11.3 Strategies to manage keratinocyte cancer in organ transplant recipients
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)[edit source]
Chemoprophylaxis with acitretin[edit source]
Acitretin 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)[edit source]
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)[edit source]
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.
The following indications have been suggested for commencement of oral acitretin in OTRs:
- 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)[edit source]
Acitretin appears not to adversely affect renal grafts in kidney transplant recipients, with several clinical trial observing no deterioration in renal function.
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 inhibition[edit source]
The 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)[edit source]
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 disease, 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 disease) was not reported. The real number of KCs may have been underestimated if Bowen’s disease was treated by techniques not requiring pathological examination.
Current clinical practice (MTOR inhibition)[edit source]
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)[edit source]
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)[edit source]
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[edit source]
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)[edit source]
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)[edit source]
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%.
Practice Points[edit source]
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.
- ↑ Lens M, Medenica L. Systemic retinoids in chemoprevention of non-melanoma skin cancer. Expert Opin Pharmacother 2008 Jun;9(8):1363-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18473710.
- ↑ 2.0 2.1 2.2 2.3 2.4 Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995 Aug;13(8):1933-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7636533.
- ↑ 3.0 3.1 3.2 3.3 George R, Weightman W, Russ GR, Bannister KM, Mathew TH. Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients. Australas J Dermatol 2002 Nov;43(4):269-73 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12423433.
- ↑ 4.0 4.1 Harwood CA, Leedham-Green M, Leigh IM, Proby CM. Low-dose retinoids in the prevention of cutaneous squamous cell carcinomas in organ transplant recipients: a 16-year retrospective study. Arch Dermatol 2005 Apr;141(4):456-64 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15837863.
- ↑ McKenna DB, Murphy GM. Skin cancer chemoprophylaxis in renal transplant recipients: 5 years of experience using low-dose acitretin. Br J Dermatol 1999 Apr;140(4):656-60 Available from: http://www.ncbi.nlm.nih.gov/pubmed/10233316.
- ↑ 6.0 6.1 6.2 6.3 Otley CC, Stasko T, Tope WD, Lebwohl M. Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects. Dermatol Surg 2006 Apr;32(4):562-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16681667.
- ↑ O'Reilly Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011 Aug;65(2):263-279 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21763562.
- ↑ 9.0 9.1 De Graaf YG, Euvrard S, Bouwes Bavinck JN. Systemic and topical retinoids in the management of skin cancer in organ transplant recipients. Dermatol Surg 2004 Apr;30(4 Pt 2):656-61 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15061851.
- ↑ 10.0 10.1 de Sévaux RG, Smit JV, de Jong EM, van de Kerkhof PC, Hoitsma AJ. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 2003 Sep;49(3):407-12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12963902.
- ↑ 11.0 11.1 Kovach BT, Sams HH, Stasko T. Systemic strategies for chemoprevention of skin cancers in transplant recipients. Clin Transplant 2005 Dec;19(6):726-34 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16313317.
- ↑ 12.0 12.1 Chen K, Craig JC, Shumack S. Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials. Br J Dermatol 2005 Mar;152(3):518-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15787821.
- ↑ Marquez C, Bair SM, Smithberger E, Cherpelis BS, Glass LF. Systemic retinoids for chemoprevention of non-melanoma skin cancer in high-risk patients. J Drugs Dermatol 2010 Jul;9(7):753-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20677528.
- ↑ Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006 Aug;5(8):671-88 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16883305.
- ↑ 15.0 15.1 Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 2004 Aug;18(4):446-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15233824.
- ↑ 16.0 16.1 Salgo R, Gossmann J, Schöfer H, Kachel HG, Kuck J, Geiger H, et al. Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial. Am J Transplant 2010 Jun;10(6):1385-93 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20121752.
- ↑ 17.0 17.1 Alberú J, Pascoe MD, Campistol JM, Schena FP, Rial Mdel C, Polinsky M, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation 2011 Aug 15;92(3):303-10 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21792049.
- ↑ 18.0 18.1 Campbell SB, Walker R, Tai SS, Jiang Q, Russ GR. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant 2012 May;12(5):1146-56 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22420843.
- ↑ 19.0 19.1 19.2 Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012 Jul 26;367(4):329-39 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22830463.
- ↑ 20.0 20.1 20.2 Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, Proby CM, Wolterbeek R, Bouwes Bavinck JN, et al. Two-year randomized controlled prospective trial converting treatment of stable renal transplant recipients with cutaneous invasive squamous cell carcinomas to sirolimus. J Clin Oncol 2013 Apr 1;31(10):1317-23 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23358973.
- ↑ Karayannopoulou G, Euvrard S, Kanitakis J. Differential expression of p-mTOR in cutaneous basal and squamous cell carcinomas likely explains their different response to mTOR inhibitors in organ-transplant recipients. Anticancer Res 2013 Sep;33(9):3711-4 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24023300.
- ↑ Lim WH, Eris J, Kanellis J, Pussell B, Wiid Z, Witcombe D, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant 2014 Sep;14(9):2106-19 Available from: http://www.ncbi.nlm.nih.gov/pubmed/25088685.
- ↑ 24.0 24.1 Asgari MM, Arron ST, Warton EM, Quesenberry CP Jr, Weisshaar D. Sirolimus use and risk of cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients (SOTRs). J Am Acad Dermatol 2015 Sep;73(3):444-50 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26138646.
- ↑ Longo MI, Wen X, Womer KL. Comment on "Sirolimus use and risk of cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients (SOTRs)". J Am Acad Dermatol 2016 May;74(5):e105-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27085243.
- ↑ 26.0 26.1 Peddi VR, Wiseman A, Chavin K, Slakey D. Review of combination therapy with mTOR inhibitors and tacrolimus minimization after transplantation. Transplant Rev (Orlando) 2013 Oct;27(4):97-107 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23932018.
- ↑ Glover MT, Deeks JJ, Raftery MJ, Cunningham J, Leigh IM. Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients. Lancet 1997 Feb 8;349(9049):398 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9033469.
- ↑ 28.0 28.1 Otley CC, Berg D, Ulrich C, Stasko T, Murphy GM, Salasche SJ, et al. Reduction of immunosuppression for transplant-associated skin cancer: expert consensus survey. Br J Dermatol 2006 Mar;154(3):395-400 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16445766.
- ↑ Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998 Feb 28;351(9103):623-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9500317.
- ↑ Otley CC, Coldiron BM, Stasko T, Goldman GD. Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants. Arch Dermatol 2001 Apr;137(4):459-63 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11295926.
- ↑ Moloney FJ, Kelly PO, Kay EW, Conlon P, Murphy GM. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg 2004 Apr;30(4 Pt 2):674-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15061854.
- ↑ Neuburg M. Transplant-associated skin cancer: role of reducing immunosuppression. J Natl Compr Canc Netw 2007 May;5(5):541-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17509256.
- ↑ Otley CC, Griffin MD, Charlton MR, Edwards BS, Neuburg M, Stasko T, et al. Reduction of immunosuppression for transplant-associated skin cancer: thresholds and risks. Br J Dermatol 2007 Dec;157(6):1183-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17916206.