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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 1  |  Page : 15-18

Fungal flora changes in head-and-neck cancer patients receiving radiotherapy


Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka, India

Date of Submission16-Dec-2020
Date of Acceptance13-Jan-2021
Date of Web Publication12-Feb-2021

Correspondence Address:
Dr. B Sandesh Rao
Department of Radiation Oncology, Father Muller Medical College, Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_70_20

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  Abstract 


Background: Oral mucositis is one of the primary toxicities of radiation in head-and-neck radiotherapy (RT). Oral fungal microflora changes have been studied to aggravate the inflammatory process leading to mucositis. The study evaluated the changes in oral fungal microflora during RT in head-and-neck cancer (HNC) using a single-institutional, prospective research and its correlation with oral mucositis. Subjects and Methods: A prospective single-institutional study was conducted on 68 biopsy-proven HNC patients on RT with or without chemotherapy treated in the Department of Radiation Oncology at Father Muller Medical College, Mangalore, between 2015 and 2017. Three samples of saliva were collected before RT, the end of the 3rd week of RT, and 4 weeks after the completion of RT and assessed for developing fungal flora changes by Sabouraud's dextrose agar growth media and CHROMagar in the number of patients. Mucositis grades are correlated with fungal pathogens. Statistical analysis was on fungal changes and mucositis using mean, percentage, standard deviation, and Chi-square test. Results: An increase in fungal microflora was found in patients receiving radiation or chemoradiation in head-and-neck malignancy. Among them, a significant increase was there in Candida albicans (1.5% of patients before RT to 44.1% of patients during RT) and Candida krusei (1.5% of patients before RT to 10.5% of patients during RT) during RT (P < 0.05). Aspergillus fumigatus was found during radiation and absent before and after radiation. Mucositis during radiation had a nonsignificant increasing trend for A. fumigatus and Candida species. Conclusion: There was a significant increase in C. albicans and C. krusei during RT when compared to before RT. A better understanding of the oral microflora's role in developing oral mucositis is needed to mitigate symptoms and improve treatment tolerance.

Keywords: Fungal flora, head-and-neck cancer, mucositis, radiotherapy


How to cite this article:
Reddy PK, Hasib A G, Rao B S, Athiyamaan M S, Shankar S, Sophia J M. Fungal flora changes in head-and-neck cancer patients receiving radiotherapy. J Radiat Cancer Res 2021;12:15-8

How to cite this URL:
Reddy PK, Hasib A G, Rao B S, Athiyamaan M S, Shankar S, Sophia J M. Fungal flora changes in head-and-neck cancer patients receiving radiotherapy. J Radiat Cancer Res [serial online] 2021 [cited 2021 Jun 25];12:15-8. Available from: https://www.journalrcr.org/text.asp?2021/12/1/15/309343




  Introduction Top


Head-and-neck cancer (HNC) (squamous cell carcinoma) is the sixth leading cancer by incidence worldwide.[1] Oral mucositis, which is the primary acute toxicity of radiotherapy (RT) in HNC patients, is exacerbated by chemotherapy. Inadequate management of mucositis can cause pain, weight loss, the requirement of feeding tubes, and low quality of life, leading to poor clinical outcomes.

The delicate balance between commensal microflora and host immune homeostasis can be changed by cancer itself and anticancer management. The impact of resident microflora in aggravating the inflammatory process, which is one of the stages involved in mucositis, has been studied well.[2] This study aims to assess the changes in oral microflora that can impact therapeutic intervention.


  Subjects and Methods Top


This study was a single-institutional, prospective study. Ethical clearance was obtained from the institutional ethics committee before the start of the study.

We analyzed 68 patients with biopsy-proven HNC treated in the Department of RT in Father Muller Medical College, Mangalore, from 2015 to 2017 of age group 18–80 years. All patients were treated by definitive radiation with intensity-modulated radiation therapy (IMRT) using standard planning objectives for Organ at risk like for the parotid gland, spinal cord, brain stem, etc., as per the Quantitative Analyses of Normal Tissue Effects in the Clinic guidelines. Patients with a history of surgery for the same, patients who received prior RT, and patients with uncontrolled diabetes and HIV positive were excluded. During RT, the maximum grade of mucositis was recorded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Mucositis was treated by analgesics and local anesthetic gels. Patients who developed oral candidiasis were treated with local antifungal lozenges initially, and if not subsided, systemic antifungal agents were added. All patients responded to antifungal treatment.

Samples were collected from the patients after rinsing their mouth with water and waited 10 min before commencing with the collection. Saliva from patients will be collected by resting (drooling method)/mechanical stimulation before the start of external beam RT, the end of the 3rd week of treatment, and 4 weeks after finishing treatment. The samples were subjected to fungal culture in Sabouraud's dextrose agar growth media. An interpretation was made after an incubation period of 24 h at 25°C. Candida species colonies appeared as cream colored, smooth, and pasty.[3] Aspergillus fumigatus colonies appeared as powdery at first white and then turned dark greenish.[4] Lactophenol cotton blue mount was done for confirmation. Further identification of various Candida species was made on CHROMagar based on colony morphology and color after an incubation period of 2–3 days at 30°C as per [Table 1].
Table 1: Color of different Candida species on CHROMagar[5]

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Statistical analysis

The statistical software IBM® SPSS® 16.0 was used for the analysis. The mean, median, and standard deviation were assessed for all patients for patient characteristics, mucositis, and fungal growth. The statistical comparison was made using McNemar's Chi-square tests. P < 0.05 was considered as statistically significant.


  Results Top


The study group included 68 patients, out of which males constituted 82.4% (56/68) and females 17.6% (12/68). The age of the treated patients ranged from 30 to 80 years (median age of 56). The most common site was oropharyngeal cancer constituting 41% (28/68), followed by hypopharyngeal cancer 27% (18/68), oral cavity cancers 16% (11/68), laryngeal cancer 13% (9/68), and nasopharyngeal cancer 3% (2/68). About 58% of the cases were in Stage IVa (40/68) at the time of presentation. Stage III was seen in 22% (15/68), Stage II 14% (10/68), and Stage IVb 4% (3/68).

All 68 patients received definitive RT of 70 Gy in 35 fractions with or without concurrent chemotherapy. About 97% (66/68) received RT by IMRT and 3% (2/68) by three-dimensional conformal radiotherapy. Ninety-three percent (63/68) received concurrent chemotherapy, out of which 78% received cisplatin, 7% carboplatin, 6% cisplatin + nimotuzumab, and 1 patient cisplatin + paclitaxel. The patient characteristics are given in [Table 2].
Table 2: Patient characteristics

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Fungal microflora changes

The most commonly identified fungal organisms are Candida albicans, Candida tropicalis, and Candida krusei. There was a significant increase in C. albicans from 1.5% of patients before irradiation to 44% of patients during irradiation (P < 0.001) and C. krusei from 1.5% of patients before irradiation to 10.3% of patients (P = 0.031). Furthermore, C. tropicalis increased by 17% from before irradiation to during irradiation. On comparing during irradiation and after irradiation, there was a significant reduction in C. albicans, C. tropicalis, and C. krusei but is present after irradiation in 25%, 4.4%, and 1.5%, respectively. A. fumigatus is seen in 2.9% during irradiation when compared to none before and after irradiation.

[Table 3] shows changes during radiotherapy as all four fungal species will increase during radiation, but after radiation therapy, they will reduce.
Table 3: Trend of fungal growth during radiation

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[Figure 1] shows fungal growth changes. There is a significant increase in C. albicans during radiation, which start reducing postradiation.
Figure 1: Fungal growth changes

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Correlation of the highest grade of mucositis developed by patients during RT with fungal flora changes was done. During treatment, 27 (39.7%) had Grade III mucositis. Microorganisms isolated during RT associated with Grade III mucositis were A. fumigatus (7.4%), C. albicans (55%), C. krusei (11%), and Candida tropicalis (22%). Patients with A. fumigatus and Candida species showed an increasing trend of Grade III mucositis than Grade II mucositis, although not significant as shown in [Table 4].
Table 4: Correlating fungal flora changes during radiotherapy with grade of mucositis

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  Discussion Top


HNC is a significant burden in India, and most of them present as advanced disease. Although local control and survival outcomes have improved with multimodality management, there has been an increase in morbidity. RT, which is one of the main modalities in the management of HNC, is associated with the most bothersome severe mucositis (Grade III and IV), accounting for 25% with conventional fractionation, which increases from 40% to 46% with altered fractionation RT.[6] Mucositis is associated with substantial pain interfering with chewing, swallowing, and affecting the quality of life and treatment compliance. Pathobiology of mucositis has suggested microbes' role in the onset and severity of mucositis.[7]

Belazi et al. in their study in 39 Head and Neck Cancer patients undergoing RT isolated oral Candida in 30/39 (77%) patients with Grade II–IV mucositis, out of which 59% had C. albicans, 8% had Candida glabrata, 5% had Candida kefyr, and 3% had C. tropicalis.[8]

Singh et al. in their study in 50 HNC patients on chemoradiation showed that 6 (12%) patients had fungal infection pretreatment, which peaked at the 6th week of RT in 23 (46%) patients, and it was persistent in 12 (24%) patients after 1 month of RT, out of which 9 patients had C. albicans, 8 had Candida parapsilosis, 5 had C. tropicalis, 2 had C. krusei, 2 had Candida guilliermondii, and 1 had C. glabrata. The maximum grade of mucositis was Grade II in 55.1%, Grade III in 28.57%, and Grade IV in 4.08%. All Grade IV and 71.42% of Grade III oral mucositis were positive for fungal infection.[9]

Sonalika et al. in their study of oral microbial carriage differences in oral cavity malignancies before and during RT showed that Candida is most frequently isolated during RT with 52.94% during RT and 58.33% at the end of RT.[10]

Our study of 68 HNC patients treated with definitive RT with or without chemotherapy showed a significant increase in C. albicans (1.5%–44.1%) and C. krusei (1.5%–10.5%) during RT (P < 0.05). Grade III and IV mucositis had a nonsignificant increasing trend of A. fumigatus and Candida species.

The study's limitations were that since different chemotherapeutic agents were used in the study, it was difficult to interpret the results. Furthermore, the impact of other risk factors like comorbidities, i.e., diabetes, could not be assessed. Moreover, longer follow-up is needed to correlate with late toxicity like xerostomia.


  Conclusion Top


The growth of certain fungal species during RT was shown a trend toward an increase in mucositis, although it was not significant. Hence, understanding the role of microorganisms involved in pathophysiological stages of mucositis and further studies in developing selective agents for therapeutic intervention is needed to reduce mucositis morbidity.

Acknowledgment

We thank our department for providing us all the help required during the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organisation. Locally Advanced Squamous Carcinoma of the Head and Neck. [internet]: World Health Organisation; 2014. p. 1-8.  Back to cited text no. 1
    
2.
Donnelly JP, Bellm LA, Epstein JB, Sonis ST, Symonds RP. Antimicrobial therapy to prevent or treat oral mucositis. Lancet Infect Dis 2003;3:405-12.  Back to cited text no. 2
    
3.
Chander J. Textbook of Medical Mycology. 4th ed. New Delhi: Jaypee Brothers, Medical Publishers Pvt. Limited; 2018. p. 411.  Back to cited text no. 3
    
4.
Chander J. Textbook of Medical Mycology. 4th ed. New Delhi: Jaypee Brothers, Medical Publishers Pvt. Limited; 2018. p. 533.  Back to cited text no. 4
    
5.
Chander J. Textbook of Medical Mycology. 4th ed. New Delhi: Jaypee Brothers, Medical Publishers Pvt. Limited; 2018. p. 854.  Back to cited text no. 5
    
6.
Fu KK, Pajak TF, Trotti A, Spencer SA, Jones CU, Phillips TL, et al. A Radiation Therapy Oncology Group (RTOG) Phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: Preliminary results of RT. Int J Radiat Oncol 1999;45:145.  Back to cited text no. 6
    
7.
Sonis ST, Cahalon L, Weiser M, Mucositis: The impact, biology, and therapeutic opportunities of oral mucositis. Oral Oncol 2009;45:1015-20.  Back to cited text no. 7
    
8.
Belazi M, Velegraki A, Koussidou-Eremondi T, Andreadis D, Hini S, Arsenis G, et al. Oral Candida isolates in patients undergoing radiotherapy for head and neck cancer: Prevalence, azole susceptibility profiles and response to antifungal treatment. Oral Microbiol Immunol 2004;19:347-51.  Back to cited text no. 8
    
9.
Singh GK, Capoor MR, Nair D, Bhowmik KT. Spectrum of fungal infection in head and neck cancer patients on chemoradiotherapy. J Egypt Natl Canc Inst 2017;29:33-7.  Back to cited text no. 9
    
10.
Sonalika WG, Amsavardani Tayaar S, Bhat KG, Patil BR, Muddapur MV. Oral microbial carriage in oral squamous cell carcinoma patients at the time of diagnosis and during radiotherapy-A comparative study. Oral Oncol 2012;48:881-6.  Back to cited text no. 10
    


    Figures

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    Tables

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



 

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