Malignancy in Patients with Renal Insufficiency

Transcription

1 XIVth Budapest Nephrology School Malignancy in Patients with Renal Insufficiency Michael Fischereder Nephrologisches Zentrum Medizinische Poliklinik Munich, Germany

2 Questions How frequent are malignancies in patients with renal disease before and after transplantation? How should we screen for this problem? What are the risks of recurrence / transmission and de novo cancer with renal transplantation? What should be done in transplant recipients with malignancy?

3 before RRT dialysis after transplant

4 Cancer incidence (SIR) and dialysis Increased cancer incidence (SIR) in dialysis patients dialysis patients pts. with cancer derived from registries selection bias regional variation Site AUS (n = 500) All 1.8 ( ) Digestive 1.2 ( ) Respiratory 1.5 ( ) Genitourinary 3.0 ( ) Cervix 4.0 ( ) Bladder 4.8 ( ) Kidney 9.9 ( ) Endocrine 5.9 ( ) Haemopoietic 1.6 ( ) EUR (n = 6849) 1.1 ( ) 0.9 ( ) 0.9 ( ) 1.4 ( ) 1.6 ( ) 1.5 ( ) 3.3 ( ) 1.9 ( ) 1.3 ( ) USA (n = ) 1.2 ( ) 1.2 ( ) 1.1 ( ) 1.1 ( ) 3.0 ( ) 1.4 ( ) 3.7 ( ) 2.4 ( ) 2.5 ( ) Maisonneuve, Lancet 1999

5 Cancer incidence (SIR) and dialysis Increased cancer incidence (SIR) in dialysis patients dialysis patients pts. with cancer derived from registries selection bias regional variation Site AUS (n = 500) All 1.8 ( ) Digestive 1.2 ( ) Respiratory 1.5 ( ) Genitourinary 3.0 ( ) Cervix 4.0 ( ) Bladder 4.8 ( ) Kidney 9.9 ( ) Endocrine 5.9 ( ) Haemopoietic 1.6 ( ) EUR (n = 6849) 1.1 ( ) 0.9 ( ) 0.9 ( ) 1.4 ( ) 1.6 ( ) 1.5 ( ) 3.3 ( ) 1.9 ( ) 1.3 ( ) USA (n = ) 1.2 ( ) 1.2 ( ) 1.1 ( ) 1.1 ( ) 3.0 ( ) 1.4 ( ) 3.7 ( ) 2.4 ( ) 2.5 ( ) Maisonneuve, Lancet 1999

6 Cancer incidence (absolute) and dialysis Cancers of the Site All AUS (n = 500) EUR (n = 6849) USA (n = ) intestine + breast + prostate occurred in 61.2 of patients Digestive Respiratory Genitourinary 73.9 per Cervix 4.9 per Bladder 22.2 per Kidney 22.9 per Endocrine 2.9 per Haemopoietic 16.7 per Maisonneuve, Lancet 1999

7 Malignancy in patients with renal failure 9% of patients with diagnosis of malignancy at initiation of dialysis Malignancy accounts for 8.2 of deaths per 1000 patient years (USRDS )

8 You can t find a fever if you don t take a temperature House of God

9 Screening for malignancy At transplantation, freedom from malignancy is essential BUT Renal failure is associated with an increased incidence of malignancy THEREFORE (Among others) patients for the transplant waiting list should be screened for the presence of malignancy.

10 Recommendations (initial evaluation) Kasiske, JASN 1995 screen for cancer Steinman, Transplantation 2001 PSA (men > 45) colonoscopy > 50 gynaecological evaluation EBPG NDT 2000 PSA, prostate sonography > 50 years renal ultrasound mammography > 40 years pelvic exam regardless of age FOBT in all patients Fritsche, Transplantation significant variation in 28 of 45 diagnostic procedures -ultrasound, urologic / GYN consult, FOBT, PSA -geographic location only significant determining factor

11 Recommendations Kasiske, Am J Transplant 2001 annual prostate exam + (level C) PSA >50 years (>40 years) renal imaging ( risk) (level C) annual breast exam annual mammogram >50 years (>40 years) (level A) annual pelvic exam / (level B) Pap smear > 20 years FOBT / colonoscopy (level A) > 50 years (> 40 years) thyroid palpation (level C) testicular exam (level C) General cancer screening recommendations annual prostate exam + PSA > 50 years (> 40 years) annual breast exam > 40 years annual mammogram >50 years (>40 years) annual pelvic exam / Pap smear > 20 years FOBT / colonoscopy > 50 years (> 40 years)

12 Recommendations (re-evaluation) Kasiske JASN It has been suggested, that older patients who have been on the transplant list for an extended period of time should be evaluated periodically for occult tumors... Danovitch JASN 2002 survey 69 % transplant centers enforce routine cancer screening

13 Dialysis = transplant waiting list Terminal renal failure Patient selection (nephrologist) wait list Patient selection (time) Transplantation

14 Fischereder, Transplant Int 2005 Prevalence of malignoma in potential recipients no malignancy bladder 6.00 kidney 7.00 prostate 6.00 other malignancy total: 45

15 Fischereder, Transplant Int 2005 Malignoma in wait list patients - organ involvement - thyroid seminoma prostate ovary melanoma lymphoma lung basalioma bladder breast carcinoid colon kidney

16 Fischereder, Transplant Int 2005 Malignoma in transplant candidates malignancy other T NT eval. invomplete removed death

17 Cancer recurrence after transplantation 1297 preexisting tumors in renal transplant recipients recurrence rates breast 23 % renal 27 % sarcoma 29 % bladder 29 % skin 53 % myeloma 67 % thyroid 8 % < 2years 2-5 years > 5 years new and cumulative recurrence Penn, Ann Transp 1997

18 Cancer recurrence after transplantation ANZDATA Cancer patients Overall recurrence 5 % not stated screening protocol tumor stage degree of selection Cancer group Number TX Number Recurrence Skin - - Kidney 37 2 Myeloma 4 0 Bladder 24 1 Breast 20 0 Colon 23 0 Prostate 5 1 Melanoma 19 2 Rectal - - Cervix 20 2 Lung - - Non-skin total Chapman, Transplant Proc 2001

19 Patient T.B. *1967 m 3 rd RTX (primary disease: nephronophtisis) donor: female, 63 years immunsuppression: tacrolimus + MMF + steroid (ATG intra-operatively) Treatment of tubulitis: methylprednisolone for 3 days physical examination: BP 120/80 mmhg, otherwise unremarkable laboratory data: hemoglobin 10,6 g/dl, leucocytes 10,2 G/l, creatinine 1,6 mg/dl, CRP 0,45 mg/dl urine (dip-stick): heme 25/µl

20 Patient T.B. transplant ultrasound

21 DD mass within the transplant malignant donor-derived renal cell carcinoma metastasis Kaposi of recipient origin PTLD metastasis benign complicated cyst angiomyolipoma aspergillus mucor malakoplakia tuberkulosis

22 Malignancy of the organ donor malignant melanoma 3 of 4 recipients (Morris-Stiff, AJT 2004) 4 of 4 recipients (Stephens, Transplantation 2000) UNOS, donors Follow-up 30 months - no malignant melanoma - no high-grade CNS-tumor recipients 21 donor-associated tumors Kauffman, Transplantation 2002

23 Renal cell CA of the transplant questionaire to 38 German transplant centres evaluation of 27 centres recipients ( ) donors: pre-existing renal cell carcinoma in 30 (0,27%) age years size: 0,4-6cm recipients: de novo renal cell carcinoma in 16 (0,15%) latency 3-12 years size: 2-2,8cm Wunderlich, Urol Int 2001

24 MRI and renal cell CA of the transplant Leonardou, Magn Reson Imag 2003

25 Renal cell CA of the transplant latency donor diagnosis treatment outcome 9 months postmortal abd. pain nephrectomy remission 84 months postmortal fatique nephrectomy deceased 85 months postmortal incidentally nephrectomy remission 120 months postmortal incidentally nephrectomy remission 157 months postmortal abd. pain part. resection remission 173 months living donor incidentally part. resection remission 228 months postmortal incidentally nephrectomy remission 240 months postmortal incidentally nephrectomy deceased 258 months living donor incidentally part. resection remission total: Cincinnatti Cancer Registry: 31 cases until 1996 Lamb, Urol Res 2003 // Roupret, Transplantation 2004

26 graft vs. tumor effect in the treatment of renal cell cancer Bregni, Blood 2002

27 Patient T.B. - MRI T2 T1 + FS + KM

28 Patient H.S. *1955 m 2nd kidney transplantation (IgA-nephritis, waiting time 7 years) paravertebral backpain, otherwise healthy immunsuppression: tacrolimus + MMF + steroid physical examination: BP 120/80 mmhg, otherwise unremarkable laboratory data: hemoglobin 12,1 g/dl, leucocytes 14,1 G/l, creatinine 1,4 mg/dl, CRP 12,5 mg/dl urine (dip-stick): heme 50/µl

29 Imaging of native kidneys after transplantation

30 H.S. *1955

31 Malignancy in transplant recipients Northern-Italy 172/3521 patients carcinomas 17 renal cell CA 11 non-basalioma 10 Colorectal CA 8 breastca 7 stomachca 7 lungca 6 bladder CA 3 mesothelioma Pedotti, Transplantation 2003

32 Kasiske,, AJT 2004 Malignancy in transplant recipients UNOS 172/3521 Patienten

33 Malignancy in transplant recipients Organ general population 1 year after transplantation UNOS prostate 162, ,4 172/3521 Patienten breast (w) / 1,5 (m) 343,4 (w) / 6,8 (m) colon 66,4 137,2 skin 24, ,1 cervix 9,4 9,4 kidney 16, ,0 non-hodgkin ,0 oral 15,8 269,4 3-fold 84-fold 42-fold 40-fold Kasiske,, AJT 2004

34 Malignancy in transplant recipients 260 patients undergoing nephrectomy at the time of transplantation ARCD (85) adenoma (35) renal cell CA (11) Denton, Kidney Int 2002

35 Risk factors for malignancy after transplantation (general) Morath, JASN 2004

36 Risk factors for acquired cystic disease Denton, Kidney Int 2002

37 How to proceed screening urine sediment? urine cytology? imaging? treatment specific immunosuppressive regimen?

38 Hematuria after transplantation 85/640 patients after renal transplantation repeatedly dip-stick + for heme McDonald, Clin Nephrol 2004

39 Urine cytology 78 patients with RTX secondary to analgesic nephropathy routine urine-cytology urothelial-ca of the native kidneys / bladder 11/78 patients (14,1%) 5-77 months after transplantation mortality 8/11 Kliem, Transpl Int 1996

40 Imaging after Transplantation prospective abdominal ultrasound of the native kidneys 840 transplant recipients 169 patients with ACKD 7 patients with renal cell carcinoma 46 patients with additional MRI 17 patients with new complex cysts Heinz-Peer, Urology 1998

41 Skin Cancer in NTX recipients Webster AC, AJT 2007

42 Malignant tumors in transplant recipients Wimmer, Kidney Int 2007

43 Immunsuppressive regimen in transplant-recipients with malignancy IS from chemotherapy IS promotes tumor growth? IS reduces tumor growth IS to maintain transplant function

44 Azathioprine and skin cancer O Donovan, Science 2005

45 Cyclosporine dose and new cancer after renal transplant P < Dantal Lancet 1998

46 MMF and malignancy after renal transplantation Robson AJT 2005

47 Sirolimus based immunosuppression and Kaposi sarcoma after renal transplantation complete partial no response author/year Lebbe, AJT Boratynska, Kolhe, Gonzales-Lopez, Descoeudres, Wasywich, Mohsin, Campistol, Boeckle, Zmonarski, Stallone, total

48 Immunsuppressive regimen in transplant-recipients with malignancy Mathew, Clin Transplant 2004

49 Wali R, AST 2006 The CONVERT Trial 111 centres Asia, Australia Europe, Middle East, South Africa North America (Canada, Mexiko, US) South America (Argentinia, Brasil, Chile) Patients: 750 expected; 830 included Randomised conversion vs. CNI continuation (2:1) Sirolimus trough level: ng/ml

50 Wali R, AST 2006 Malignancy after conversion 10 SRL CNI (n=555) (n=274) Rate,% 5 p = p = p = total p = , ,4 0,2 0 skin PTLD other

51 Summary Patients with renal insufficiency have a significantly increased incidence of malignant disease, especially of the urogenital system. Transmission of malignant tumors with the transplant is extremely rare (exception: melanoma). 4 Solid tumors of the transplant (most frequently de novo renal cell CA) can be controlled surgically. 4 After transplantation, the incidence of renal cell carcinoma within the native kidneys is substantially increased (671/ pat.). 4 Acquired cystic disease (ARCD) is significantly correlated with adenomas or carcinomas. 4 Routine sonography is recommended as screening procedure.

52 Future perspectives Trends towards improved cancer therapy, increased use of cytotoxic therapy, prolonged waiting time and screening programs will result in increased cancer detection in potential transplant candidates. Future strategies have to identify patients at risk to assure intensive monitoring for recurrence and consideration of specific immunosuppressive protocols.

53

54 Accuracy of screening Renal cell carcinoma nephrectomy at Tx 260 (349) recipients age 42.7 (± 12.7) years dialysis 1.0 (0-16) years histology: acquired cyst 33 % adenoma 14 % carcinoma 4.2 % oncocytoma 0.6 % Characteristic Odds ratio (CI) P value Age 1.1 ( ) a Male 10.8 ( ) White 0.8 ( ) HD 0.4 ( ) PD 0.6 ( ) Dialysis duration 1.3 ( ) b Glomerulonephritis 3.0 ( ) Diabetes mellitus 0.8 ( ) 0.88 a per year of age b per year on dialysis Denton, KI 2002

55 Recommendations: What is missing... evidence level A (except breast and colorectal) population specific recommendations frequency enforcement of screening procedures

56 Konversion von CNI zu Sirolimus - aktuelle eigene Erfahrungen - Event Patienten ml/min Stomatitis 2 p=0,065 Epistaxis Schwere Infektion 2 50 (mit stationärer Behandlung) Transplantatverlust 0 35,9 39, CNI SRL Tod 0 MDRD 25 20

57 Konversion von CNI zu Sirolimus - aktuelle eigene Erfahrungen - Umstellungsgrund Neoplasie, n = 6 Event Patienten ml/min Stomatitis 1 p=0,049 Epistaxis Schwere Infektion (mit stationärer Behandlung) Transplantatverlust ,9 44, CNI SRL Tod 0 MDRD 25 20

58 Malignoma in wait list patients - therapeutic intervention - curative 30 palliative 2 Fischereder, Transplant Int 2005

59 Imaging of native kidneys after transplantation

60 Cancer incidence and uremia Median survival diagnosis < 90 days before dialysis 2.61 years diagnosis > 90 days before dialysis 8.95 years ANZDATA Cancer before dialysis Cancer after dialysis Cancer group N RR % 5y n RR % 5y Skin Kidney Myeloma Bladder Breast Colon Prostate Melanoma Rectal Cervix Lung Non-skin total Chapman, Transplant Proc 2001

61 Prevalence of malignoma in potential recipients single center review all patients deemed transplant candidates (n = 346) malignancy histologically confirmed: n = 42 evaluation ongoing: n = 3 total: n = 45 (13 %) Fischereder, Transplant Int 2005

62 Malignoma in wait list patients - organ involvement - no malignancy basalioma bladder breast carcinoid colon kidney lung lymphoma melanoma ovary prostate seminoma thyroid Fischereder, Transplant Int 2005

63 Fischereder, Transplant Int 2005 Prevalence of malignoma in potential recipients malignancy No malignancy p value % male Age 51.1 (±17.3) 50.2 (±12.2) n.s. Previous transplants n.s. Dialysis (years) NPL prior Dialysis prior < n.s.

64 Malignancy in transplant recipients Influence of growth hormones 47 children with follow-up of years age at transplantation 0,5 15,6 years renal cell carcinoma in 2/47 2 patients with growth hormone treatment Living-related renal transplantation after 7 and 8 years acquired cysts within the transplant nephrektomy Tyden, Transplantation 2000 // Englund, Transplantation 2003