Renal Cell Carcinoma And Kidney Transplantation: A Narrative Review Ⅲ

Screening for RCC After Transplantation 

There are no clinical trials of cancer screening in KTRs demonstrating improved survival. Although the risk of cancer is high, so is the competing risk of noncancer death, precluding generalizations from cancer screening trials in the general population.29 A recent review highlighted the discrepancies and other shortcomings of cancer screening guidelines in transplant recipients, including the lack of clinical trial evidence and involvement of key stakeholders.80 The review found inconsistent recommendations to screen for RCC in KTRs, with the 2002 European Best Practice Guidelines in favor and the 2011 Renal Association Clinical Practice Guidelines in disfavor of screening, while 5 other guidelines provided no clear recommendations. 

NEW HERBAL FORMULATION FOR CARING FOR KIDNEY TRANSPLANT PATIENTS

The 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients notes that several centers are screening for RCC in KTRs without evidence of a mortality benefit.81 Further, the KDIGO states that screening will likely detect many unimportant lesions though may be beneficial in certain high-risk groups such as KTRs with prior RCC, tuberous sclerosis, ACKD, and analgesic nephropathy, and a randomized controlled study is advised.81 A Markov model of ultrasound screening for RCC found minimal survival benefit, that is, only 2 deaths avoided from RCC per 1000 KTRs screened annually for 62 y, at an incremental cost-effectiveness ratio of >$300000 per life-y saved.82 In conclusion, in most KTRs, there is little evidence to support screening for RCC.

FIGURE 3. Overview of recommendations. Please refer to Table 3 for details

Treatment of RCC in KTRs 

No specific guidelines exist for the evaluation or treatment of tumors in renal allografts or RCC in KTRs.83 In practice, treatment strategies outlined for the general population are used as long as appropriate with some modifications. Localized RCC in dysfunctional native kidneys is often treated with nephrectomy, whereas for localized RCC in the allograft, several case reports describe successful nephron-sparing surgery or ablative therapy.44,84 A systematic review on solid masses in kidney allografts found 175 tumors reported in 163 patients, mostly clearcell RCC (46%) or papillary RCC (42%).2 The majority were treated with partial nephrectomy (68%), fewer with allograft nephrectomy (19%), radiofrequency ablation (10%), and cryoablation (2%). Cancer recurrence after partial nephrectomy was 3.6% after 3.1 y, which is similar to non-transplanted patients.2

For metastatic RCC in KTRs, it is not known if immune checkpoint inhibitor combination therapy provides survival benefits, as recently shown in non-transplanted patients. Case reports caution that maintenance emusuppression may render the checkpoint inhibitors less effective and there is a high risk of rejection and graft loss.85 A recent systematic review on immune checkpoint inhibitors in solid organ recipients identified 83 treated patients, of whom 53 were KTRs.86 Most patients had melanoma or other skin cancers, and only 2 had RCC. Acute rejections were seen in 39.8%, often (71%) leading to graft failure. Stable or responsive disease was noted in 3 (3.6%) and 23 (27.7%) patients, respectively. Tumor response was not associated with immune-related adverse events, time since transplant, specific immunosuppressant drugs, or rejection. Receipt of at least 1 immunosuppressant drug other than steroids was associated with less rejection but also a trend for lower progression-free survival. The median survival was 36 wk, and 48 (57.8%) patients died, mostly attributed to tumor progression. Even though 19.3% were alive and free from rejection and tumor progression at the end of the study, this review highlights the difficult tradeoffs facing transplant specialists and oncologists managing solid organ recipients with cancer.87 Clearly, better predictive biomarkers are needed to decipher which patients will benefit from these treatments.

TABLE 3. Suggested recommendations

Although immunosuppression is a recognized risk factor for the development of malignancies, the optimal adjustments to maintenance immunosuppression in KTRs with de novo cancer are uncertain.88 For some malignancies, that is, posttransplant lymphoproliferative disease and Kaposi sarcoma, a reduction of immunosuppression89 or switch to mTOR inhibitor90 has been shown to facilitate tumor regression, respectively. For other cancer types, reduction of immunosuppression has not proven beneficial. One cohort study found that immunosuppression reduction did not prolong cancer-free survival.91 A recent study from France in kidney and liver transplant recipients with de novo malignancy found that optimal oncologic treatment and introduction of mTOR inhibition were associated with improved survival.92 Notably from this study, optimal oncologic therapy was delivered in 80% and 38% of patients with localized and advanced cancer, respectively, and among the latter, 27% had only supportive care.92 For RCC, no trials of mTOR inhibition included KTRs, and other trials of mTOR inhibition in KTRs warrant caution. A systematic review and meta-analysis of 5876 KTRs domized to sirolimus immunosuppression found a 40% reduced risk of malignancy, driven by a 56% reduced risk of nonmelanoma skin cancer though at a 43% increased risk of mortality.93 Moreover, in organ transplant recipients, a switch to mTOR inhibition seems to be most effective in early-stage cancer. For instance, in KTRs with skin cancer, the effect of mTOR conversion is significant only in subgroups with less advanced disease at baseline, ie, ≤1 previous skin cancer.94 Similarly, in a randomized study in liver transplant recipients, sirolimus conversion for HEPAto cellular carcinoma surprisingly only benefited patients with low-risk cancer.95 Thus, the effect of mTOR conversion in KTRs with metastatic RCC would need confirmation in a randomized trial. Nevertheless, reduction in the maintenance immunosuppression regimen is customary in KTRs with active cancer.29 No particular pattern of reduction is discernible from the current literature.96 Reduction or stopping the antimetabolite would be beneficial to avoid leukopenia, others would advocate for switching the calcineurin-inhibitor to mTOR, particularly knowing the benefits of mTOR inhibitors as treatment options for non-transplanted patients with RCC. For patients planning immune checkpoint inhibitor treatment, some would favor an mTOR combined with 10mg of prednisolone,97 though as stated above, there is no clinical supporting evidence.86 The option of gastrectomy and stopping all immunosupprecision followed by checkpoint inhibition has, to our knowledge, not been explored, though stopping immunosuppression was recommended in the era of interleukin 2 treatment.98

With these highly uncertain outcomes of treatment, shared decision-making between a fully informed patient, the oncologist, and the transplant nephrologist is essential. Many patients will likely decline immunotherapy, in particular if frail or unable/unwilling to return to dialysis (in whom rejections are indeed life-threatening). No treatment, an introduction of an mTOR inhibitor, and/or therapy with TKI are all valid options. No trial evidence exists for TKI in KTRs, few case reports show effect in localized99,100 and metastatic101-103 disease, though as for immune checkpoint inhibitors, toxicity may limit treatment.104,105 Based on the currently available data, we present our suggested recommendations as an overview in Figure  3 and with details in Table 3. 

CONCLUSIONS 

KTRs are at increased risk of RCC, in particular of the native kidneys. Screening for RCC in all KTRs is not cost-effective but may be of value in high-risk subsets, such as patients with a previous RCC and patients with known ACKD. Localized RCC is treated similarly to the nontrans-planted population. For advanced RCC, there is currently no trial evidence for the optimal immunosuppression regimens or oncological treatment. Prospectively collected data and randomized trials are urgently needed.

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