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Immunosuppressive Regimens and Cancer Risk: Are All Anti-rejection Treatments the Same?

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Based on the following article: J Am Soc Nephrol 2006;17(2):581-9

Transplantation March 2006

Reported by: G.V. Ramesh Prasad, MB, BS, MSc, FRCPC

Assistant Professor of Medicine University of Toronto Toronto, Ontario

Staff Physician St. Michael’s Hospital Toronto, Ontario

As discussed by Dr. Josep Campistol, Provincial Hospital Clinic, Barcelona, Spain, cancer is now a leading cause of death in organ transplant recipients. Dr. Campistol was recently speaking at the 7th International Conference on New Trends in Immunosuppression and Immunotherapy in Berlin. As he indicated, 80% of transplant recipients will develop a malignancy between 10 and 30 years after receiving their donor organ. While the majority of these malignancies will be skin cancer, non-dermatological cancers occur in a significant proportion of transplant recipients as well, often proving to be fatal, Dr. Campistol noted.

For example, one Australian study found that after 10 years, approximately 25% of all deaths in a renal transplant cohort were attributable to cancer (Penn I. Clin Transpl 1998;147-58). It has also been reported that compared with the general US population, renal transplant recipients have a 90-fold increased risk for non-melanoma skin cancer and a sixfold increased risk for melanoma three years after receiving their donor kidney (Kasiske et al. Am J Transplant 2004;4(6):905-13). The high risk of malignancy in the renal transplant population is related to their inherently immunosuppressed state as a result of kidney failure, as well as their need for chronic immunosuppression.

Some immunosuppressive agents may also possess cancer-promoting properties, particularly the calcineurin inhibitors (CNIs) including cyclosporine (CsA) and tacrolimus. According to recently published data, the two agents have been shown, at least experimentally, to accelerate tumour growth and metastases (Campistol et al. J Am Soc Nephrol 2006;17(2):581-9). In other studies, investigators observed a pro-neoplastic effect of CsA in mice, an effect they found was related to the enhancement of tumour angiogenesis (Guba et al. Transplantation 2004; 77(12):1777-82). Other researchers have posited that the risk of developing certain cancers in the setting of CsA immunosuppression may be exacerbated by other known risk factors for cancer, including ultraviolet (UV) light (Marcil I, Stern RS. Lancet 2001; 358(9287):1042-5). It is noteworthy that the incidence of skin cancer in Australian transplant patients who are exposed to intense UV radiation is dramatically higher than it is in their European counterparts.

Data linking the CNI tacrolimus to malignancy is considerably more limited than it is for CsA but researchers have reported an elevated incidence of tumours in liver transplant patients receiving either tacrolimus or CsA (Jonas et al. Cancer 1997; 80:1141-50). As noted by Guba et al., tacrolimus may stimulate transforming growth factor (TGF) beta 1 expression, as does CsA, and thus may promote metastases as well.

In contrast, sirolimus, which binds to the mammalian target of rapamycin (mTOR), appears to either halt or at least retard the same neoplastic processes. In work cited by Campistol et al., sirolimus appeared to inhibit several enzymes that play a role in the development and progression of different cancers. Experimental work in mice also suggests that sirolimus may oppose the tumour-enhancing effects of CsA. In one study, rapamycin inhibited tumour growth and metastases both in the presence and absence of CsA (Luan et al. Transplantation 2002; 73(10):1565-72.)

The tumour-suppressing effect of mTOR inhibitors has been supported by observations from the United Network for Organ Sharing (UNOS) database, in which it was demonstrated that mTOR inhibitors reduced the relative risk of a de novo malignancy 963 days after transplantation by 61% in patients, whether or not they were on a CNI-based regimen (Kauffman et al. Transplantation 2005;80(7):883-9). Rates of de novo solid tumours in the same analysis were 0.47% for the mTOR inhibitor plus CsA/tacrolimus regimens vs. 1.0% for the CsA/tacrolimus regimens minus an mTOR inhibitor. It is still not clear, however, if sirolimus can prevent mutations that lead to cancer, although it may help prevent their transformation and eventual growth into malignant tumours.

From a clinical perspective, the distinct advantage of using an mTOR inhibitor is that effective immunosuppressive doses coincide with those that promote anti-angiogenic effects. This fortunate concurrence would allow for the simultaneous treatment of organ rejection and cancer prevention, as Guba et al. noted. It also suggests that the use of rapamycin or its analogues, at least in therapeutic serum concentrations, may be able to reduce the high risk of malignancy in organ transplant recipients, although this may not be true if higher doses are required.

LOWER INCIDENCE OF MALIGNANCY

Hints that sirolimus may attenuate the incidence of malignancy following kidney transplantation emerged clinically in studies cited by Guba et al. and presented at the 2002 American Transplant Congress (abstract 58). In one of these studies, 5% of patients receiving CsA had developed a neoplasm two years after transplantation, compared with none of those who received sirolimus. Results of an earlier, single-centre study also cited by Guba et al. identified no malignancy in patients maintained on a CNI-free, sirolimus-based regimen following kidney transplantation, compared with 12 malignancies among those receiving a CNI-based regimen (Campistol et al. American Transplant Congress 2002, abstract 1013). As researchers noted, these data—which were collected for up to five years post-transplantation—are consistent with 10-year follow-up data of renal transplant patients in which the overall rate of malignancy was low, including the incidence of skin cancer, at 1.9% in recipients receiving a CsA/sirolimus regimen (Kahan et al. Transplant Proc 2003;35(3 suppl):25S-34S).

Guba et al. concluded that studies to date suggest a “potential beneficial effect” of mTOR inhibition on the development of cancer in transplant recipients, although the authors also stressed that longer-term clinical studies are needed to come to any firm conclusion.

MAINTENANCE REGIMEN TRIAL

The Rapamune Maintenance Regimen Trial would now appear to add weight to previous observations that mTOR inhibition reduces the risk of malignancy in kidney transplant recipients. In the current analysis of five-year malignancy data, the use of a sirolimus-based, CsA-free immunosuppressive regimen was associated with a significantly lower incidence of both skin and non-skin malignancies compared to a CsA-containing regimen (Campistol et al. J Am Soc Nephrol 2006; 17(2):581-9).

In this trial, CsA was withdrawn three months after patients had received their donor kidney. This was followed by the introduction of concentration-controlled sirolimus maintenance therapy. Outcomes for patients in this arm of the study were compared with those in patients who continued to receive CsA plus sirolimus. The authors stressed that both treatment groups received sirolimus; the only difference between the two groups was that patients who received CsA/sirolimus received standard or near-standard doses of CsA, while those in whom CsA was withdrawn after the initial three months received approximately twofold higher sirolimus trough levels than the comparator group.

Investigators calculated the incidence of both skin and non-skin malignancies for on-therapy patients, as well as according to an intent-to-treat (ITT) analysis. On-therapy analysis of the malignancy data showed that the mean annualized rate of skin carcinoma was significantly lower (P<0.001) in the sirolimus group than in the combination group. The median time to the first event was also significantly longer at 1248.5 days in the sirolimus group compared to the sirolimus/CsA arm at 401.5 days (P=0.021). For the ITT analysis, the median time to an event among patients who developed skin cancer was 1126 days in the sirolimus arm compared to 491 days for the sirolimus/CsA arm (P=0.007).

The relative risk of developing a skin malignancy was also 64% lower in the sirolimus arm compared to the CsA-containing arm, again according to the ITT analysis (P<0.001). In both analyses, the relative risk of patients developing squamous cell carcinoma (SCC) was also significantly higher in the sirolimus/CsA arm than in the sirolimus-alone arm, as was the incidence of basal cell carcinoma (BCC) according to the ITT analysis. In both the on-therapy and the ITT analyses, the median time to a first event in those who did develop a BCC was also significantly shorter for those in the combination arm.

As the authors noted, the CNI-free regimen also had a “favourable impact” on the mean annualized rate for both BCC and SCC, where it had “a pronounced effect” in delaying the median time to first occurrence of a BCC. In the on-therapy analysis, the mean annualized rate of malignancy (expressed as the number of events/1000 patients/year) was 151.6 for the CsA-containing arm compared to 22.1 for the sirolimus arm, while the same outcome in the ITT analysis was 107.7 for the CsA-containing arm compared to 35.8 for the sirolimus arm. Of note, only one patient in each treatment group developed a melanoma.

NON-SKIN MALIGNANCIES

Cancers other than those of the skin in the same cohort included lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid and cervix. Leukemia, lymphoma and other more rare cancers were also documented. In the ITT analysis, a significant difference in the incidence of non-skin cancer was seen in favour of the sirolimus arm at 3.7% compared to an 8.4% incidence in the combination group (P=0.043). In the on-therapy analysis, the difference between the two arms did not reach statistical significance. Seven patients died of their cancer during follow-up, five in the sirolimus/CsA arm and two in the sirolimus arm. As Campistol et al. noted, more than half of patients on the sirolimus-based regimen completed five years of therapy vs. approximately 10% of patients on the CsA-containing arm.

OTHER IMMUNOSUPPRESSIVE REGIMENS

Associations between other molecules used in immunosuppressive regimens and cancer are much less clear at this point in time. According to one study cited by Guba et al., there was an increased incidence of Kaposi’s sarcoma in patients who had been chronically treated with steroids (Trattner et al. Cancer 1993;72(5):1779-83). However, the effect of corticosteroid therapy alone on cancer development in the transplant population is difficult to assess, as Guba et al. pointed out, especially as they are now used largely to support other strategies to prevent rejection.

The same may also be said for azathioprine (AZA). Prior to the introduction of CsA, AZA was used to treat autoimmune disease and from this era, reports that AZA does promote malignancy, especially lymphoma, began to appear. However, as Guba et al. argued, AZA is used far less intensely now and its direct effect on tumour development is again difficult to assess.

The literature suggests that mycophenolate mofetil (MMF) may actually possess certain anti-neoplastic properties, as Guba et al noted, and it has been shown to inhibit some malignant cell lines as well. Several registries, including the UNOS and the Collaborative Transplant Study, suggest that the use of MMF is associated with a “small but significant” reduction in de novo malignancy, but as Guba et al. stated, any anti-cancer effects attributable to MMF are only just beginning to be explored.

CLINICAL IMPLICATIONS

The Rapamune Maintenance Regimen Trial is the first major clinical study that has used malignancy as an end point, so it can be considered a landmark trial. It was also carried out prospectively and events were carefully recorded so that we now have a better idea of what the true incidence of cancer is in transplant recipients. It is also important to recognize, however, that the overall incidence of cancer in the cohort was low, and there are several statistical concerns that make findings difficult to interpret.

In the on-therapy analysis, the difference in patients who developed a malignancy in the sirolimus/CsA arm (16 patients) was not statistically different from the sirolimus arm (eight patients), although the number of malignancies in the CsA-containing arm (80) was significantly higher than the number of malignancies in the sirolimus arm (24). Consequently, it has been suggested that the data from this study is robust enough to recommend a CsA-free regimen for all transplant recipients in order to reduce their risk of malignancy. Provided a sirolimus-based regimen does not compromise effective immunosuppression, it seems reasonable to consider a regimen that may be associated with a lower risk of malignancy and which will hopefully allow patients to maintain a functioning graft and a good quality of life over a longer interval of time.

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