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 Table of Contents  
CASE REPORT
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 32-34

Cyclophosphamide-induced cancers in pemphigus patients –A report of three cases


Department of Dermatology, JNMC, Wardha, Maharashtra, India

Date of Submission19-Feb-2020
Date of Decision06-Jun-2020
Date of Acceptance08-Jun-2020
Date of Web Publication23-Jun-2020

Correspondence Address:
Dr. Vikrant Abhay Saoji
22, Dandige Layout, Shankar Nagar, Nagpur - 440 010, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_6_20

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  Abstract 


Introduction: Cyclophosphamide is an important steroid-sparing immunosuppressive drug that was found to be effective for the treatment of autoimmune bullous disorders such as pemphigus. However, cyclophosphamide (an alkylating drug) is a mutagenic drug and is associated with the risk of malignancies. Three cases of cancers developing due to cyclophosphamide use in pemphigus are presented. Case Report: A 50-year-old male patient of pemphigus vulgaris received over 50 g of cyclophosphamide over 3 years. He died of bladder cancer 9 years after stopping the treatment. A 57-year-old male patient, a known case of diabetes, received over 100 g of cyclophosphamide for over 4 years for pemphigus foliaceus diagnosed with bladder cancer 5 years after stopping treatment. A 50-year-old male received around 100 g of cyclophosphamide over 3 years for pemphigus foliaceus diagnosed with squamous cell carcinoma of oral mucosa 2 years after stopping treatment. Conclusion: Cyclophosphamide is a mutagenic drug and is associated with the risk of malignancy which can appear many years after stopping the treatment; hence, long-term follow-up is important.

Keywords: Cancers, cyclophosphamide, pemphigus


How to cite this article:
Saoji VA. Cyclophosphamide-induced cancers in pemphigus patients –A report of three cases. Indian J Drugs Dermatol 2020;6:32-4

How to cite this URL:
Saoji VA. Cyclophosphamide-induced cancers in pemphigus patients –A report of three cases. Indian J Drugs Dermatol [serial online] 2020 [cited 2020 Jul 4];6:32-4. Available from: http://www.ijdd.in/text.asp?2020/6/1/32/287438




  Introduction Top


Steroids are used for the treatment of autoimmune bullous disorders such as pemphigus for long time. However, due to the chronicity of this unpredictable disease, high-dose long-term steroids are required which can be associated with high mortality and morbidity. When immunosuppressants were introduced as steroid-sparing agents, it prevented many complications associated with long-term use of steroids. Cyclophosphamide is an important steroid-sparing immunosuppressive drug that was found to be effective for the treatment of autoimmune bullous disorders such as pemphigus. Dr. Pashricha popularized steroids and cyclophosphamides containing dexamethasone-cyclophosphamide pulse (DCP) therapy. However, cyclophosphamide (an alkylating drug) is a mutagenic drug and is associated with risk of malignancies. We are presenting three cases of cancers (two with urinary bladder carcinoma and one with squamous cell carcinoma) that developed in patients with pemphigus who received cyclophosphamide.


  Case Reports Top


Case 1

A 50-year-old male was diagnosed with pemphigus vulgaris at another medical center presented in April 2000 with severe disease. Earlier, he had received high-dose steroids, which resulted in numerous side effects. He was put on tablet cyclophosphamide 50 mg OD along with low-dose betamethasone that resulted in a complete remission of his pemphigus. He received cyclophosphamide for a total period of 3 years (till May 2003). He was asymptomatic during the follow-up period of 5 years. This patient presented to a physician with hematuria in April 2012. He was diagnosed with bladder carcinoma and died in September 2012. He had received over 50 g of cyclophosphamide during the course of his 3-year treatment.

Case 2

A 57-year-old male, a known case of diabetes mellitus Type 2, was diagnosed with pemphigus foliaceus in January 2008. He was treated with low-dose betamethasone and cyclophosphamide 50 mg OD, but because of inadequate response, the dose was increased to 100 mg OD after 4 months. He was treated by the author for 3 years (till 2011) and another 1½ years by a physician from his native place in Madhya Pradesh (till July 2012). In October 2017, he was diagnosed as high-grade urothelial carcinoma of the bladder. He had received a total dose of over 100 g of cyclophosphamide in over 4 years.

Case 3

A 50-year-old male with no known history of tobacco abuse was diagnosed with pemphigus foliaceus in April 2006. He received low-dose betamethasone tablets along with cyclophosphamide 50 mg OD tablets for 6 months and 100 mg daily for 2½ years thereafter. His treatment was stopped in June 2009. In April 2011, 2 years after stopping cyclophosphamide, he was diagnosed with squamous cell carcinoma of the buccal mucosa, which was treated with wide excision. There was no metastasis. He had received around 100 g of cyclophosphamide over 3 years.


  Discussion Top


Cyclophosphamide is a cytotoxic drug with more pronounced action on B-lymphocytes;[1] hence, it is commonly used as immunosuppressant therapy for antibody-mediated (produced by B-lymphocytes) autoimmune conditions such as bullous disorders and connective tissue diseases. Cyclophosphamide is an alkylating agent that acts by crosslinking and damaging (alkylating) DNA, which results in mutagenesis and carcinogenesis and cell death.[1] Cyclophosphamide is metabolized in the liver with acrolein as one of the metabolic derivatives. Most of these metabolic byproducts are excreted in the urine. However, acrolein is an irritant to the bladder mucosa, which can cause hemorrhagic cystitis.[1] Genitourinary complications such as hemorrhagic cystitis and bladder cancer are the most important concern for cyclophosphamide therapy. Hemorrhagic cystitis occurs in 5%–41% of patients on cyclophosphamide.[1] Mesna is a drug that binds with acrolein and reduces the bladder irritation and is protective against hemorrhagic cystitis. Mesna is typically recommended for patients using high-dose cyclophosphamide and not recommended for low-dose use in dermatology and rheumatology.[1] Increasing hydration, frequent voiding, and addition of mesna reduce the chances of cystitis. Mesna was not used in any of our patients.

Since cyclophosphamide has mutagenic properties, its use is a known risk factor for carcinogenesis, especially in the development of bladder cancer. Out of 145 patients with Wegener's granulomatosis who received cyclophosphamide, hematuria occurred in 50% of patients and 7 of which developed bladder cancer.[2] In 6 out of these 7 patients who developed cancer, the dose of cyclophosphamide used was more than 100 g and the duration of therapy exceeded 2.7 years.[2] In a study out of 100 patients of cyclophosphamide-induced hemorrhagic cystitis, bladder cancer developed in only 5 patients, and for these 5 patients, the average dosage of cyclophosphamide was 195 g for 60 months much higher than other patients.[3] Both these studies link bladder cancer to hemorrhagic cystitis.[2],[3] However, in a population-based Swedish study to assess the relative risk of bladder cancer after exposure to cyclophosphamide involving 1065 patients of Wegner's granulomatosis, Knight et al. concluded that bladder cancers appear without connection to hemorrhagic cystitis, and the two conditions may not arise from the same mechanisms.[4] The carcinogenic effects, however, are more likely to be mediated through molecular changes caused by the alkylating properties of cyclophosphamide, such as mutations in the p53 tumor suppressor gene.[4],[5] If so, hemorrhagic cystitis would not be a good marker of the increased risk of bladder cancer, nor would Mesna be cancer preventive.[4] Bladder irritation or mutagenesis whatever may be the cause of bladder malignancy but the risk of bladder cancer is definitely increased with cyclophosphamide use. The risk of bladder cancer increases with increasing doses and duration of cyclophosphamide therapy. Exposure to cyclophosphamide for longer than 13 months was associated with a near eightfold increased risk of bladder cancer.[4] A clear dose–response relationship between cyclophosphamide exposure and malignancy risk has been reported with non-Hodgkin's lymphoma. In these patients, the risk increased 2.4- and 14.5-fold when the cumulative dose was less than 20 g and over 50 g, respectively.[6] Bladder carcinoma incidence is supposed to be lower in patients receiving intravenous cyclophosphamide, likely due to the lower total cumulative dose used with this form of therapy. All our three patients presented with severe disease and received over 50 g of oral cyclophosphamide over a period of 3 years. In two of the patients, the dose of cyclophosphamide required to control the disease was actually higher (100 g). None of these three patients complained of urinary symptoms anytime during the treatment. They had normal investigations including urine analysis while on treatment and during the follow-up period.

The association between cyclophosphamide administration and cancer development was not substantially confounded by smoking status, prior immunosuppressive therapy, or family history of malignancy.[7] The latency from stopping cyclophosphamide treatment to the diagnosis of bladder cancer varied between 0 and 14 years, with a median latency time of 2 years and 7 months.[4] In our two patients, this latency was 9 years and 5 years, respectively. These cases indicate that long-term follow-up is necessary. Bladder cancer induced by cyclophosphamide may arise many years after the therapy.[1]

In addition to the risk of bladder cancer, cyclophosphamide is associated with the risk of development of other malignancies such as lymphoma, leukemia, and squamous cell carcinoma.[1] This risk is associated with the high dose and long duration of therapy. One of our patients developed squamous cell carcinoma. Of the 50 cancers seen in 37 patients out of 119 rheumatoid arthritis patients who received cyclophosphamide, 9 of the malignancies were bladder cancers and 19 were skin cancers compared to no bladder cancers and 6 skin cancers in the control group.[8] Three of the bladder cancers occurred 14, 16, and 17 years after cyclophosphamide had been discontinued.

In all our three patients, cyclophosphamide use resulted in very good control of the disease activity with greatly reducing the steroid requirement and improving the quality of life. Cyclophosphamide is a very effective drug, but due to the potential toxicity, many dermatologists tend to avoid cyclophosphamide for the treatment of autoimmune bullous disorders and prefer azathioprine. However, azathioprine is also considered as carcinogen,[9] especially if used in high doses and for a long period of time. Immunosuppressant use increases the risk of malignancy by either affecting the immune surveillance against cancer (especially when cell-mediated immunity is suppressed, e.g., cyclosporine) or by damaging DNA causing mutagenicity (cyclophosphamide and azathioprine) and by activating latent oncogenic viruses due to immunosuppression. In the treatment of immunobullous disorders, immunosuppressants are used in higher doses and for longer term, which carry the risk of malignancies. Surprisingly, no malignancy has been reported with DCP therapy even though cyclophosphamide is used for over 2 years. The development of malignancy may be much delayed; hence, these patients should be kept under observation for a long duration.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
High WA. Cytotoxic agents. In: Wolverton SE, Talar-Williams C, Hijazi YM, Walther MM, editors. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelphia: Elsevier-Saunders; 2013. p. 212-72.  Back to cited text no. 1
    
2.
Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I,et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996;124:477-84.  Back to cited text no. 2
    
3.
Stillwell TJ, Benson RC Jr. Cyclophosphamide-induced hemorrhagic cystitis. A review of 100 patients. Cancer 1988;61:451-7.  Back to cited text no. 3
    
4.
Knight A, Askling J, Granath F, Sparen P, Ekbom A. Urinary bladder cancer in Wegener's granulomatosis: Risks and relation to cyclophosphamide. Ann Rheum Dis 2004;63:1307-11.  Back to cited text no. 4
    
5.
Khan MA, Travis LB, Lynch CF, Soini Y, Hruszkewycz AM, Delgado RM, et al. p53 mutations in cyclophosphamide-associated bladder cancer. Cancer Epidemiol Biomarkers Prev 1998;7:397-403.  Back to cited text no. 5
    
6.
Travis LB, Curtis RE, Glimelius B, Holowaty EJ, Van Leeuwen FE, Lynch CF, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst 1995;87:524-30.  Back to cited text no. 6
    
7.
van den Brand JA, van Dijk PR, Hofstra JM, Wetzels JF. Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2014;9:1066-73.  Back to cited text no. 7
    
8.
Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin A, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis A 20-year followup study. Arthritis Rheum 1995;38:1120-7.  Back to cited text no. 8
    
9.
National Toxicology Program. Report on Carcinogens, Fourteenth Edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service; 2016. Available from: https://ntp.niehs.nih.gov/go/roc14 (EndNote XML). [Last accessed on 2019 Jul 28].  Back to cited text no. 9
    




 

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