Sirolimus use and risk of cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients (SOTRs)

doi:10.1016/j.jaad.2015.05.029

Journal of the American Academy of Dermatology

Volume 73, Issue 3, September 2015, Pages 444-450

https://doi.org/10.1016/j.jaad.2015.05.029 Get rights and content

Background

Little is known about the use of sirolimus for primary prevention of cutaneous squamous cell carcinoma (SCC) among solid organ transplant recipients (SOTRs).

Objective

We examined the association between sirolimus exposure and incident SCC risk among SOTRs within Kaiser Permanente Northern California.

Methods

Using a retrospective cohort of all Kaiser Permanente Northern California members given a diagnosis of SOTR from 2000 through 2010, we evaluated incident posttransplantation SCC risk in relation to sirolimus exposure. Sirolimus use was determined from electronic pharmacy records, and incident posttransplantation SCCs were identified from health plan electronic pathology records. We used extended Cox regression to examine the independent association between receipt of sirolimus and risk of SCC.

Results

Among 3539 SOTRs, 488 were exposed to sirolimus and 47 developed an incident SCC. SCC risk was not associated with ever use of sirolimus (adjusted hazard ratio 1.18, 95% confidence interval 0.84-1.16) or cumulative duration of sirolimus exposure (adjusted hazard ratio 2.75, 95% confidence interval 0.84-9.04, comparing long-term users with nonusers).

Limitations

No information was available for some known SCC risk factors, such as skin type and sun exposure.

Conclusions

Among a large cohort of SOTRs, sirolimus exposure was not associated with a reduction in incident posttransplantation SCC risk.

Section snippets

Methods

This is a retrospective cohort study of all adult KPNC SOTRs given a diagnosis of between 2000 and 2010. This study was approved by the Kaiser Foundation Research Institute Institutional Review Board.

Cohort characteristics

Among 3539 individuals in the KPNC SOTR cohort, the mean age was 52.1 ± 13.6 years and 60.3% were men. During follow-up, 488 subjects received sirolimus therapy, and there was no significant difference in sex for exposed versus unexposed individuals (63.1% male exposed vs 59.9% male unexposed, P = .18), although exposed individuals were younger than unexposed (mean age 50.0 years exposed vs 52.4 years unexposed, P < .001). The mean number of years of follow-up was 3.7 years (median 2.9 years).

Discussion

In a large cohort of SOTRs, we observed no significant association between sirolimus exposure and risk of incident posttransplantation SCC. The observed crude risk of incident posttransplantation SCC was noted to be higher (not lower, as initially hypothesized) with both any use of sirolimus therapy and with increasing duration of treatment, although these associations were attenuated after adjustment for potential confounders. This result was sustained even when the study population was

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Pediatric Kidney Transplantation: Cancer and Cancer Risk
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Children with end-stage kidney disease (ESKD) face a lifetime of complex medical care, alternating between maintenance chronic dialysis and kidney transplantation. Kidney transplantation has emerged as the optimal treatment of ESKD for children and provides important quality of life and survival advantages. Although transplantation is the preferred therapy, lifetime exposure to immunosuppression among children with ESKD is associated with increased morbidity, including an increased risk of cancer. Following pediatric kidney transplantation, cancer events occurring during childhood or young adulthood can be divided into two broad categories: post-transplant lymphoproliferative disorders and non-lymphoproliferative solid tumors. This review provides an overview of cancer incidence, types, outcomes, and preventive strategies in this population.
European consensus-based interdisciplinary guideline for invasive cutaneous squamous cell carcinoma. Part 1: Diagnostics and prevention–Update 2023
2023, European Journal of Cancer
Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in white populations, accounting for 20% of all cutaneous malignancies. Overall, cSCC mostly has very good prognosis after treatment, with 5-year cure rates greater than 90%. Despite the overall favourable prognosis and the proportionally rare deaths, cSCC is associated with a high total number of deaths due to its high incidence. A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV) and the European Organization of Research and Treatment of Cancer (EORTC), was formed to update recommendations on cSCC, based on current literature and expert consensus. Part 1 of the guidelines addresses the updates on classification, epidemiology, diagnosis, risk stratification, staging and prevention in immunocompetent as well as immunosuppressed patients.
Cohort and nested case-control study of cutaneous squamous cell carcinoma in solid organ transplant recipients, by medication
2022, Journal of the American Academy of Dermatology
Citation Excerpt :
Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy in solid organ transplant recipients (SOTR)1-3 and results largely from the chronic use of immunosuppressants.4-9
Knowledge is needed about the risk of cutaneous squamous cell carcinoma (cSCC) in solid organ transplant recipients (SOTRs) using contemporary immunosuppressive regimens.
Evaluate the risk of cSCC in relation to medications used by SOTRs.
The cohort and nest case-control study included 3308 SOTRs and 65,883 persons without transplantation during 2009-2019. Incident cSCC was identified from pathology data, and medications were identified from pharmacy data. Adjusted hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards analysis, with voriconazole examined as a time-dependent variable.
The annual incidence of cSCC was 1.69% in SOTRs and 0.30% in persons without transplantation. The adjusted hazard ratio of cSCC associated with lung transplant was 14.83 (95% CI, 9.85-22.33) for lung and 6.53-10.69 for other organs. Risk in Latinx persons was higher than in other non-White groups. Among lung recipients, the hazard ratio was 1.14 for each month of voriconazole use (95% CI, 1.04-1.26). Azathioprine use for ≥7 months, relating to mycophenolate mofetil intolerance, was associated with a 4.22-fold increased risk of cSCC (95% CI, 1.90-9.40). Belatacept and other immunsuppressive medications were not associated with risk.
The number of events was somewhat small.
The knowledge of risks and benefits in diverse patients can translate to improvements in care.
Sirolimus diminishes the expression of GRO-α (CXCL-1) /CXCR2 axis in human keratinocytes and cutaneous squamous cell carcinoma cells
2021, Journal of Dermatological Science
Citation Excerpt :
A clear decrease in the incidence of skin malignancies was also observed in OTRs, who were switched to mTOR inhibitors after three months of treatment with cyclosporine A (the CONVERT study) [10]. mTOR plays a central role in the regulation of cell growth, metabolism, survival and angiogenesis [11]. However, also direct effects on keratinocyte carcinogenesis are possible.
Organ transplant recipients show a high incidence for the formation of cutaneous squamous cell carcinoma (cSCC), while sirolimus appears to reduce the risk. GRO-α is a chemokine, which is overexpressed in many tumor entities and associated with malignant transformation. However, little is known about the expression and function of GRO-α in human cSCC.
Our aim was to investigate the relevance of the GRO-α (CXCL-1)/ CXCR2 axis in human cSCC and the potential impact of sirolimus.
We analyzed the GRO-α expression in human keratinocytes, different cSCC cell lines as well as cSCC tissue and investigated its effect on cell proliferation and migration. Additionally, we incubated cells with sirolimus and measured the expression of GRO-α and its receptor CXCR2.
We showed that both constitutive as well as induced GRO-α expression is higher in in cSCC cell lines compared to keratinocytes and that GRO-α protein is detectable in human cSCC tissue. By GRO-α exposure and shRNA knock down, we identified GRO-α as a driving factor in proliferation and migration. Moreover, in a dermis equivalent GRO-α knocked down cSCC cell lines displayed a reduced capacity in tumor nest formation. Incubation with sirolimus significantly inhibited GRO-α expression in keratinocytes as well as tumor cell lines. Moreover, sirolimus decreased the expression of the corresponding receptor CXCR2.
Taken together, our results suggest that the GRO-α/CXCR2 axis plays a role in human keratinocyte carcinogenesis and might represent a molecular mechanism for the preventive effect of mTOR inhibitors in cSCC development.
European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 1. epidemiology, diagnostics and prevention
2020, European Journal of Cancer
Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in the white populations, accounting for 20% of all cutaneous malignancies. Factors implicated in cSCC etiopathogenesis include ultraviolet radiation exposure and chronic photoaging, age, male sex, immunosuppression, smoking and genetic factors. A collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organisation of Research and Treatment of Cancer (EORTC) was formed to update recommendations on cSCC classification, diagnosis, risk stratification, staging and prevention, based on current literature, staging systems and expert consensus. Common cSCCs are typically indolent tumors, and most have a good prognosis with 5-year cure rates of greater than 90%, and a low rate of metastases (<4%). Further risk stratification into low-risk or high-risk common primary cSCC is recommended based on proposed high-risk factors. Advanced cSCC is classified as locally advanced (lacSCC), and metastatic (mcSCC) including locoregional metastatic or distant metastatic cSCC. Current systems used for staging include the American Joint Committee on Cancer (AJCC) 8th edition, the Union for International Cancer Control (UICC) 8th edition, and Brigham and Women’s Hospital (BWH) system. Physical examination for all cSCCs should include total body skin examination and clinical palpation of lymph nodes, especially of the draining basins. Radiologic imaging such as ultrasound of the regional lymph nodes, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography–computed tomography (PET-CT) scans are recommended for staging of high-risk cSCC. Sentinel lymph node biopsy is currently not recommended. Nicotinamide, oral retinoids, and topical 5-FU have been used for the chemoprevention of subsequent cSCCs in high-risk patients but are not routinely recommended. Education about sun protection measures including reducing sun exposure, use of protective clothing, regular use of sunscreens and avoidance of artificial tanning, is recommended.
Evolving Role of Systemic Therapies in Non-melanoma Skin Cancer
2019, Clinical Oncology
Citation Excerpt :
Systemic chemoprevention is usually considered in patients at high risk for new keratinocyte cancer, including a history of keratinocyte cancer or risk of developing multiple, potentially aggressive keratinocyte cancers, as in OTR and other immunosuppressed patients. Current practice includes use of systemic retinoids [87–89], capecitabine [90,91], nicotinamide [92–94] and, where relevant, revision of immunosuppressive medication [86,95–101]. This is discussed in detail in the review by Collins et al. [102] in this special issue.
Keratinocyte cancers – basal and cutaneous squamous cell carcinoma (BCC, cSCC) – are the most common forms of non-melanoma skin cancer (NMSC) and there has been a significant increase in their incidence globally in recent decades. Although the majority of BCC and cSCC are cured with conventional surgery or radiotherapy, certain tumour or patient-determined factors may result in these modalities being inadequate or inappropriate, for example, locally advanced or metastatic disease, high tumour multiplicity, patient comorbidities and patient preferences. In these clinical circumstances, systemic treatment may be indicated, and over the past 10 years a number of new systemic agents have been approved. Nonetheless, effective systemic therapy for keratinocyte cancers remains an area of significant unmet clinical need. Improved understanding of the molecular and immune pathogenesis underlying tumour growth and development is critical for driving future advances and is a research priority. The aim of this review is to provide clinicians with an overview of systemic treatments for BCC and cSCC and will focus on current evidence for conventional chemotherapy, targeted therapies, immunotherapy, adjuvant and neoadjuvant therapy, chemoprevention and future prospects for novel systemic treatment approaches.

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: Supported in part by the National Cancer Institute (R01 CA 166672 to Dr Asgari) and the Kaiser Foundation Research Institute (Community Benefits Grant KR021179 to Dr Asgari).

: Disclosure: Dr Asgari received grant funding to Kaiser Permanente from Pfizer Inc and Valeant Pharmaceuticals, but the research topic was not relevant to this work. Drs Arron, Quesenberry, and Weisshaar, and Ms Warton have no conflicts of interest to declare.

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Original articleSirolimus use and risk of cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients (SOTRs)

Background

Objective

Methods

Results

Limitations

Conclusions

Section snippets

Methods

Cohort characteristics

Discussion

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Am J Transplant

Am J Transplant

Skin cancer in solid organ transplant recipients: advances in therapy and management: part I. Epidemiology of skin cancer in solid organ transplant recipients

J Am Acad Dermatol

Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study

Arch Dermatol

Immunosuppressive treatment after solid organ transplantation and risk of post-transplant cutaneous squamous cell carcinoma

Nephrol Dial Transplant

Skin cancer risk among solid organ recipients: a nationwide cohort study in Denmark

Acta Derm Venereol 90

Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation

J Am Soc Nephrol

Original article
Sirolimus use and risk of cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients (SOTRs)