Objectives: We evaluated patients with nonmelanoma skin cancer after kidney transplant and the effects of immunosuppression reduction and switching to a mammalian target of rapamycin inhibitor drugs.
Materials and Methods: Kidney transplant recipients were evaluated retrospectively from patient medical records (between January 2000 and December 2014). A 30% increase in serum creatinine was accepted as indicating renal failure progression.
Results: Of 18 patients included (mean follow-up 98 ± 66 mo), 7 (38.8%) had squamous cell carcinoma, 7 (38.8%) had Kaposi sarcoma, and 4 (22.2%) had basal cell carcinoma. At cancer diagnosis, average serum creatinine was 1.6 ± 0.7 mg/dL and proteinuria was 410 ± 766 mg/d. Immunosuppression regimen was changed in 15 patients (83.3%), with new regimen being a single-drug (only prednisolone) in 4 patients, double-drug in 6 patients, and triple-drug protocol in 8 patients. Eight patients were switched to a mammalian target of rapamycin inhibitor-based double (4 patients) or triple (4 patients) regimen. During follow-up after starting new treatment (average 46 ± 50 mo), 6 patients (33.3%) had progressive kidney failure (0 were receiving triple regimen). Those that progressed were using mammalian target of rapamycin inhibitor-based drugs relatively less (33% vs 50%), although often receiving a single-drug immunosuppression treatment (50% vs 8.3%). Three patients (33.3%) had acute rejection (2 receiving double and 1 receiving single immunosuppression treatment). Five patients (27.7%) had local recurrence of the primary tumor. Mammalian target of rapamycin inhibitor use was relatively less common in patients with tumor relapse (20% vs 46%). One patient died (heart failure), and 1 with chronic rejection returned to dialysis.
Conclusions: Mammalian target of rapamycin inhibitor-based drugs could reduce local recurrence rate in kidney transplant recipients with nonmelanoma skin cancers. Aggressive reduction and/or cessation of immunosuppressive drugs after skin cancer can lead to graft rejection.
Key words : Clinical outcomes, Kaposi sarcoma, mTOR inhibitor, Skin cancer
Malignancy is the most serious and difficult to treat adverse effect of immunosuppressive drugs and is responsible for 10% to 30% of deaths after transplant.1 Among all malignancies, nonmelanoma skin cancer (NMSC), which includes basal (BCC) and squamous cell carcinoma (SCC), is the most common type, and its incidence is over 10-fold compared with that shown in the general population.2 Mammalian target of rapamycin inhibitors (mTORi, which include sirolimus and everolimus) have been used hypothetically to reduce malignancy and the related deaths after transplant; however, the results of observational studies and randomized controlled trials have conflicted. A patient group in a low-dose sirolimus arm of a major study did not demonstrate reductions in both overall survival and NMSC incidence compared with those who received a calcineurin inhibitor-based triple regimen.3 The Collaborative Transplant Study, which analyzed data of 4279 patients receiving mTORi and 73 867 patients not receiving mTORi (all were first recipients of deceased-donor kidney transplants), reported a significant reduction only in the risk of BCC (hazard ratio of 0.56; P = .004) but not in risk of SCC of the skin (hazard ratio of 0.87; P = .54) after kidney transplant.4 On the other hand, a meta-analysis of 21 randomized controlled trials comparing immunosuppressive protocols with and without mTOR inhibitors in kidney transplant showed a 56% reduction in the risk of NMSC in patients who had received sirolimus.1
The specification of an optimal immunosuppressive protocol is an important issue for those who develop skin cancer after kidney transplant. In a joint analyses of 3 studies that included 36 patients with posttransplant Kaposi sarcoma, elimination of calcineurin inhibitors and switching to sirolimus resulted in clinically and/or histologically confirmed complete remission in 24 patients, partial remission in 8 patients, and stable disease in 4 patients.5-7 Moreover, when the mean sirolimus trough level was held between 6 and 10 ng/mL, kidney graft function was preserved in almost all patients.5,7 When considered from this aspect, sirolimus appears as a promising treatment for posttransplant Kaposi sarcoma.
In this retrospective study, we analyzed patients who developed NMSC and Kaposi sarcoma after renal transplant and evaluated the costs and benefits of immunosuppression reduction and switching to mTOR inhibitor drugs.
Materials and Methods
We retrospectively evaluated medical records of 1016 kidney transplant recipients who were seen between January 2000 and December 2014 at 2 training and research hospitals (Bozyaka and Tepecik Hospitals, Kidney Transplantation Units, Izmir, Turkey). Patients with de novo NMSC after transplant but who already had a functional graft were included. All included patients had complete follow-up, as shown in the clinical and histopathologic databases. Patients with de novo Kaposi sarcoma or SCC of the skin had undergone computed tomography scans of the chest and abdomen and esophagogastroduodenoscopy to exclude visceral involvement.
Acute allograft rejections were always confirmed by biopsy and treated essentially with pulse methylprednisolone (0.5-1.0 g/d for 3 days) with or without rabbit antithymocyte globulin. Immunoadsorption and intravenous immunoglobulin were implemented in those who had antibody-mediated acute rejection. Serum creatinine level was used as a measure of kidney function, with values elevated over 30% of baseline accepted as indication of renal disease progression.
Statistical analyses were performed with SPSS software for Windows (SPSS: An IBM Company, version 15.0, IBM Corporation, Armonk, NY, USA). Means and standard deviation of all values were calculated. Mean values were compared by t test or by a nonparametric test if the data were not normally distributed. P < .05 was considered statistically significant.
Fourteen recipients of living-donor and 4 recipients of deceased-donor kidney transplants (including 6 preemptive transplants) were included in our study. Twelve patients were men and 6 were women. Mean age at transplant was 45.4 ± 12.0 years. The average number of mismatches was 3.4 ± 1.6. Panel reactive antibody was negative in all patients, although mildly elevated (5.5%) in 1 patient who had a second transplant. Fourteen patients (77.7%) received induction immunosuppression (12 with rabbit antithymocyte globulin and 2 with interleukin 2α receptor blocker). The maintenance immunosuppressive protocol was cyclosporine in combination with azathioprine and steroids in 5 patients (28%), steroids + mycophenolic acid + mTORi in 3 patients (16%), and steroids + mycophenolic acid or mycophenolate mofetil + a calcineurin inhibitor in 10 patients (56%).
Six patients (33.3%) had acute rejection before the development of skin cancer. Biopsies from 5 patients revealed moderate to severe intimal arteritis (T-cell mediated rejection ≥ Banff IIA criterion). The 6th patient demonstrated C4d positivity with capillary and glomerular inflammation. All patients were treated with pulse steroid and antithymocyte globulin, with the 6th patient additionally receiving immunoadsorption and intravenous immunoglobulin. Graft function improved in all patients after treatment.
Nonmelanoma skin cancer developed an average of 52.3 ± 55.9 months (range, 5-169 mo) after kidney transplant. The mean age at the time of cancer diagnosis was 49.7 ± 12.2 years. Seven patients (38.8%) had SCC, 7 (38.8%) had Kaposi sarcoma, and 4 (22.2%) had BCC. All SCC and BCC lesions were single. There were no systemic metastases at whole body screening in 17 patients. One patient with Kaposi sarcoma of the lower extremity had concomitant pulmonary involvement.
At the time of cancer diagnosis, average serum creatinine level was 1.6 ± 0.7 mg/dL (range, 0.7-3.2 mg/dL) and proteinuria was 410 ± 766 mg/d. At cancer diagnoses, immunosuppressive treatment consisted of a calcineurin inhibitor-based triple-drug regimen in 12 patients, an mTOR-based triple-drug regimen in 3 patients, and a double-drug regimen in 3 patients. Immunosuppressive treatment was modified in 15 patients (83.3%) after the onset of NMSC, with 10 patients receiving a triple-drug regimen and 8 patients receiving a double- or single-drug regimen. Eight patients were started on an mTORi-based immunosuppressive protocol (4 with double-drug and 4 with triple-drug). The clinical course of patients with Kaposi sarcoma is shown in Table 1.
The maintenance immunosuppression protocol of 7 patients before the emergence of Kaposi sarcoma did not include any mTORi drugs. After diagnosis of Kaposi sarcoma, all calcineurin inhibitors were eliminated, and triple-drug immunosuppression regimens were converted to a steroid-based single- or double-drug regimen with dose reduction. A switch to everolimus was conducted in 2 patients.
After immunosuppression intensity was reduced, gingival Kaposi lesions completely disappeared and extremity lesions significantly regressed in all patients. Despite the excellent early response, 3 patients had acute rejection and required pulse steroids and augmentation of maintenance immunosuppression. Thus, reduction of immunosuppression resulted in acute graft dysfunction in 3 patients and chronic graft dysfunction in 5 patients, with mandatory immunosuppression modification after rejection resulting in Kaposi sarcoma recurrence.
The mean follow-up after NMSC diagnosis was 46 ± 50 months (range, 6-189 mo). The maintenance immunosuppression protocols after NMSC and efficacy outcomes are shown in Table 2. Progressive kidney failure was observed in 6 patients (33.3%) during this period. When compared with patients with stable graft function, those who progressed were more likely to use a single immunosuppressive drug (50% vs 8.3%; P = .08). In addition, the use of an mTOR inhibitor was less common in this group (33% vs 50%; P = .54). Of these 6 patients, 3 had acute rejection (mean of 10.6 ± 1.4 mo after NMSC) and were treated with pulse steroids. Acute rejection was unlikely in NMSC patients with triple-drug maintenance immunosuppression, with all rejections occurring in patients with double- or single-drug maintenance therapy (Table 2).
During follow-up after transplant (mean 98.3 ± 66.3 mo), 5 patients (27.7%) had local recurrence of NMSC. The primary lesion was Kaposi sarcoma in 4 patients and SCC in 1 patient. None of the patients with recurrent Kaposi sarcoma were using mTOR inhibitors as the maintenance immunosuppressive therapy. With respect to a second malignancy, 1 patient developed papillary transitional cell carcinoma of the bladder 47 months after primary diagnosis (SCC of the conjunctiva). During follow-up, 1 patient died from heart failure and another returned to hemodialysis because of chronic rejection.
In this study, we investigated the efficacy and safety of reduced immunosuppression with or without mTORi switch in kidney transplant recipients diagnosed with first NMSC. We observed a trend toward increased risk of acute allograft rejection in patients whose maintenance immunosuppression protocol was converted to a reduced-dose double-drug or single-drug regimen after NMSC diagnoses. Indeed, although none of our patients who had received reduced-dose triple-drug immunosuppression had acute rejection, 3 of 8 patients using a single- or double-drug regimen had a rejection episode. In a recent review, Fatahzadeh and associates reported that dose reduction and modification of immunosuppression protocols after Kaposi sarcoma facilitated acute allograft rejection.8 In a different study, excessive reduction or withdrawal of immunosuppression after the development of Kaposi sarcoma yielded to a statistically significantly increased risk of graft loss.9 Similarly, in an observational study, 2 of 11 patients with nonmetastatic cancer lost their grafts due to chronic rejection after conversion to sirolimus.10 On the other hand, escalation of immunosuppressive drug dose after rejection enhances the relapse of the primary tumor. In our series, almost one-third of the patients diagnosed with first NMSC developed either a recurrence or de novo primary tumor of a remote organ after tailored treatment for NMSC. Surprisingly, most patients in this group (4/5 patients) had received single- or double-drug immunosuppressive regimen. However, 2 of these patients were receiving a calcineurin inhibitor-based double-drug immunosuppression regimen and the other 2 had pulse steroid therapy and maintenance drug dose escalation for treatment of rejection. This result suggests that it is the intensity of immunosuppression responsible for the relapse rather than the particular drug itself.11
Finally, dose reduction or elimination of immunosuppressive agents after diagnosis of NMSC can potentially provide regression of the tumor. However, this policy and in particular the use of a single-drug immunosuppressive regimen may lead to rejection and progression to renal failure. Therefore, novel drug combinations possessing both sustainable immunosuppressive and antioncogenic properties with acceptable adverse effects are needed for treatment of NMSC after transplant.
Volume : 15
Issue : 1
Pages : 236 - 239
DOI : 10.6002/ect.mesot2016.P112
From the 1Department of General Surgery and the 2Department of Nephrology, Izmir Bozyaka Education and Research Hospital, Izmir, Turkey; and from the 3Department of Nephrology and the 4Department of General Surgery, Izmir Tepecik Education and Research Hospital, Izmir, Turkey
Acknowledgements: This study was not funded by any company, and the authors declare no conflicts of interest.
Corresponding author: Erhan Tatar, Izmir Bozyaka Education and Research Hospital, Division of Nephrology, 9035170, Karabaglar, Izmir, Turkey
Phone: +90 232 250 5050
Table 1. Location, Primary and Modified Immunosuppression Therapies, and Graft Outcomes of Patients With De Novo Kaposi Sarcoma
Table 2. Maintenance Immunosuppression Protocols after Nonmelanoma Skin Cancer and Efficacy Outcomes