Daniel%20Berg%20M.D.,%20FRCPC

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Update on Skin Cancer in Organ Transplant
Recipients 2008
Daniel Berg M.D., FRCPC Director Dermatologic
Surgery Professor, Dermatology University of
Washington
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Cosmas and Damien Patron Saints of Transplantation
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Whats Old
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(No Transcript)
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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

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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

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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

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Imiquimod
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Imiquimod (Aldara)

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

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Imiquimod (Aldara)

• RCT. N43 (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)
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Reduction Immunosuppression
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Changes in Immunosuppression
of all kidney transplants on medication at time
of discharge
MEDICATION 1992 2001 2006
Azathioprine 87 5 0.9
Mycophenolate Mofetil 0 77 76
Mycophenolate Sodium 0 0 11.7
Cyclosporine 94 39 12
Tacrolimus 3 56 82.4
Sirolimus 0 17 8.3
Everolimus 0 0.1 0.5
Source OPTN 2007 Report. Table 5.6e
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Evidence Supporting Reduction of
Immunosuppression

• More NMSC with 3- vs 2-drug regimen

CAP gt AP or CP
Reviewed in Otley, Maragh. Dermatol Surg 2005
31163-8.
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Which Agent is Worst?

• Heart gt Kidney
• Less skin cancer in non-transplant patients on
  one agent
• E.g. IBD on Azathioprine
• Conclusion
• Overall intensity of immunosuppression most
  important

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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. Lancet1998351(9103)623.
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Dantal, J et al. Lancet1998351(9103)623.
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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)
• Kaposis Sarcoma, PTLD, Merkel Cell Ca regresses
  with RI

Reviewed in Otley, Maragh. Dermatol Surg 2005
31163-8.
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Skin Cancer Scenarios Transplant MD/Derm Opinion Level of reduction of immunosuppression to consider Level of reduction of immunosuppression to consider Level of reduction of immunosuppression to consider
Skin Cancer Scenarios Transplant MD/Derm Opinion RENAL ALLOGRAFT CARDIAC ALLOGRAFT LIVER ALLOGRAFT
1. No history of actinic keratoses or skin cancer None None None
2. History of actinic keratosis None None None
3. History of lt 1 NMSC per year None None Mild
4. History of 2-5 NMSC per year Mild Mild Mild
5. History of 6-10 NMSC per year Moderate Mild Moderate Mild Moderate Mild
6. History of 11-25 NMSC per year Moderate Mild Moderate Mild Moderate Mild
7. History of gt 25 NMSC per year Moderate Moderate Moderate
8. Individual high risk skin cancer 1 mortality over 3 years (average risk SCC cutaneous/oral KS stage IA melanoma) Moderate Moderate Mild
9. Individual high risk skin cancer 5 mortality over 3 years (moderate risk SCC stage IB melanoma) Moderate Moderate Moderate
10. Individual high risk skin cancer 10 mortality over 3 years ( high risk SCC early Merkel cell stage IIA melanoma) Severe Moderate Moderate
11. Individual high risk skin cancer 25 mortality over 3 years (very high risk SCC stage IIB melanoma) Severe Moderate Moderate
12. Individual high risk skin cancer 50 mortality over 3 years (metastatic SCC stage IIC/III melanoma aggressive Merkel cell carcinoma visceral KS) Severe Severe Severe
13. Individual high risk skin cancer 90 mortality over 3 years (untreatable metastatic SCC stage IV melanoma metastatic Merkel cell carcinoma) Severe Severe Severe
Otley, Berg, Ulrich ... Br J Derm
2006154395-400.
Otley et al. Brit J Derm 2007 157, pp11831188
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Proliferation Signal InhibitorsSirolimusEverolim
us
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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.

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PSIs

• M-TOR key target in
• Translation
• Angiogenesis
• Proliferation
• Active trials in other cancers
• Efficacy IN
• SCC in OTRs Kaposis Sarcoma
• Angiomyolipomas in Tuberous Sclerosis

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• PSIs Target mTOR
• Key player in
• Translation
• Angiogenesis
• Proliferation

• Active Trials In
• AML CML
• Lymphoma
• Myeloma
• Sarcoma
• Others

Curr Opin Hem 20081588
The Oncologist 2007121007
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Rapamycin and Skin Cancer

• gt1000 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 gt50 Patients
  African-American or Hispanic
• Kahan et al. Transplantation 200580(6)749.

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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 plt 0.01
• CyA Rapa (high dose) 2.8 plt0.05
• 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 200418446-9.

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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 200580883
• 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 2005352(13)1317.

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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 Feb17(2)581-9
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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 2236-41
There are no evidence-based guidelines for the
use of PSIs in renal transplant patients with
malignancies..
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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

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Rapamycin and Wound Healing

• For General Surgery
• Most studies show Increased Incidence of
• Dehiscence
• Incisional Hernia
• Fluid collections

Grim et al. Transplantation Proceedings, 38,
35203523 (2006)
Knight et al. Clin Transplant 2007 21 460465
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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
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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 200834216-223

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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 200834216-223
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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

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Does Skin Cancer Affect Decision to Transplant?
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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
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American Journal of Transplantation20055(9),2079-
2084
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Melanoma in Transplant Patients
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Melanoma in Transplant Patients

• Three Scenarios of Interest
• De Novo Melanoma
• Recipient with previous history of melanoma
• Melanoma from Donor

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Melanoma in Transplant Patients

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

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PreTransplant Melanoma in Recipient

• Management of Patient waiting for organ with
  history of melanoma

Previous History of Transplant? Waiting Period
In-situ MM Yes None
T1a (lt1mm) Yes 2 years
gtT1a or b Yes 5 years
Metastatic MM No N/A
From Christensen L. Melanoma in Otley et al.
Skin Disease in Organ Transplant Patients. Text
2008
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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 1996274-278
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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),
  358362.
• ...therefore, donors with a history of melanoma
  should not be used.
• Kaufman et al. Transplantation 200784272

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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 Transplantation
200784 272274.
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PreTransplant Melanoma in Donor

• Other notes
• 140 donors had melanoma (Breslow unknown)
• 27 of these had MM lt 5 years prior to death
• Only one recipient died from melanoma
• 32 years out other recipients didnt get MM
• ? Diagnosis accurate

Kaufman et al. Deceased Donors With PMHx of
Malignancy A UNOS/OPTN Update Transplantation
200784 272274.
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PreTransplant Melanoma in Donor

• Conclusion
• Dont transplant with donor history of metastatic
  melanoma
• Do transplant melanoma in situ
• Probably transplant T1a if gt 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.

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Further Reading Reviews

• Kauffman et al. Post-transplant de novo
  malignancies in renal transplant recipients the
  past and present.
• Transpl Int. 2006 Aug19(8)607-20.
• Berg D, Otley CC. Skin Cancer in organ transplant
  recipientsepidemiology, pathogenesis and
  management. J Am Acad Dermatol 200247(1)1-17
• Euvrard S et al. Skin Cancers after organ
  transplantation. N Engl J Med 2003348(17)1681-91
  .
• Guttierez-Dalmau, Campistol. Immunosuppressive
  Therapy and Malignancy in Organ Transplant
  Recipients a systematic review.
• Drugs 200767 (8)1167-1198

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

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www.itscc.org
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www.at-risc.org
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The End
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Changes in Immunosuppression
Source OPTN 2007 Report. Table 5.6f
of all kidney transplants on medication 1 year
after
MEDICATION 1997 2001 2005
Tac MM St 17.6 37.5 43.9
Tac MM 2.3 2.8 20.5
CyA MM St 37 24.2 8.8
Tac /- Steroids 7 6.9 6.2
PSI /- Steroids 0.3 0.9 0.8
CyA PSI /- Steroids 1.5 3.5 2
MM PSI 0 0.3 1.6
Tac PSI /- Steroids 0 8.9 4.1
80
8.5
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Tuberous Sclerosis Complex

• Angiomyolipomas
• In 80 of TS patients
• Slow-growing but significant
• Renal failure
• Renal hemorrhage
• Current Rx only surgery

• Open Label Study n25
• Mean volume reduction 47
• At one year
• Tend to regrow after stopping

Bissler et al. Sirolimus for Angiomyolipoma in
TS Complex. NEJM 2008358140.
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Which Agent is Worst?

• Animal data
• Azathioprine gt Cyclosporine gt steroids
• Human data
• Data Uncontrolled with Variable results
• ?MMF Tacrolimus better than CyA AZA
• No diff between AZA and MMF in skin cancer
• Systematic Review in Trans Proc 200436(7)2068
• No diff between Tacrolimus and CyA
• Cochrane Review 2005 Oct 19(4)CD003961
• Other studies show clear benefit with Tac v CyA

Reviewed in Guttierez-Dalmau Campistol 2007.
Drugs 67(8)1167-1198