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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 4  |  Page : 165-169

Promising role of hyperthermia concurrent with radiation in the treatment of head-and-neck cancers: A retrospective comparative study


1 Department of Radiation Oncology, Nanavati Superspeciality Hospital, Mumbai, Maharashtra, India
2 Department of Advanced Centre for Radiation Oncology, Dr. Balabhai Nanavati Hospital, Mumbai, Maharashtra, India

Date of Submission29-Jan-2020
Date of Acceptance01-Feb-2020
Date of Web Publication14-Feb-2020

Correspondence Address:
Dr. Nagraj G Huilgol
Department of Radiation Oncology, Nanavati Superspeciality Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_3_20

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  Abstract 


Aim: We aimed to investigate retrospectively the cases of head-and-neck cancer treated with hyperthermia along with radiation in comparison with chemoradiation in terms of local control, survival, and toxicities. Materials and Methods: One hundred twenty-seven cases of head-and-neck cancer who were treated in our department during the period of 2005–2017 with radiation, chemotherapy, and hyperthermia were analyzed. All the patients underwent radiation treatment on Elekta Precise with 6 MV photons to a planned dose of 66–70 Gy. Hyperthermia was delivered on modified Thermatron, Japan, which is a radio frequency-based heating device operating at 9 MHZ. Hyperthermia was initiated after precooling for 5–10 min and impedance matching. The input energy was gradually raised over 2–3 min to the tolerance limits. Input varied from 400 to 800 kW. Cases enrolled in the CTRT group were 74, whereas 53 cases were in HTRT group. Results: In CTRT group, 49 (66.2%) cases had complete response as compared to 48 (90.6%) cases in HTRT group with statistical significance with P= 0.001. Kaplan–Meir survival curve showed a statistical benefit in those treated with CTRT over HTRT. The mean survival in HTRT group was 45.3 months and the median survival was 41.7 months. In the CTRT group, the median survival was 51.5 months and the mean survival was 55.6 months. However, more patients were lost to follow-up in the HTRT group. The difference between median survival times between CTRT and HTRT groups was more than 3 months and 10 days. Conclusion: Combining hyperthermia with radiation gives better results in terms of response, toxicities, and survival and can be used in the treatment of head-and-neck cancer patients in all stages. Better patient follow-up would have given much accurate data for the analysis of toxicities.

Keywords: Chemoradiation (CTRT), hyperthermia with radiation (HTRT), hyperthermia


How to cite this article:
Huilgol NG, Pemmaraju G, Dusane R. Promising role of hyperthermia concurrent with radiation in the treatment of head-and-neck cancers: A retrospective comparative study. J Radiat Cancer Res 2019;10:165-9

How to cite this URL:
Huilgol NG, Pemmaraju G, Dusane R. Promising role of hyperthermia concurrent with radiation in the treatment of head-and-neck cancers: A retrospective comparative study. J Radiat Cancer Res [serial online] 2019 [cited 2020 Feb 18];10:165-9. Available from: http://www.journalrcr.org/text.asp?2019/10/4/165/278409




  Introduction Top


Head-and-neck cancers represent the sixth most prevalent cancer worldwide. The 5-year survival rate is about 50% of all sites and stages. Radiotherapy has been used either alone as a definitive treatment or in combination with chemotherapy in the management of head-and-neck cancers. As tumor hypoxia is known to confer radioresistance in head-and-neck cancers, numerous trials have been undertaken to explore to sensitize hypoxic cell fraction using a wide range of hypoxic cell sensitizers such as senazole, nimorazole, and hyperbaric oxygen.[1],[2]

Hyperthermia is a promising therapeutics of cancer including surgery, chemotherapy, radiotherapy, and immunotherapy. Hyperthermia helps to improve clinical response and reduces toxicities when used in combination with radiotherapy or chemotherapy.[3]

Hyperthermia at 39°C–45°C is the most potent radiosensitizer through the inhibition of DNA damage repair and sensitization of “S” phase cells besides hypoxic cell sensitization, particularly of nutritionally deficient cells at low pH.[2] There is evidence to prove that hyperthermia combined with radiotherapy has better clinical outcomes in malignancies of the pelvis, breast, sarcoma, and head and neck.[4],[5],[6],[7]

The addition of chemotherapy to radiotherapy in nonmetastatic squamous cell carcinomas of the head and neck gives a better control and survival benefit than radiotherapy alone (meta-analysis of chemotherapy in head-and-neck cancer)[8] but with higher toxicity rates.[9] Concurrent chemoradiation has been the preferred mode of treatment in locally advanced head-and-neck cancers, as the addition of chemotherapy has improved the clinical outcome by around 4%–6% as compared to radiotherapy alone.

Radiation with hyperthermia which has shown improved outcomes [12] has been practiced in lieu of chemotherapy in the past and in certain selected cases in the recent past.

The present study aims at comparing the results of treatment with hyperthermia with radiotherapy and chemotherapy with radiotherapy retrospectively.


  Materials and Methods Top


This study was a retrospective analysis of 127 cases of head-and-neck cancers who were treated in our department during the period of 2005–2017 with radiation, chemotherapy, and hyperthermia. Written consent was obtained before the start of treatment. The analysis was done in terms of immediate response, toxicity, and survival. A comparison was done between hyperthermia plus radiation and chemotherapy with radiation groups and the results were analyzed.

Patients' archived files were retrieved and tabulated for demographics, frequency of hyperthermia sessions, dose of radiation, and response. Patients all of them underwent radiation treatment on Elekta Precise with 6 MV photons. Patients were treated with intensity-modulated radiation therapy except a few of them who received treatment by conventional technique. Patients were treated with conventional fractionation 5 days a week to a planned dose of 66–70 Gy. Hyperthermia was delivered on modified Thermatron, Japan, which is a radio frequency-based heating device operating at 9 MHZ. Patients were treated in a recumbent position with electrodes placed across the neck to encompass both the primary and metastatic neck nodes. Patients with thick and fat neck were excluded from the treatment. The dominant antenna was placed in close proximity to the side of the tumor. Patients with bilateral neck node were not included for hyperthermia.

Hyperthermia was initiated after precooling for 5–10 min and impedance matching. The input energy was gradually raised over 2–3 min to the tolerance limits. Input varied from 400 to 800 kW.

Patients were monitored every week for mucositis, thermal burns, and nutritional status. All the adverse sequelae due to radiation were addressed by the attending doctor.

The response was graded according to the response evaluation criteria in solid tumors 1.1 as complete, partial, and no response or progressive disease. Mucositis was graded from I to IV. Skin reaction due to radiation was recorded for dry and wet desquamation. Thermal burns were noted and classified as superficial or deep.


  Results Top


Patients who underwent radical radiation treatment with or without hyperthermia for locally advanced head-and-neck cancer between 2005 and 2017 were retrospectively analyzed.

A total of 127 cases were included in the study. Patients were categorized into two groups: hyperthermia with radiation (HTRT) and chemotherapy with radiation (CTRT). Cases enrolled in the CTRT group were 74, whereas 53 cases were in the HTRT group.

The mean age in the CTRT group was 57.61 years as compared to 63.66 years in the HTRT group. There was a preponderance of males in both the groups 64 patients in CTRT and 50 patients in the HTRT group with no statistically significant difference [Table 1].
Table 1: Demographics

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  • In the present study, the age of the cases was ranging from 31.00 to 88.00 years with the average age being 57.61 years among CT + RT, which was significantly less as compared to 63.66 years among HT + RT
  • About 86.5% of the cases were male among CT + RT which was less as compared to 94.3% of the cases among HT + RT, but the difference was not significant.


The hypopharyngeal and oral cavity cases were 23 and 22, respectively, were more in the CTRT group, whereas 24 laryngeal cancer cases were predominant in the HTRT group [Figure 1] and [Table 2].
Figure 1: Comparison of sites between the groups

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Table 2: Comparision between sites and groups

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Profile of sites in both the groups

Patients were staged as per the TNM system of stratification 1978 (Union for International Cancer Control). A maximum number of patients in both CTRT and HTRT groups have Stage III malignancy. There was no statistically significant difference between the two groups.

Comparison of stages between the groups

In this study, 47.3% of the cases belonged to Stage III among CT + RT, which was more as compared to 32.1% in HT + RT, but the difference was not significant [Figure 2] and [Table 3].
Figure 2: Comparison of stages between the groups

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Table 3: Comparision between stages and groups

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The initial follow-up of patients after completion of the treatment was 6 weeks, subsequent follow-ups were 3 monthly for the 1st year after completion of the treatment, 6 monthly in 2nd year, and yearly thereafter.

In CTRT group, 49 (66.2%) cases had a complete response as compared to 48 (90.6%) cases in HTRT group, 21 (28.4%) cases in CTRT, and 4 (7.5%) cases in HTRT group had Partial response with P = 0.001, which was statistically significant [Figure 3].
Figure 3: Comparison of response between the groups

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Comparison of response between the groups

About 66.2% of the cases had complete response among CT + RT, which was significantly less as compared to 90.6% among HT + RT.

The maximum number of patients who had complete response in both the groups belonged to Stage– II followed by Stage III; there was no statistically significant difference (P = 0.967) between the two groups [Table 4].
Table 4: Comparision of response between groups

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Association between stages and response

Among CT + RT group

About 84.6% of the cases with Stage II had a clinical response which was more as compared to 51.4% of the cases with Stage III and 73.1% of the cases with Stage IV, but the difference was not significant [Figure 4] and [Table 5].
Figure 4: Association between stages and response among CT + RT group

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Table 5: Association between stages and response among CT+RT group

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Association between stages and response

Among HT + RT group

Nearly 92.3% of the cases with Stage II had a clinical response which was more as compared to other stages, but the difference was not significant [Figure 5] and [Table 6].
Figure 5: Association between stages and response among HT + RT group

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Table 6: Association between stages and response among HT +RT group

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  Discussion Top


Head-and-neck cancers constitute a very heterogeneous group with diverse phenotypes. The treatment of these cancers is complex with multiple modalities deployed in various combinations. Chemoradiation is now considered a standard of care in those locally advanced patients of head-and-neck cancers who are suitable to receive chemotherapy.[10] A large number of patients who remain ineligible for chemotherapy face an unmet need. Hyperthermia which has shown to be effective in clinical trials is an avenue which has been inadequately explored. The current retrospective analysis helps to fill in the gap.[11]

The initial response in the HTRT group was 90.6% as compared to 66.2% in the CTRT group. However, the overall survival (26.7%) is more in the CTRT group at 24 months. The patients who were lost to follow-up are more in the HTRT group which may be the reason for the difference. The initial response may be a good surrogate marker for disease-free survival but not overall survival. Patients alive in both the groups were 22 (29.7%) in CTRT and 15 (28.3%) in the HTRT group, which was not statistically significant (P = 0.861).

The administration of chemoradiation can be challenging in those with compromised liver and renal functions, poor performance status, and considerable comorbidities. The addition of hyperthermia in lieu of chemotherapy or biologicals is an option which is worth exploring. The present study has shown a very high initial response as compared to chemoradiation. The median survival which is significantly better in CTRT seen in this retrospective analysis will need a larger study for confirmation.

A prospective randomized trial is unlikely to be conducted ever. A pooled retrospective analysis of data with a better follow-up should help.


  Conclusion Top


Combining hyperthermia with radiation gives better results in terms of response, toxicities and survival and can be used in the treatment of head and neck cancer patients in all stages. Better patient follow up would have given much accurate data for analysis of toxicities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Henk JM, Bishop K, Shepherd SF. Treatment of head and neck cancer with CHART and nimorazole: Phase II study. Radiother Oncol 2003;66:65-70.  Back to cited text no. 1
    
2.
Adams GE, Dische S, Fowler JF, Thomlinson RH. Hypoxic cell sensitisers in radiotherapy. Lancet 1976;1:186-8.  Back to cited text no. 2
    
3.
Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck – A systematic review and meta-analysis. Radiother Oncol 2011;100:22-32.  Back to cited text no. 3
    
4.
Falk MH, Issels RD. Hyperthermia in oncology. Int J Hyperthermia 2001;17:1-8.  Back to cited text no. 4
    
5.
van der Zee J, González González D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: A prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 2000;355:1119-25.  Back to cited text no. 5
    
6.
Valdagni R, Amichetti M, Pani G. Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: A prospective randomized clinical trial. Int J Radiat Oncol Biol Phys 1988;15:13-24.  Back to cited text no. 6
    
7.
Huilgol NG, Gupta S, Sridhar CR. Hyperthermia with radiation in the treatment of locally advanced head and neck cancer: A report of randomized trial. J Cancer Res Ther 2010;6:492-6.  Back to cited text no. 7
    
8.
Blanchard P, Baujat B, Holostenco V, Bourredjem A, Baey C, Bourhis J, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): A comprehensive analysis by tumour site. Radiother Oncol 2011;100:33-40.  Back to cited text no. 8
    
9.
Le X, Hanna EY. Optimal regimen of cisplatin in squamous cell carcinoma of head and neck yet to be determined. Ann Transl Med 2018;6:229.  Back to cited text no. 9
    
10.
Iqbal MS, Chaw C, Kovarik J, Aslam S, Jackson A, Kelly J, et al. Primary concurrent chemoradiation in head and neck cancers with weekly cisplatin chemotherapy: Analysis of compliance, toxicity and survival. Int Arch Otorhinolaryngol 2017;21:171-7.  Back to cited text no. 10
    
11.
Datta NR, Rogers S, Ordóñez 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;32:31-40.  Back to cited text no. 11
    
12.
Gao S, Zheng M, Ren X, Tang Y, Liang X. Local hyperthermia in head and neck cancer: Mechanism, application and advance. Oncotarget 2016;7:57367-78.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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