineural invasion were possible significant factors in disease-free (p = 0.003 and p = 0.005, respectively) and distant metastasis-free (p = 0.011 and p = 0.034, respectively) survival. Tumor regression, resection margin status, and other molecular genetic factors showed no correlation with survival. Although a limited analysis of a small number of patients, mEHT was feasible considering long-term survival. A relatively low dose irradiation (40 Gy) plus mEHT setting could ensure comparable clinical outcomes with possible mEHT-related prognostic features.

Keywords: neoadjuvant chemoradiation; rectal cancer; regional hyperthermia; survival.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CONSORT diagram (CRT: chemoradiation, mEHT: modulated electro-hyperthermia).
Figure 2
Figure 2
Energy profile of modulated electro-hyperthermia (mEHT) at each mEHT session (a) and from the perspective of total value line-up (b).
Figure 2
Figure 2
Energy profile of modulated electro-hyperthermia (mEHT) at each mEHT session (a) and from the perspective of total value line-up (b).
Figure 3
Figure 3
Survival analysis of the study population. (a) Overall survival, (b) disease-free survival, (c) loco-regional recurrence-free survival, and (d) distant metastasis-free survival.
Figure 3
Figure 3
Survival analysis of the study population. (a) Overall survival, (b) disease-free survival, (c) loco-regional recurrence-free survival, and (d) distant metastasis-free survival.
Figure 4
Figure 4
Survival comparison according to modulated electro-hyperthermia (mEHT) total energy by log rank test. (a) Overall survival, (b) disease-free survival.
Figure 4
Figure 4
Survival comparison according to modulated electro-hyperthermia (mEHT) total energy by log rank test. (a) Overall survival, (b) disease-free survival.
Figure 5
Figure 5
Survival comparison according to perineural invasion by log rank test. (a) Overall survival, (b) disease-free survival (CR: complete response, PNI: perineural invasion).
Figure 5
Figure 5
Survival comparison according to perineural invasion by log rank test. (a) Overall survival, (b) disease-free survival (CR: complete response, PNI: perineural invasion).

References

    1. De Haas-Kock D.F., Buijsen J., Pijls-Johannesma M., Lutgens L., Lammering G., van Mastrigt G.A., De Ruysscher D.K., Lambin P., van der Zee J. Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane Database Syst. Rev. 2009;3:CD006269. doi: 10.1002/14651858.CD006269.pub2.
    1. Vancsik T., Kovago C., Kiss E., Papp E., Forika G., Benyo Z., Meggyeshazi N., Krenacs T. Modulated electro-hyperthermia induced loco-regional and systemic tumor destruction in colorectal cancer allografts. J. Cancer. 2018;9:41–53. doi: 10.7150/jca.21520.
    1. Kuo I.M., Lee J.J., Wang Y.S., Chiang H.C., Huang C.C., Hsieh P.J., Han W., Ke C.H., Liao A.T.C., Lin C.S. Potential enhancement of host immunity and anti-tumor efficacy of nanoscale curcumin and resveratrol in colorectal cancers by modulated electro- hyperthermia. BMC Cancer. 2020;20:603. doi: 10.1186/s12885-020-07072-0.
    1. Krenacs T., Meggyeshazi N., Forika G., Kiss E., Hamar P., Szekely T., Vancsik T. Modulated electro-hyperthermia-induced tumor damage mechanisms revealed in cancer models. Int. J. Mol. Sci. 2020;21:6270. doi: 10.3390/ijms21176270.
    1. Andocs G., Renner H., Balogh L., Fonyad L., Jakab C., Szasz A. Strong synergy of heat and modulated electromagnetic field in tumor cell killing. Strahlenther. Onkol. 2009;185:120–126. doi: 10.1007/s00066-009-1903-1.
    1. Lee S.Y., Kim J.H., Han Y.H., Cho D.H. The effect of modulated electro-hyperthermia on temperature and blood flow in human cervical carcinoma. Int. J. Hyperth. 2018;34:953–960. doi: 10.1080/02656736.2018.1423709.
    1. You S.H., Kim S. Feasibility of modulated electro-hyperthermia in preoperative treatment for locally advanced rectal cancer: Early phase 2 clinical results. Neoplasma. 2020;67:677–683. doi: 10.4149/neo_2020_190623N538.
    1. Dworak O., Keilholz L., Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int. J. Colorectal. Dis. 1997;12:19–23. doi: 10.1007/s003840050072.
    1. Cox J.D., Stetz J., Pajak T.F. Toxicity criteria of the radiation therapy oncology group (rtog) and the european organization for research and treatment of cancer (eortc) Int. J. Radiat. Oncol. Biol. Phys. 1995;31:1341–1346. doi: 10.1016/0360-3016(95)00060-C.
    1. Rau B., Wust P., Hohenberger P., Loffel J., Hunerbein M., Below C., Gellermann J., Speidel A., Vogl T., Riess H., et al. Preoperative hyperthermia combined with radiochemotherapy in locally advanced rectal cancer: A phase ii clinical trial. Ann. Surg. 1998;227:380–389. doi: 10.1097/00000658-199803000-00010.
    1. Kim S., Lee J.H., Cha J., You S.H. Beneficial effects of modulated electro-hyperthermia during neoadjuvant treatment for locally advanced rectal cancer. Int. J. Hyperth. 2021;38:144–151. doi: 10.1080/02656736.2021.1877837.
    1. Kang M.K., Kim M.S., Kim J.H. Clinical outcomes of mild hyperthermia for locally advanced rectal cancer treated with preoperative radiochemotherapy. Int. J. Hyperth. 2011;27:482–490. doi: 10.3109/02656736.2011.563769.
    1. Haddad P., Ghalehtaki R., Saeedian A., Farhan F., Babaei M., Aghili M. Current approaches in intensification of long-course chemoradiotherapy in locally advanced rectal cancer: A review. Radiat. Oncol. J. 2021;39:83–90. doi: 10.3857/roj.2021.00108.
    1. Ott O.J., Gani C., Lindner L.H., Schmidt M., Lamprecht U., Abdel-Rahman S., Hinke A., Weissmann T., Hartmann A., Issels R.D., et al. Neoadjuvant chemoradiation combined with regional hyperthermia in locally advanced or recurrent rectal cancer. Cancers. 2021;13:1279. doi: 10.3390/cancers13061279.
    1. Fiorentini G., Sarti D., Casadei V., Milandri C., Dentico P., Mambrini A., Nani R., Fiorentini C., Guadagni S. Modulated electro-hyperthermia as palliative treatment for pancreatic cancer: A retrospective observational study on 106 patients. Integr. Cancer Ther. 2019;18:1534735419878505. doi: 10.1177/1534735419878505.
    1. Minnaar C.A., Kotzen J.A., Ayeni O.A., Naidoo T., Tunmer M., Sharma V., Vangu M.D., Baeyens A. 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:e0217894. doi: 10.1371/journal.pone.0217894.
    1. Schroeder C., Gani C., Lamprecht U., von Weyhern C.H., Weinmann M., Bamberg M., Berger B. Pathological complete response and sphincter-sparing surgery after neoadjuvant radiochemotherapy with regional hyperthermia for locally advanced rectal cancer compared with radiochemotherapy alone. Int. J. Hyperth. 2012;28:707–714. doi: 10.3109/02656736.2012.722263.
    1. Maluta S., Romano M., Dall’oglio S., Genna M., Oliani C., Pioli F., Gabbani M., Marciai N., Palazzi M. Regional hyperthermia added to intensified preoperative chemo-radiation in locally advanced adenocarcinoma of middle and lower rectum. Int. J. Hyperth. 2010;26:108–117. doi: 10.3109/02656730903333958.
    1. Tsutsumi S., Tabe Y., Fujii T., Yamaguchi S., Suto T., Yajima R., Morita H., Kato T., Shioya M., Saito J., et al. Tumor response and negative distal resection margins of rectal cancer after hyperthermochemoradiation therapy. Anticancer Res. 2011;31:3963–3967.
    1. Kato T., Fujii T., Ide M., Takada T., Sutoh T., Morita H., Yajima R., Yamaguchi S., Tsutsumi S., Asao T., et al. Effect of long interval between hyperthermochemoradiation therapy and surgery for rectal cancer on apoptosis, proliferation and tumor response. Anticancer Res. 2014;34:3141–3146.
    1. Cui L., Shi Y., Zhang G.N. Perineural invasion as a prognostic factor for cervical cancer: A systematic review and meta-analysis. Arch. Gynecol. Obstet. 2015;292:13–19. doi: 10.1007/s00404-015-3627-z.
    1. Fagan J.J., Collins B., Barnes L., D’Amico F., Myers E.N., Johnson J.T. Perineural invasion in squamous cell carcinoma of the head and neck. Arch. Otolaryngol.-Head Neck Surg. 1998;124:637–640. doi: 10.1001/archotol.124.6.637.
    1. Huh J.W., Kim H.R., Kim Y.J. Prognostic value of perineural invasion in patients with stage ii colorectal cancer. Ann. Surg. Oncol. 2010;17:2066–2072. doi: 10.1245/s10434-010-0982-7.
    1. Peng J., Sheng W., Huang D., Venook A.P., Xu Y., Guan Z., Cai S. Perineural invasion in pt3n0 rectal cancer: The incidence and its prognostic effect. Cancer. 2011;117:1415–1421. doi: 10.1002/cncr.25620.
    1. Liebig C., Ayala G., Wilks J., Verstovsek G., Liu H., Agarwal N., Berger D.H., Albo D. Perineural invasion is an independent predictor of outcome in colorectal cancer. J. Clin. Oncol. 2009;27:5131–5137. doi: 10.1200/JCO.2009.22.4949.
    1. Shapiro J., van Lanschot J.J.B., Hulshof M., van Hagen P., van Berge Henegouwen M.I., Wijnhoven B.P.L., van Laarhoven H.W.M., Nieuwenhuijzen G.A.P., Hospers G.A.P., Bonenkamp J.J., et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (cross): Long-term results of a randomised controlled trial. Lancet Oncol. 2015;16:1090–1098. doi: 10.1016/S1470-2045(15)00040-6.
    1. Yang H., Liu H., Chen Y., Zhu C., Fang W., Yu Z., Mao W., Xiang J., Han Y., Chen Z., et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (neocrtec5010): A phase iii multicenter, randomized, open-label clinical trial. J. Clin. Oncol. 2018;36:2796–2803. doi: 10.1200/JCO.2018.79.1483.
    1. Gani C., Schroeder C., Heinrich V., Spillner P., Lamprecht U., Berger B., Zips D. Long-term local control and survival after preoperative radiochemotherapy in combination with deep regional hyperthermia in locally advanced rectal cancer. Int. J. Hyperth. 2016;32:187–192. doi: 10.3109/02656736.2015.1117661.
    1. Gani C., Lamprecht U., Ziegler A., Moll M., Gellermann J., Heinrich V., Wenz S., Fend F., Konigsrainer A., Bitzer M., et al. Deep regional hyperthermia with preoperative radiochemotherapy in locally advanced rectal cancer, a prospective phase ii trial. Radiother. Oncol. 2021;159:155–160. doi: 10.1016/j.radonc.2021.03.011.

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