Interestingā¦ I will dig more into this.
We investigated the effect of sirolimus on development of cancer and on survival among transplant recipients using data from randomized trials. We hypothesized that sirolimus would be associated with a significant reduction in both malignancy and death.
The primary outcome was the development of any new malignancy after randomization. This outcome included any type of cancer (such as basal cell skin cancer, lymphoma, etc). Secondary outcomes included non-melanoma skin cancer, other cancer, and death.
Primary analysis
In total 243 patients developed a malignancy: 127 in the sirolimus group and 116 in the control group. The cumulative incidence of cancer was lower in the sirolimus group than in the control group
There was a 20% reduction in risk of malignancy in women compared with men
Overall, the causes of cancer were significantly different in the sirolimus and control groups (P=0.004; table C in appendix 1). There was a higher proportion of squamous (2.0% v 1.3%) and basal (1.4% v 0.79%) cell skin cancer in the control group compared with the sirolimus group, while there were more hematological malignancies in the sirolimus group
There were 202 deaths: 133 in the sirolimus group and 69 in the control group
Overall patient survival was significantly reduced in the sirolimus group (P=0.04; fig 4ā4).). After multivariable adjustment, sirolimus use was associated with a 43% increased risk of death compared with the control group (adjusted hazard ratio 1.43, 1.21 to 1.71; P<0.001) (table 2ā2).). The causes of death were significantly different in the two groups (P=0.002; table D in appendix 1). There were relatively few deaths attributed to malignancy, but the proportions were similar in the two groups (0.21% sirolimus, 0.19% control). There was a higher proportion of death from infection (0.58% v 0.15%) and cardiovascular disease (1.28% v 0.54%) in the sirolimus group compared with the control group.
Sirolimus use was associated with a 68% reduction in the risk of non-melanoma skin cancer (0.32, 0.24 to 0.42; P<0.001) and a 48% reduction in the risk of other cancers (0.52, 0.38 to 0.69; P<0.001). As with the overall analysis, sirolimus use was associated with an increased risk of death in the conversion trials
Discussion
Principal findings
This study included individual patient level data from 21 randomized trials comparing sirolimus with other immunosuppressive regimens in 5876 recipients of kidney transplant. There was a 40% reduction in the risk of malignancy and a 56% reduction in risk of non-melanoma skin cancer for those randomized to sirolimus.
Although a reduction in cancer was seen in patients converted to sirolimus, the increased risk of death highlights a concerning consequence of this strategy that was not evident from previous trials. By pooling individual patient data, we were able to perform survival analyses, not just on occurrence of cancer but also on overall survival of patients. Our findings help to clarify the benefits and harms associated with sirolimus use regarding reduction of malignancy after kidney transplantation.
As we observed no reduction in mortality related to cancer, the trade-off of fewer cancers with an increased mortality does not seem justified. Perhaps a subset of patients at greatest risk of cancer might benefit from this strategy, but this would be difficult to predict at the individual level
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In patients who did not receive induction therapy, however, there was a significant reduction in cancer with no effect on mortality in those treated with sirolimus
For recipients of a transplant from a deceased donor, sirolimus was associated with a reduction in cancer and an increased risk of death similar to the overall findings. For recipients from living donors, however, sirolimus had a null effect with respect to mortality
Unlike the trial level subgroups (for example, de novo or conversion) patients were not randomized to treatment groups based on induction therapy or donor type. This is an important distinction as these subgroups might be imbalanced with respect to other factors that could influence occurrence of cancer or death. While interesting clinically, the findings from these subgroup analyses should be interpreted cautiously.
We could not identify the mechanism of cancer reduction in our analysis.
but we did see a consistent effect on cancer reduction regardless of whether the trial used high or low doses of sirolimus. Whether the reduction in malignancy was because of an overall reduction in immunosuppression, removal of oncogenic immunosuppression (such as cyclosporine), or a combination of these factors remains unknown
The excess risk of death associated with sirolimus could not be directly explained by our data. We found an increase in both cardiovascular deaths and deaths related to infection, the two most common causes of death in patients with kidney transplantation.7 Over-immunosuppression with sirolimus could have contributed to the increase in infection related mortality, but this could not be confirmed without data on drug concentration.
We did, however, see a significantly increased risk of death in the subgroup of trials that used high dose sirolimus.
Patients treated with sirolimus could have had higher net immunosuppression because of the increased risk of acute rejection seen in some of the included trials.2022 23 This in turn could have contributed to increased infection related mortality.
Although we did not have relevant individual patient level data, an increase in these known cardiac risk factors might have contributed to the increase in cardiovascular death seen in our analysis.
