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Daniel Berg M.D., FRCPC Director Dermatologic Surgery Professor, Dermatology University of Washington

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  1. Update on Skin Cancer in Organ Transplant Recipients 2008 Daniel Berg M.D., FRCPC Director Dermatologic Surgery Professor, Dermatology University of Washington

  2. Cosmas and Damien Patron Saints of Transplantation

  3. What’s “Old”

  4. Skin Cancer Facts: • Skin cancer incidence and aggressiveness increased in OTRs • After the fourth year post-transplant, 27% of heart patients in Australia die of skin cancer • OTRs need increased • Surveillance • Education • Lower threshold for biopsy

  5. Skin Cancer Facts: • Treat AKs aggressively • LN2, topicals, PDT • Treat Skin Cancers with usual methods more aggressively applied • Special issues: • Field resection (e.g. hand) • Reduction of Immunosuppression • Retinoid Chemoprevention

  6. Update Topics • Aldara Literature Update • Study shows safety and efficacy • Reduction of Immunosuppression • Guidance for Discussion with Transplant Docs • New Survey Data • Update on mTOR Inhibitors • Mechanism • Data for Efficacy (SCC in OTRs, KS, Tuberous Sclerosis) • Side Effects • Wound Healing Issue • Melanoma in Transplant Patients

  7. Imiquimod

  8. Imiquimod (Aldara) • Is it effective in OTRs? • Are there side effects (e.g. rejection)?

  9. Imiquimod (Aldara) • RCT. N=43 (small) • 3X/week for 16 weeks • Face, forehead or bald scalp • 100cm2 field (2 sachets/application) • 4-10 AKs within each field. • 62% complete clearance vs 0% placebo. • No evidence graft rejection Ulrich, C.et al. Brit J Derm, Volume 157, Supplement 2, December 2007 , pp. 25-31(7)

  10. Reduction Immunosuppression

  11. Changes in Immunosuppression % of all kidney transplants on medication at time of discharge Source: OPTN 2007 Report. Table 5.6e

  12. Evidence Supporting Reduction of Immunosuppression • More NMSC with 3- vs 2-drug regimen CAP > AP or CP Reviewed in: Otley, Maragh. Dermatol Surg 2005; 31:163-8.

  13. Which Agent is Worst? • Heart > Kidney • Less skin cancer in non-transplant patients on one agent • E.g. IBD on Azathioprine • Conclusion: • Overall intensity of immunosuppression most important

  14. RCT Study • Kidney transplant recipients on CyA/Imuran • Compared high to low dose CYA regimens • Trough CyA 75-125 vs 150-250 • 66 months follow-up • More rejection episodes with low dose but: • Fewer skin and other malignancies • Same Overall AND Graft Survival Dantal, J et al. Lancet1998;351(9103):623.

  15. Dantal, J et al. Lancet1998;351(9103):623.

  16. Evidence Supporting Reduction of Immunosuppression • Case Series: • Decreased skin cancer after cessation of immunosuppression (Otley et al) • Prolonged disease free survival from metastatic skin cancer with RI (Moloney et al) • Kaposi’s Sarcoma, PTLD, Merkel Cell Ca regresses with RI Reviewed in: Otley, Maragh. Dermatol Surg 2005; 31:163-8.

  17. Otley, Berg, Ulrich ... Br J Derm 2006:154:395-400. Otley et al. Brit J Derm 2007 157, pp1183–1188

  18. Proliferation Signal InhibitorsSirolimusEverolimus

  19. Rapamycin • May be different than other immunosuppressants and skin cancer • Anti-angiogenic, anti-neoplastic properties • Both drugs FDA approved (Sirolimus 1999) • Pharmacokinetic differences • e.g. T1/2 60 (Rapa) vs 28 (Everolimus) • Sirolimus better studied for skin cancer.

  20. PSIs • M-TOR key target in: • Translation • Angiogenesis • Proliferation • Active trials in other cancers • Efficacy IN • SCC in OTRs; Kaposi’s Sarcoma • Angiomyolipomas in Tuberous Sclerosis

  21. PSIs Target mTOR • Key player in: • Translation • Angiogenesis • Proliferation • Active Trials In: • AML &CML • Lymphoma • Myeloma • Sarcoma • Others Curr Opin Hem 2008;15:88 The Oncologist 2007;12:1007

  22. Rapamycin and Skin Cancer • >1000 Patients on Rapa/CyA • U Texas Houston Cohort • 2.4% incidence of skin cancer/5 yr mean • Compare with 7% historical controls. • Ratio only 1.58 that of general population (SEER data)/5 yr • Problem: No control; >50% Patients African-American or Hispanic • Kahan et al. Transplantation 2005;80(6):749.

  23. Rapamycin and Skin Cancer • Pooled (5) rapamycin studies - 2 year data • Skin cancer incidence • CyA 6.9% • CyA + Aza 4.3% • CyA + Rapa (low dose) 2.0% p< 0.01 • CyA + Rapa (high dose) 2.8% p<0.05 • Rapa vs CyA: 0% vs 1.3% (NS trend) • Rapa + CyA withdrawal vs Rapa + CyA: 2.3 vs 5.1% (NS trend) Ref: Mathew Clin Transplan 2004;18:446-9.

  24. Rapamycin and Skin Cancer • Retrospective UNOS/OPTN Review (963 days) • TOR Inhibitor Maintenance showed 60% reduced risk of any post-transplant malignancy • Kauffman et al. Transplantation 2005;80:883 • Case Series: 16/16 renal transplant patients with cutaneous KS complete remission at 3 months with conversion from CyA to Rapa • Stallone et al. NEJM 2005:352(13):1317.

  25. Rapamycin and Skin Cancer • At 3 months after renal transplant. 430 patients randomized to remain on CsA-SRL-steroids vs SRL-steroids alone (SRL troughs doubled): • At 5 yr: • Median time to first skin CA 491d vs 1126d • Estimated rate of non skin cancer: 9.6% vs 4% Campistol JM et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006 Feb;17(2):581-9

  26. Recommendations of clinical guidance for conversion from calcineurin inhibitors to proliferation signal inhibitors in renal transplant recipients From: Campistol, J. M. et al. Nephrol. Dial. Transplant. 2007 22:36-41 “There are no evidence-based guidelines for the use of PSIs in renal transplant patients with malignancies…..”

  27. Rapamycin and Side Effects • Hyperlipidemia • Wound Healing • Renal Function • May help CNI-induced CAN • May exacerbate CyA induced nephrotoxicity if used at same time • Increased risk of rejection if used immediately post transplant • Others • e.g. rare pneumonitis • Proteinuria • Edema • Generalized • Leg • Upper Body • Myelosuppression • Thrombocytopenia • Leukopenia • Anemia • Dermatologic • Acne • Oral Ulcers

  28. Rapamycin and Wound Healing • For General Surgery • Most studies show Increased Incidence of: • Dehiscence • Incisional Hernia • Fluid collections Grim et al. Transplantation Proceedings,38, 3520–3523 (2006) Knight et al. Clin Transplant 2007: 21: 460–465

  29. Rapamycin and Wound Healing • For General Surgery • If desired for primary immunosuppression, optimal to hold for 3-4 weeks post transplant. • For elective surgery many hold preop (60hr ½ life) and for 6 weeks after switching to FK506 • In Emergency Surgery, modify technique • Slower absorbing  sutures, • Use marlex mesh or pre-peritoneal  technique for hernia repair • Leave skin sutures in longer Personal Communication: 2007: R Hirose, D Salomon, Jeff Haldorson

  30. Rapamycin and Wound Healing • What about Derm Surgery? • Relatively little experience • Fewer patients, shorter time on drug, possible decreased skin cancers • Main issues: infection, slow healing, dehiscence • Typically manageable • One Study: • Brewer et al. Dermatologic Surgery 2008;34:216-223

  31. Sirolimus and Healing 26 Sirolimus Patients • “Non-significant” Trend to: • Higher number of infections • More dehiscence • Pt rated slower healing Brewer et al. Dermatologic Surgery 2008;34:216-223

  32. Rapamycin and Wound Healing • Derm Surgery Recommendations: • Do not need to stop Rapamycin • Minimize tension on closures • Use monofilament absorbable sutures • Consider 2nd intention healing • Lower threshold for antibiotics

  33. Does Skin Cancer Affect Decision to Transplant?

  34. Should Patients With Prior Skin Cancer Be Transplant Donors Or Recipients? • Depends on specifics of cancer • Validated prognostic factors • Accentuation of risk by immunosuppression poorly quantified • Consult with transplant dermatologist Otley,C., Hirose, R , Salasche, S. (2005). Skin Cancer as a Contraindication to Organ Transplantation. American Journal of Transplantation 5(9),2079-2084

  35. American Journal of Transplantation2005;5(9),2079-2084

  36. Melanoma in Transplant Patients

  37. Melanoma in Transplant Patients Three Scenarios of Interest: • De Novo Melanoma • Recipient with previous history of melanoma • Melanoma from Donor

  38. Melanoma in Transplant Patients De Novo Melanoma • Standard guidelines plus: • Consider reduction of immunosuppression in: • Those with > 1mm • Positive Sentinel Node • Consider cessation of immunosuppression in metastatic melanoma particularly if donor-derived. • Anecdotal reports suggest that this may help.

  39. PreTransplant Melanoma in Recipient • Management of Patient waiting for organ with history of melanoma From Christensen L. Melanoma in: Otley et al. Skin Disease in Organ Transplant Patients. Text 2008

  40. PreTransplant – Melanoma in Donor • 20 recipients from 11 donors with retrospectively diagnosed MM • 6/11 had been diagnosed with primary brain tumor (3) or CV hemorrhage (3) • 17/20 recipients got stage 4 metastatic MM • 11 of these died of it • 5 had complete remission with cessation immunosuppression Penn. Transplantation 27 Jan 1996:274-278

  41. PreTransplant – Melanoma in Donor • “…because melanoma, … pose(s) a high transmission risk, we recommend avoiding donors who have a past history of … these cancers.” • Kaufman et al. Transplantation 2002: 74(3), 358–362. • ...therefore, donors with a history of melanoma should not be used. • Kaufman et al. Transplantation 2007;84:272

  42. PreTransplant – Melanoma in Donor • In U.S. 2% of donors have a past hx of CA. • Review 2000-2005 (n = 40,000 donors) • 1069 donors with Hx CA gave 2508 transplants • Most common CA = NMSC (776/1069 = 73%) • #2 CNS (642); #3 Cervix (336); Melanoma (140) • 4 Recipients from 2 Donors died • 3 from glioblastoma; 1 from MM (32 years prior) Kaufman et al. Deceased Donors With PMHx of Malignancy: A UNOS/OPTN Update Transplantation2007;84: 272–274.

  43. PreTransplant – Melanoma in Donor • Other notes: • 140 donors had melanoma (Breslow unknown) • 27% of these had MM < 5 years prior to death • Only one recipient died from melanoma • 32 years out; other recipients didn’t get MM • ? Diagnosis accurate Kaufman et al. Deceased Donors With PMHx of Malignancy: A UNOS/OPTN Update Transplantation2007;84: 272–274.

  44. PreTransplant – Melanoma in Donor • Conclusion: • Don’t transplant with donor history of metastatic melanoma • Do transplant melanoma in situ • Probably transplant T1a if > 2 years out? • In metastatic melanoma in transplant patient • confirm if donor or recipient • If donor let other recipients know. • Withdrawal immunosuppression or Allograft explantation or retransplantation may provide a survival benefit.

  45. Further Reading: Reviews • Kauffman et al. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transpl Int. 2006 Aug;19(8):607-20. • Berg D, Otley CC. Skin Cancer in organ transplant recipients;epidemiology, pathogenesis and management. J Am Acad Dermatol 2002;47(1):1-17 • Euvrard S et al. Skin Cancers after organ transplantation. N Engl J Med 2003;348(17):1681-91. • Guttierez-Dalmau, Campistol. Immunosuppressive Therapy and Malignancy in Organ Transplant Recipients; a systematic review. Drugs 2007;67 (8):1167-1198

  46. Otley CC • Stasko T. • Skin Disease in Organ Transplantation. Cambridge. 2008

  47. www.itscc.org

  48. www.at-risc.org