Cancer and immunosuppression are not a good combination. Immunosuppression can accelerate the growth and spread of cancer when administered to patients with tumors, and immunosuppressed patients have an increased risk of developing de novo malignancy. Therefore, an immunosuppressant that has antineoplastic effects is conceptually appealing, especially for patents who receive transplants for cancer. If one adds to that therapeutic profile an absence of neurotoxicity, nephrotoxicity, and diabetogenesis, sirolimus fits the description.1–3 Exploitation of the antiproliferative effect of sirolimus was a prime consideration when it was used in the first small series of liver recipients who had hepatocellular cancer (HCC).4 The period of follow-up wasn't long enough to prove an oncological benefit.
In this issue of Liver Transplantation, Kneteman and colleagues5 publish data on 40 recipients grafted for cirrhosis and HCC using sirolimus-based immunosuppression. Sirolimus is an effective immunosuppressant in liver recipients, and it can be used in a variety of protocols in combination with other agents.6–8 To achieve its maximum oncological effect, it is rational to use it not as an adjunct but in its full dose, as in the Kneteman series. Theoretically, patients get the benefit of reliable immunosuppression and daily systemic chemotherapy. Some of the side effects of sirolimus are typical of oncological agents. In this series, 30% of patients experienced mouth ulcers, 55% needed treatment for anemia, and 43% of patients experienced leukopenia, some of whom needed G-CSF therapy. Dose adjustments to manage side effects were common and sirolimus was discontinued in 8.3% of recipients because of side effects.
The median waiting time to transplantation was short (2 months), and some of the patients received neoadjuvant ablative therapy (chemoembolization, alcohol injection, resection). Very good results were achieved using a protocol that minimized exposure to calcineurin inhibitors and steroids. Although all patients received sirolimus, the immunosuppressive regimen was not uniform. The first 10 patients received cyclosporine, and the subsequent 30 patients received tacrolimus. Low drug levels were targeted, and calcineurin inhibitors were eventually discontinued. Almost half of the patients (the first 18) had rapid steroid taper and withdrawal, whereas the remainder received no steroids but were induced with daclizumab. Notwithstanding these variations, very good overall survival rates were achieved, and effectiveness of the immunosuppressive therapy was confirmed by a 30% incidence of rejection and no steroid-resistant rejection. Twenty-four of 35 survivors were maintained on sirolimus therapy only. Before concluding that sirolimus should be the immunosuppressant of choice in all liver recipients with HCC, the data needs to be carefully compared to the results of other reported series.
There are 2 patient populations in the study, and they should be considered separately. Nineteen patients satisfied the criteria for early (Milan) tumors—i.e., solitary tumors less than 5 cm in diameter, or 3 or fewer tumors none greater than 3 cm in diameter. The 4-year tumor-free survival was 81.1% in that group, and tumor recurrence was low (5.3%). Those results are excellent, but early tumors have been shown by several groups to have very good outcomes using immunosuppressive regimens that have not included sirolimus. The seminal report from Milan recorded recurrence-free survival of 83% at 4 years and a tumor recurrence rate of 8%.9 Immunosuppression was a cyclosporine-based regimen with discontinuation of azathioprine after 1 month and cessation of steroids by 6 months. Tumors were understaged in more than one-quarter of the patients in that series. When only those who met the predetermined Milan criteria were included, the recurrence-free survival rate was 92% at 4 years. A report from Barcelona analyzed patients who received liver grafts as primary treatment for HCC that included fewer than 5 nodules and none greater than 5 cm in diameter.10 The 5-year survival was 79%, and the tumor recurrence rate was 8%. The immunosuppressive regimen consisted of thymoglobulin induction, steroids, cyclosporine, and azathioprine. In that study too, there was early discontinuation of steroids. Another Barcelona series of solitary tumors less than 5 cm in diameter recorded a 74% 5-year survival and tumor recurrence rate of 3.5%.11 One-third of the patients had multiple tumors on final pathological examination. Immunosuppression was cyclosporine-based, with discontinuation of azathioprine after 1 month and cessation of steroids by 18 months. It is clear from these series and others12, 13 that for tumors that meet accepted criteria for designation as early, results are achievable without sirolimus therapy that compare favorably with the early tumors reported in the series of Kneteman et al. The case can be made that minimal immunosuppression is desirable, and early discontinuation of steroids is preferable, but it cannot be concluded from the published data that a particular immunosuppressive regimen is the best for tumors that meet early criteria. Indeed, when a variety of immunosuppressive protocols can achieve posttransplant survival rates in patients with early HCC that equal those after transplantation for nonmalignant disease, it is most unlikely that any regimen could be proven to be superior from an oncological perspective.
The second group of patients in this series had tumors that were beyond the early stage and were designated as extended tumors by the authors. Patients with HCC who potentially have the most to gain from an antineoplastic immunosuppressive protocol should logically be those who are at greatest risk of HCC recurrence. Patients with larger, multifocal tumors and those with vascular invasion are the obvious candidates. Kneteman et al. selected solitary tumors up to 7.5 cm in diameter and any number of tumors with a maximum diameter of 5 cm in this category. They excluded poorly differentiated tumors that exceeded 5 cm in diameter and tumors that had imaging evidence of portal venous or vena cava invasion. Pathological analysis revealed that the median number of tumors was 4 and the median size was 4.5 cm in diameter (see figure of the Kneteman paper on p. 1303). In 21 patients with tumors that met the extended criteria, the 4-year tumor-free survival was 76.8%, and the tumor recurrence rate was 19% after transplantation. Those are good results, and they support the emerging view that some expansion of tumor limits beyond the Milan criteria is reasonable in the selection of candidates with HCC for transplantation.
Comparison of their extended group to other series of more advanced cancers is problematic because criteria for size and number differ. Also, various neoadjuvant treatments (chemoembolization, percutaneous ablation, etc.) are more likely to be confounding variables in this group of patients because they are frequently used to either downstage disease or prevent disease progression while patients wait for transplants. The pitfalls of comparing series that have little uniformity are obvious. Nevertheless, the results of 2 other series from centers that accepted tumors beyond the Milan limits need to be considered. Neither one used sirolimus. A series of 70 recipients from the University of California—San Francisco (UCSF) included tumors that were slightly more conservative than the extended criteria of Kneteman et al.14 They included solitary lesions up to 6.5 cm in diameter, fewer than 4 tumors up to a maximum 4.5 cm in diameter, or total tumor diameter up to 8 cm. For tumors that did not exceed the criteria, the 5-year patient survival rate was 75.2% and the tumor recurrence rate was 11.4% after transplantation. In 10 patients whose tumors exceeded the limits, the 1-year survival was only 50%. A subsequent analysis from the same center showed that patients whose tumors met the UCSF criteria and exceeded the Milan limits had a 2-year estimated survival of 86%.15 Immunosuppression was a triple-drug regimen consisting of steroids, either cyclosporine or tacrolimus plus either azathioprine or mycophenolate mofetil (stopped after 6 months to 1 year). The majority (60%) of the patients received chemoembolization before transplantation, whereas only 29% of patients in the Kneteman series received various neoadjuvant treatments. Another study from Spain included solitary tumors up to 6 cm in diameter and up to 3 tumors none exceeding 5 cm diameter.16 Immunosuppression consisted of cyclosporine or tacrolimus, azathioprine and prednisone. Most of the patients were given chemoembolization. Patient survival was 70% at 5 years, not significantly different from a cohort of recipients without HCC at that center. Tumors recurred in 13% of recipients. Patient survival rates and cancer recurrence rates in each of these series are good and not much different from one another. Together they show that restriction of transplant candidacy to tumors that meet Milan criteria is too rigid. They lack the similarities that would be desirable to make direct comparisons. They differ in their selection criteria, exclusion criteria, waiting times between cancer diagnosis and transplantation, and the type and frequency of neoadjuvant therapies. Those differences make it especially difficult to attribute a specific benefit to the immunosuppressive protocol in any of them. Kneteman's data does not provide conclusive evidence that sirolimus was the reason for the outcomes in their group of extended HCC patients, but there is no denying that the results are excellent.
The anecdotal cases of extended survival in spite of HCC recurrence are interesting. The time to tumor recurrence was long (almost 2 years) compared to other series, and survival after recurrence averaged another 2 years. How does one prove that sirolimus delayed the development and spread of metastatic disease? One patient who had resection of a recurrence within the liver graft was tumor free more than 4 years later. Another patient developed pulmonary and hepatic metastases more than 4 years posttransplant and, in spite of receiving no treatment (other than sirolimus monotherapy) was still alive more than 3 years later. It is very tempting to claim that an antineoplastic effect of sirolimus was responsible for the late and indolent recurrences in this series, but the evidence is only circumstantial. All transplant programs occasionally have patients with tumors that defy odds and behave in an unexpected fashion.
The selection of candidates with HCC for transplantation is evolving, and tumor criteria are being redefined. The experience of Kneteman et al. is a valuable contribution. How expanded the limits should be cannot be stated with certainty at this time, nor can a clear winner in terms of immunosuppression be declared.