Introduction
Radiotherapy plays a vital role in the multimodality management of cancers. Its utility in managing benign/non-oncological diseases is increasingly being explored. The groups of diseases include inflammatory, degenerative, hyperproliferative, functional and infectious diseases. Reference Seegenschmiedt, Micke and Muecke1 Many studies have been conducted to treat pneumonia, orthopaedic infections and otolaryngological infections with radiotherapy in the pre-antibiotic era. Reference van Dijk, Lemans, Hoogendoorn, Dadachova, de Klerk and Vogely2 Because of concerns about long-term toxicity, interest in using external beam radiotherapy had waned. With antibiotic and antifungal resistance development, there is a renewed interest in using radiotherapy as an alternative in refractory cases of infectious diseases.
Mycetoma is a chronic infection of the skin and subcutaneous tissue. The WHO declared it a ‘neglected tropical disease’ in 2016. Mycetoma is predominantly distributed in tropical and subtropical regions of the world. This includes countries such as Chad, Ethiopia, India, Venezuela, Mexico, Senegal, Sudan, Thailand and Yemen, collectively belonging to the ‘Mycetoma belt’. The mode of infection is through traumatic inoculation of the fungi or bacteria. This usually affects manual labourers working in agricultural fields without protective gear such as footwear or gloves. 3
Mycetoma can be broadly divided into two categories based on the causative agents. Reference Seegenschmiedt, Micke and Muecke1,Reference Chalmers and Archibald4 Actinomycetoma is caused by bacteria, and eumycetoma is caused by fungi. The common bacterial agents include Actinomadura pelletieri, Actinomadura madurae, Streptomyces somaliensis, Nocardia brasiliensis and Nocardia asteroids, and the common fungal agents include Madurella mycetomatis, Madurella fahalii, Madurella tropicana and Medicopsis romeroi. Eumycetoma is commonly referred to as ‘Madura mycosis’. This name comes from the name of the South Indian city of Madurai. It was from here that John Gill, in 1842, first reported about the disease that caused deformity of the foot associated with ‘fungoid excrescences’. Reference Chalmers and Archibald4 The clinical features of mycetoma include painless plaques, discharging sinuses and characteristic granular grains or microcolonies.
The treatment of actinomycetoma includes using a combination of antibiotics, while prolonged use of antifungals and surgery is needed for eumycetoma. The long duration of use of antifungals such as triazole antifungals can also cause side effects such as hepatotoxicity, skin reactions, renal toxicity, CNS toxicity and cardiac toxicity. Reference Neofytos, Avdic and Magiorakos5 In this context, attempts are being made to reintroduce radiotherapy in refractory eumycetoma cases. Reference Gupta, Sharma, Gupta, Sharma, Dev and Singh6 Here, we present a case of refractory eumycetoma of the foot, which was treated by radiotherapy.
Case Report
The patient, a 41-year-old male, presented to the orthopaedics outpatient department with a complaint of localised swelling with the discharging sinus of the left foot in 2016. A clinical diagnosis of fungal osteomyelitis was made, and a wedge biopsy was taken from the papule in the left foot, which showed that the dermis infiltrated with a dense inflammation consisting of lymphocytes, plasma cells, neutrophils and eosinophils and a large fungal colony in the superficial dermis (Figure 1). He underwent debridement of the lesion twice, in 2016 and 2018. He was on oral itraconazole, oral terbinafine, oral fluconazole and the modified Ramam regimen for varying periods before 2019. In January 2019, he was started on table itraconazole 200 mg twice daily for 18 months. The frequency of discharge of grains reduced from two to three episodes per month before starting itraconazole to one episode per month after beginning therapy. After that, the patient was started on tablet voriconazole 200 mg twice a day for 3 months. The discharge frequency was reduced from one episode per month to one episode per 3 months. The patient developed voriconazole-induced deranged liver function tests. Then, the patient was referred to the radiation oncology department for radiotherapy (Figure 2). (All images were taken with due permission from the patient.)
Figure 1. Periodic acid-Schiff staining of the wedge biopsy specimen from the foot showing the fungal colony along with infiltration of the dermis with lymphocytes, plasma cells, neutrophils and eosinophils.
Figure 2. The fungal osteomyelitis lesion on the left foot upon presentation at the radiation oncology department.
The patient was simulated in the feet-first supine position using a 1-cm-thick bolus made of dental wax (Figure 3). The CT simulator was GE & Optima CT580. A thermoplastic cast was used for immobilisation. Three-dimensional conformal radiotherapy was the treatment technique. Three beams (anteroposterior, right lateral and left lateral) were used to cover the target volume, which was the left foot (Figure 4). 20 Gy in five fractions at 4 Gy/fraction was given in December 2021 using the high-energy linear accelerator Elekta Versa HD with 10 megavolt photon energy. The tissue around the foot was softened with a reduction in the serosanguinous discharge and that of grains. This response was sustained till September 2022 (9 months) (Figure 5). Another course of radiotherapy was planned because of the excellent response to the first course. 15 Gy was delivered in five fractions at 3 Gy/fraction (September 2022). The response was sustained for another 11 months before the initial symptoms reappeared, and he was restarted on antifungals.
Figure 3. The image showing the immobilisation for CT (computed tomography) simulation of the left foot using bolus.
Figure 4. The dose colour wash of the three-dimensional conformal radiotherapy plan using anteroposterior, right lateral and left lateral beams.
Figure 5. The appearance of the left foot post 9 months of completion of radiotherapy course.
Discussion
The delay in diagnosis, the protracted course of treatment and the ignorance among the group of people who are more prone to develop this cancer all contribute to the tag of neglected disease to mycetoma. The use of radiotherapy in its management protocol has been rarely explored before this attempt. Only one case study stood as a guide to our treatment. Reference Gupta, Sharma, Gupta, Sharma, Dev and Singh6 17.5 Gy in five fractions at 3.5 Gy per fraction was used for the first course in that study. The response was short-lived (2 months). Another 15 Gy in five fractions at 3 Gy per fraction was delivered, which gave a sustained response for 15 months. The initial poor response could be attributed to the reduced dose, as evident from our experience. For the first course, the biologically equivalent dose was 23.6 Gy10 in that study compared with 28 Gy10 in our study. This could be a pointer toward the role of a higher dose in the first treatment phase for a longer response duration.
Radiation has been used to sterilise fungi in the agricultural/food processing sector at a much lower dose. Reference Nurtjahja, Dharmaputra, Rahayu and Syarief7,Reference Nemţanu, Braşoveanu, Karaca and Erper8 Most studies on treating eumycetoma treated haemoptysis caused by pulmonary mycetoma. Reference Falkson, Sur and Pacella9 They used a dose range from 7 Gy to 14 Gy, which gave a definitive relief from symptoms. Haemoptysis due to chronic pulmonary aspergillosis refractory to bronchial artery embolisation is being routinely treated by radiotherapy. The latest efforts at incorporating stereotactic body radiotherapy have also met with success. Because the intention of treatment is palliative, the dose fractionation ranged from 20 Gy in ten fractions to 16 Gy in two fractions. Reference Koch, Schanne, Günther, Aebersold and Elicin10
The haemostatic action of radiotherapy can be explained by its ability to cause obliterative endarteritis. However, the mechanism of antifungal action needs to be further investigated.
Conclusion
Radiotherapy can be used as a salvage treatment in the case of refractory eumycetoma. It can also be used in case of adverse reactions to antifungals. More studies are recommended to reach a consensus on the dose and fractionation.
Open access
