- 1 Background
- 2 Overview of evidence (non-systematic literature review)
- 2.1 Chemoprophylaxis with acitretin
- 2.2 MTOR inhibition
- 2.3 Reduction in immunosuppression
- 3 Practice Points
- 4 References
Targeted strategies for the management of keratinocyte cancer (KC) in organ transplant recipients (OTRs) include chemoprophylaxis with systemic acitretin and revision of immunosuppression. This revision may involve reduction of immunosuppression or treatment with mechanistic target of rapamycin kinase (MTOR) inhibitors.
These strategies are generally reserved for OTRs who develop multiple or high-risk KCs. Potential adverse effects of such strategies need to be considered and these decisions should be made in a multidisciplinary setting.
Overview of evidence (non-systematic literature review)
Chemoprophylaxis with acitretinAcitretin is a synthetic retinoid which is thought to aid in chemoprevention through its effects on cell cycle control, induction of apoptosis, promotion of cellular differentiation, and immunomodulation as well as inhibition of ornithine decarboxylase, cellular proliferation and keratinisation.
Clinical trials in organ transplant recipients (chemoprophylaxis)
A single randomised double-blind placebo-controlled trial was identified that evaluated acitretin in OTRs. It included 38 kidney transplant recipients, of whom 19 received treatment with 30 mg of acitretin daily. Over the 6-month trial period there was a significant reduction in new cSCCs in the treatment group, compared with the placebo group. The effect was most marked in patients with a history of KC.
An Australian prospective open randomised crossover trial of 23 kidney transplant recipients with a history of KC allocated to either 25 mg of acitretin daily or placebo and crossed over at one year also showed fewer cSCCs while on acitretin than in the medication-free period.Both these studies observed a rebound in the number of cSCCs after cessation of treatment in the treatment group, which was also seen in other studies.The effect appears to be most marked in those taking acitretin for longer than 12 months.
Current clinical practice (chemoprophylaxis)
Acitretin is usually reserved for high-risk patients as an adjunct therapy to standard skin cancer management, given the limited evidence supporting its use in primary prevention, its adverse effect profile, and the need for long-term treatment.
- development of multiple (5–10) KC lesions per year
- development of countless actinic keratoses with multiple KC lesions
- acceleration in the frequency of occurrence of KC lesions
- development of multiple KC lesions in high-risk areas
- high-risk KC (risk for metastasis >20%)
- eruptive keratoacanthomas
- solid organ transplantation with a history of leukemia or lymphoma and KC.
The effective dose of acitretin varies across studies and low doses may be sufficient. Clinical response should be assessed and the risk-benefit ratio should be considered in determining maintenance dosing. Ongoing treatment with acitretin is required to establish long-term effectiveness.
Safety profile and adverse effects (chemoprophylaxis)
Drug tolerability is a limiting factor, although most side effects are reversible. The most common adverse effects necessitating dose reduction or treatment cessation are mucocutaneous xerosis (70–100%), alopecia (44–47%), headache (40%) and myalgia (20–35%). In the three trials, 8– 39% of patients withdrew due to adverse effects, while additional patients interrupted treatment for several weeks.
High-dose treatment may cause osteoporosis, hyperostotic axial skeletal changes and liver function abnormalities as well as tendon and ligament calcification. However long-term data in the organ transplant population are lacking. These adverse effects may be mitigated by gradual dose titration and monitoring of symptoms and laboratory tests, including full blood count, renal function tests, liver function tests and fasting lipid profile.
Retinoids are highly teratogenic, so strict contraceptive measures should be employed in women of childbearing age.
Current data suggest acitretin is relatively safe and effective in reducing KC in select OTRs.
MTOR inhibitionThe MTOR inhibitors, particularly sirolimus and everolimus, were initially used in the immunosuppression regimen for kidney transplant recipients to mitigate calcineurin inhibitor (CNI)-induced renal dysfunction and thus enhance graft survival. Further investigation confirmed the dual immunosuppression and antineoplastic properties of MTOR inhibitors, leading to the speculation that they may confer additional survival benefit by protecting against the development or progression of malignancies.
Clinical trials in organ transplant recipients (MTOR inhibition)
There is more evidence for sirolimus use than for everolimus, because sirolimus has been in use at least a decade longer than everolimus.
Similarly, there is more evidence for the use of MTOR inhibitors in kidney transplant recipients, due to the early uptake of sirolimus in that group, compared with other OTRs. Of note, both sirolimus and everolimus are now used in kidney transplant recipients, whereas everolimus is primarily used in liver transplant recipients and heart transplant recipients.
A double-blind randomised controlled trial (RCT) investigating the elimination of calcineurin inhibition and substitution with MTOR inhibition demonstrated that sirolimus use was associated with reduced risk in the development of KC in kidney transplant recipients. Multiple clinical trials have shown reduced numbers of KC in OTRs after a therapeutic switch to, or addition of, MTOR inhibitors. This benefit was magnified if there was a prior history of KC, and there was a greater effect on the development of cSCC and Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC), compared with BCC. The greater impact on cSCC formation may relate to differential phospho-MTOR expression.
A systematic review of 29 trials has shown decreased KC incidence, better preservation of renal function, increased risk of acute organ rejection and no difference in mortality among OTRs treated with MTOR inhibitors, compared with those treated with CNIs. A meta-analysis of data from 21 RCTs in 5876 kidney transplant recipients confirmed a 56% reduction in the risk of KC development among sirolimus-treated patients, compared with the control group (treatment regimens not containing sirolimus). However, there was a significantly increased risk of death from all causes in patients on sirolimus.There is a small amount of evidence challenging the findings of these studies. In a retrospective study of a sizeable Californian cohort of 3539 OTRs (kidney, liver, heart and lung), which investigated the relationship between sirolimus exposure (488 patients) and KC incidence, sirolimus use was not associated with a lower risk of developing KC; in fact, there was a non-significant increase in KC in this group.  The investigators postulated that prior studies reporting the benefits of MTOR inhibitors on KC development might have been examining the positive effect of co-interventions, namely CNI dose reduction or elimination. These findings have been challenged in turn, citing lack of information regarding doses of MTOR inhibitors (only low-dose MTOR inhibitors are antineoplastic), previous or concomitant exposure to CNI, immunosuppression regimens, and skin cancer clinical risk factors, such as skin type and sun exposure. Furthermore, histological subtype of cSCC (invasive cSCC versus Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC)) was not reported. The real number of KCs may have been underestimated if Bowen’s diseasecSCC in situ (also known as intra-epidermal SCC) was treated by techniques not requiring pathological examination.
Current clinical practice (MTOR inhibition)
An expert consensus panel recommended a moderate reduction of immunosuppression once 25 or more KCs develop per year.
However, the optimal time to reduce immunosuppression appears to be after the development of the first KC. Recent data suggest that, once multiple KCs have developed, the benefit of introducing MTOR inhibitors (and switching from CNIs or reducing their dose) may be lost. Prophylactic use of MTOR inhibitors does not seem warranted, particularly given their adverse effect profile.
Safety profile and adverse effects (MTOR inhibition)
Adverse effects of MTOR inhibitors include oedema, impaired wound healing, acneiform eruptions, aphthous ulcers, proteinuria, hyperlipidaemia, lymphocele, pneumonitis and myelosuppression. Intolerance of these adverse effects has limited the widespread uptake and long-term use of MTOR inhibitors by OTRs.
Moreover, the high rate of dose reduction or discontinuation (up to 39%) due to treatment-related adverse effects in many MTOR inhibitor studies makes it difficult to interpret the data and judge whether reported outcomes are clinically meaningful.
Successful side-effect management is the key to taking advantage of the potential benefits of MTOR inhibition.Although complete discontinuation of CNIs and antimetabolites appears beneficial with respect to malignancy risk, it must be weighed against the risk of transplant rejection. While antimetabolite use has been phased out in newer immunosuppression regimens for OTRs, it has not been feasible to eliminate CNI in all types of organ transplants, due to the issues with tolerability of MTOR inhibitors. Therefore, some regimens involve a combination of both agents (i.e. low-dose CNI with low-dose MTOR inhibitors), keeping their trough levels to the minimum required for immunosuppression.
Summary (MTOR inhibition)
In summary, there is a role for MTOR inhibitors in the prevention and management of KC, the most common cancer faced by OTRs in the long term.
Multiple clinical trials, especially in the kidney transplant population, have explored the role of sirolimus, and to a lesser extent, everolimus, in the immunosuppression regimen. Multiple clinical trials have shown reduced numbers of KC in OTRs after a therapeutic switch to, or addition of, MTOR inhibitors. The overall trend is toward benefit without increased risk of acute graft rejection, particularly in those with a history of, or high risk for, cancer. Only a few studies have not shown a clear advantage over current immunosuppression regimens.
Despite these positive findings, the use of MTOR inhibitors in the transplant setting remains low, due to poor tolerability and physician concerns regarding adverse effects. Thus, complete CNI elimination has proven to be unachievable in many circumstances.
To improve the morbidity and mortality related to KC, a combination of low-dose CNI and low-dose MTOR inhibitors should be considered on a case-by-case basis.
Reduction in immunosuppression
The correlation between intensity of immunosuppression and the risk of KC is well established and provides a rationale that reduction of immunosuppression can reduce the burden and behaviour of KC in OTRs.Coincident with the increasing trend towards the use of combination MTOR inhibitor and CNI therapy in OTRs with increased KC load, little new evidence is available from studies investigating the reduction of MTOR inhibitors and CNI immunosuppression (either in combination or alone) as a means of adjunctive management of high-risk/multiple KCs.
Clinical trials in organ transplant recipients (reduction in immunosuppression)
The largest randomised control trial, conducted over 20 years ago, studied cyclosporin dose reduction versus non-reduction in 231 kidney allograft recipients 12 months after transplant. Halving cyclosporin trough blood levels reduced malignant complications but had no effect on long-term graft function or survival. However, increased acute graft rejection episodes were noted with lower cyclosporin doses, though these episodes were medically manageable and had no effect on overall graft survival.Subsequently, reductions of KC load have been reported in small series of OTRs where immunosuppression was ceased due to allograft failure or high load of KC.
Current clinical practice (reduction in immunosuppression)Expert consensus guidelines have advised mild reduction of immunosuppression once the number of skin cancers exceeds 25 per year, or for skin cancers with a 3-year risk of mortality estimated at 10%.
PP 11.3.1. Chemoprophylaxis with systemic acitretin should be considered for reducing tumour burden in patients who develop multiple keratinocyte cancers.
PP 11.3.2.Reduction of immunosuppression should be considered in organ transplant recipients who develop multiple keratinocyte cancers.
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