Early and Severe Radiation Toxicity Associated with Concurrent Sirolimus in an Organ Transplant Recipient with Head and Neck Cutaneous Squamous Cell Carcinoma: A Case Report

Discussion

Tacrolimus is a calcineurin inhibitor that inhibits the secretion of interleukin-2 (IL-2), preventing the activation of T and B cells. Sirolimus blocks the downstream response to IL-2 binding by inhibiting mTOR via the phosphoinositide 3-kinase (PI3K)/protein Kinase B (Akt) pathway (8). This pathway is responsible for the regulation of cell survival, proliferation and angiogenesis. Akt and mTOR have been shown to be up-regulated in cSCC cell lines, and hyper-activation of this pathway has been associated with enhanced tumor cell proliferation, up-regulation of angiogenesis and increased hypoxia, all important factors which can contribute to resistance to chemotherapy and radiation therapy (9, 10). Pre-clinical models and early clinical trials have demonstrated that inhibition of the downstream effects of this pathway likely account for the anti-neoplastic properties of sirolimus in skin malignancy, non-small cell lung cancer, post-transplant lymphoproliferative disease, glioblastoma multiforme, among many other types of malignancies (6, 7, 9-11). In contrast, calcineurin inhibitors, such as tacrolimus and cyclosporine, contribute to tumor development through decreased immunosurveillance, as well as carcinogenic properties specific to the drug (4, 8).

There is a growing body of evidence to support the use of sirolimus for immunosuppression in OTR to reduce the rate of cSCC development. Euvrard et al. conducted a multi-center, randomized controlled trial to evaluate the effect of sirolimus on secondary prevention of cSCC in renal transplant patients compared to those receiving tacrolimus. There were fewer cSCC and the time to development of cSCC was significantly longer in the sirolimus-treated group (15 vs. 7 months; p=0.02). There were significantly more serious adverse events in the sirolimus-treated group, the most common being diarrhea and pneumonitis. Twenty-three percent of patients were required to discontinue the drug due to adverse side-effects (4).

The toxicity to normal tissue, significantly out of proportion, to the radiation dose delivered may be associated with concurrent use of sirolimus with radiation therapy. In addition to its anti-neoplastic effect, continuous mTOR inhibition with radiation therapy has been shown to disrupt key signal transduction pathways which may be responsible for radiosensitization and subsequent enhanced toxicity to normal tissue (12-14). Data regarding the radiosensitizing effects of mTOR inhibition are conflicting, with in vivo studies confirming this observation, while in vitro studies do not replicate these results (7). Increased G₂-M cell-cycle arrest (the most radiosensitive phase of the cell cycle), reduced vascular density, down-regulation of tumor angiogenic response, and decreased cell survival were demonstrated in mouse xenograft models of soft tissue sarcoma cell lines and breast cancer cell lines treated with radiation therapy combined with sirolimus compared to those treated with radiation therapy alone (15, 16). Multi-cellular glioblastoma multiforme U87 spheroids and mouse U87 xenografts treated with fractionated radiation and sirolimus were found to have reduced cell proliferation and survival, which supports the hypothesis that inhibition of tumor re-population by sirolimus may contribute to the sensitization effect of this drug when used concurrently with radiation. This same study found that in in vitro monolayer cultures of glioblastoma multiforme, sirolimus inhibited cellular proliferation, but had no significant impact on cell survival and radiation sensitivity compared to control-treated cells (7). Therefore, the authors concluded that oxygenation may be responsible for these disconcordant results. Other well-established radiosensitizers, such as cetuximab and bevacizumab, have also demonstrated radiosensitization in vivo but not in vitro (17, 18).

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Figure 1.

The patient was planned to receive adjuvant radiation therapy to a total of 6,400 cGy in 32 fractions. Pre-treatment intensity-modulated radiation therapy (IMRT) quality assurance revealed only a 0.2% difference in the measured vs. the prescribed dose.

The literature is limited regarding the clinical translation of these biological findings, and a reaction of this severity requiring cessation of therapy has not been described as far as we are aware of. Shinohara et al. described a case of a patient with a history of liver transplantation who received concurrent sirolimus (1 mg/day) and radiation therapy for T2N0M0 SCC of the larynx. The patient demonstrated an unusually early complete clinical response after seven fractions of radiation, although he required a 5-day treatment break after 11 fractions due to grade 2 odynophagia and mucositis which did not require for hospitalization. The patient eventually completed treatment and was found to have no evidence of disease at one-year follow-up (5). A phase I trial of seven patients with stage III non-small cell lung cancer studied the effect of sirolimus combined with the use of thoracic radiation therapy, 6,000 cGy in 30 fractions, with concurrent cisplatin. Three patients received 2 mg/day sirolimus and four received 5 mg/day. The study found no dose-limiting toxicity in patients treated with 2 mg/day. One patient treated with 5 mg/day had dose-limiting grade 3 esophagitis and odynophagia earlier than expected in treatment, but was able to complete treatment. When reduced to 2 mg/day, the patient had no further dose-limiting toxicity, which suggests that the dose of sirolimus may be an important factor in radiosensitization of normal tissue (6). Additionally, there is evidence that sirolimus enhances radiation-induced apoptosis and increases the efficacy of concurrent cisplatin in vitro (19). The patient presented in this case was found to have a supratherapeutic sirolimus level and was treated with concurrent cisplatin, all of which could have contributed to the severe toxicity to normal tissue observed. The patient's medication list was reviewed, and no other suspected radiosensitizers were used during the time of radiation therapy.

Based on these early studies, mTOR inhibitors such as sirolimus may contribute to enhancing the cytotoxic effects of radiation therapy and contribute to dose-limiting toxicity. While there is evidence of anti-neoplastic benefit on the addition of sirolimus in this patient population, the case that we have presented suggests caution when concurrently administering sirolimus and radiation therapy. Further study is certainly needed to explore this observation and better-characterize the potential for enhanced radiotoxicity with concurrent use of sirolimus.