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CASE REPORT
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Increased skin reactions with hydroxychloroquine during breast radiotherapy


1 Department of Radiation Oncology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
2 Department of Dermatology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey

Date of Submission24-Jan-2021
Date of Acceptance06-May-2021
Date of Web Publication25-Apr-2022

Correspondence Address:
Halil Cumhur Yildirim,
Department of Radiation Oncology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_145_21

 > Abstract 


With the advances in radiation technology, skin reaction due to postoperative radiotherapy (RT) in breast cancer patients is generally mild and tolerable. However, certain drugs may increase the radiation effect. In literature, only few cases of adverse reactions in the radiation field have been reported with the use of Chloroquine. This report describes the case of a 30-year-old young female who had enhanced skin reactions with hydroxychloroquine (HCQ) treatment during breast RT. HCQ should be used with caution in patients undergoing RT due to its potential radiosensitizer effect.

Keywords: Hydroxychloroquine, radiosensitizer, radiotherapy



How to cite this URL:
Yildirim HC, Şahin M, Engin B, Öksüz D&. Increased skin reactions with hydroxychloroquine during breast radiotherapy. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=343913




 > Introduction Top


Hydroxychloroquine (HCQ), a quinine analog, has long been used in malaria, dermatological, and rheumatic diseases. It was also one of the drugs prescribed in COVID-19 treatment, although its effectiveness is uncertain.[1] Recently, preclinical studies have showed that HCQ administration increased the efficacy of various anti-cancer drugs and radiotherapy (RT). The most widely accepted anti-cancer mechanism of HCQ is inhibition of autophagy and its effects on the tumor microenvironment and tumor vasculature.[2] However, safety, dose, combination, and the administration schedule have not been known due to inconsistent results. In the literature, few case reports have been noted that radiation dermatitis was triggered by the use of HCQ.[3],[4],[5] Here, we report a rare case of increased skin reactions during breast RT with the use of HCQ due to COVID-19.


 > Case Report Top


A 30-year-old young female underwent right mastectomy and axillary lymph node dissection for T3N1M0, triple negative, invasive ductal breast carcinoma. She received four cycles of adriamycin and cyclophosphamide followed by four cycles of docetaxel as an adjuvant chemotherapy regimen. RT was started 25 days after completing chemotherapy. Right chest wall and the peripheral lymphatics including undissected axilla (level 3), supraclavicular and internal mammary lymph nodes were irradiated. Eclipse version 8.6 treatment planning system was used for contouring and treatment planning. 3-Dimentional Conformal RT plan was created using forward planning field-in-field techniques with 6 and 15 MV photon beams. The monoisocentric technique was used. Chest wall and internal mammary lymph nodes were treated with two opposing tangential fields and anterior-posterior field was applied to irradiate supraclavicular and level 3 axillary lymph nodes. The doses of 50 Gy were prescribed in 25 fractions, and the treatment was delivered with a Varian Rapid Arc linear accelerator (Varian Medical Systems, Palo Alto, CA). At fraction 11, the patient complained of cough and dyspnea. Her clinical situation and the thorax computed tomography were reported to be compatible with COVID-19 disease and she was hospitalized. Meanwhile, there was only Grade I skin reaction in the right chest wall. She was treated with HCQ sulfate (a loading dose of 2 × 400 mg and 2 × 200 mg for 4 days), azithromycin (1 × 500 mg for the first day and 1 × 250 mg for 4 days), and oseltamivir (2 × 75 mg for 5 days). On the 3rd day of medication, an itchy erythema appeared on the irradiated area. Reaction was relieved with topical mometasone furoate. When RT resumed after 14 days break, there was an itchy and erythematous skin reaction on the irradiated chest wall, but it was better as compared to previous days. We locally prescribed dexpanthenol plus chlorhexidine, silver sulfadiazine, and hamamelis virginiana in addition to mometasone.[6] At 5th fraction after resuming RT, unexpected severe hyperpigmentation and dry desquamation was observed in the irradiated area [Figure 1]. RT plans were checked, but neither target volume delineation nor planning protocol violation was noticed. Five days after observation, the skin reaction was stable. She underwent RT again for 5 days, but the reaction was getting worse and we decided to end the RT at 42 Gy. A month later, the reactions almost completely resolved and she had no complaints.
Figure 1: Unexpected skin reactions during radiotherapy of breast carcinoma at 30 Gy (a) anterior view, (b) posterior view

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 > Discussion Top


Post-mastectomy RT is indicated for breast cancer patients with node positive and/or locally advanced tumors. Recently, with the advances in RT technologies, acute skin reaction is generally mild. In our case, the skin reaction might be due to radiosensitization. Radiosensitization is defined as enhancing the radiation effect with certain drugs and tends to peak at the same time or up to 3 days after irradiation. Whereas radiation recall dermatitis is an inflammatory reaction that occurs in the irradiated area and is initiated with a particular drug days to years after RT. Although timing is arbitrary, it can be called radiation recall dermatitis if intense skin reaction is observed 7 days after the RT or after all acute reactions have completely recovered.[7]

In published works, we can only find 3 case reports about excessive interaction with RT and HCQ. The first case in seventies was a 54-year-old arthritic woman who were 2 years on chloroquine therapy. She was treated with RT because of a recurrent breast tumor on left chest wall. After completion of RT, a brisk erythema without desquamation was noted. However, it was progressed to a chest wall necrosis a few months later.[3] The other case was a 12-year-old girl with brainstem glioma. She had an empirical treatment of malaria during the 5th week of RT and developed moist desquamation on the scalp after the 3rd day of chloroquine treatment. After 1 week break, a significant healing was observed and RT completed safely.[4] The same group reported a 57-year-old female who had breast RT for locally advanced breast carcinoma. The day after completion of whole breast RT, she was treated with chloroquine due to fever with rigors. On the 3rd day of chloroquine treatment, she had a striking moist desquamation involving inframammary fold.[5]

We thought that HCQ is the most possible agent responsible of this unforeseen adverse side effect. Neuromyotoxicity, retinal damage, and cutaneous adverse effects of HCQ have been reported. It can also cause itching, and skin pigmentation for prolonged treatment. Furthermore, significant sequestration of the drug by the tissues causes a large volume of distribution in the body. In previous studies, the median value of the terminal elimination half-life is 40 days.[8] Recently, there are ongoing trials of HCQ and chemotherapeutic agent combinations used concurrently with RT in the treatment of pancreas cancer, prostate cancer, glioblastoma, etc.[9] The radiosensitizer effect of this drug is thought to be mostly by inhibiting autophagy. Autophagy is a catabolic mechanism that maintains homeostasis by degrading and recycling of cytoplasmic ingredients and organelles. This is a cytoprotective process by assisting cells to adapt stressful conditions. It was shown that HCQ accumulates in the lysosomes, and inhibits the lysosomal degradative enzymes. An augmented increase in lysosomal volumes was observed at 24 h or later after the addition of RT in the chloroquine treated cells.[10] At present, it is not clear which patients are prone to develop intensified reactions during or after the use of HQ with RT.

The contribution of other drugs is less pronounced. Elimination half-life values of osteltamivir and azithromycin are a few hours and a few days, respectively. Although both can cause skin toxicity, it is unlikely to occur skin reactions after 14 days of drug withdrawal. In addition, COVID-19 has skin manifestations itself. However, skin eruptions related to COVID-19 are mostly generalized and in erythematous, vesiculopapular, and urticarial forms. On the contrary, in our case, skin reaction was seen only in the RT field and characteristics of the reaction were not similar to the eruptions seen in COVID-19.[11],[12] There are also patient-related factors such as smoking, obesity that may increase the severity of skin reaction. However, we could not detect any patient related factor or comorbidity in our case.


 > Conclusion Top


In conclusion, HCQ should be used with caution in patients undergoing RT. Prolonged tissue storage of chloroquine requires a careful history of past drug use. Close follow-up during and after RT are needed.

Ethical statement

Written informed consent was provided by the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 2020;323:1824-36.  Back to cited text no. 1
    
2.
Gewirtz DA. The autophagic response to radiation: Relevance for radiation sensitization in cancer therapy. Radiat Res 2014;182:363-7.  Back to cited text no. 2
    
3.
Utley JF, Sachatello CR, Maruyama Y, Avila J, King R. Radiosensitization of normal tissue by chloroquine. Radiology 1977;124:255-7.  Back to cited text no. 3
    
4.
Rustogi A, Munshi A, Jalali R. Unexpected skin reaction induced by radiotherapy after chloroquine use. Lancet Oncol 2006;7:608-9.  Back to cited text no. 4
    
5.
Munshi A, Kakkar S, Budrukkar A, Jalali R. Unusual intensification of skin reactions by chloroquine use during breast radiotherapy. Acta Oncol 2008;47:318-9.  Back to cited text no. 5
    
6.
Rosenthal A, Israilevich R, Moy R. Management of acute radiation dermatitis: A review of the literature and proposal for treatment algorithm. J Am Acad Dermatol 2019;81:558-67.  Back to cited text no. 6
    
7.
Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 2001;59:237-45.  Back to cited text no. 7
    
8.
Browning DJ. Hydroxychloroquine and Chloroquine Retinopathy. New York: Springer Science+Business Media; 2014. p. 40.  Back to cited text no. 8
    
9.
Verbaanderd C, Maes H, Schaaf MB, Sukhatme VP, Pantziarka P, Sukhatme V, et al. Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience 2017;11:781.  Back to cited text no. 9
    
10.
Zhao H, Cai Y, Santi S, Lafrenie R, Lee H. Chloroquine-mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of cell death by necrosis. Radiat Res 2005;164:250-7.  Back to cited text no. 10
    
11.
Najar Nobari N, Seirafianpour F, Mashayekhi F, Goodarzi A. A systematic review on treatment-related mucocutaneous reactions in COVID-19 patients. Dermatol Ther 2021;34:e14662.  Back to cited text no. 11
    
12.
Genovese G, Moltrasio C, Berti E, Marzano AV. Skin manifestations associated with COVID-19: Current knowledge and future perspectives. Dermatology 2021;237:1-12.  Back to cited text no. 12
    


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