Abstract
Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.
Highlights
Medullary thyroid cancer (MTC) accounts for about 1–2% of all thyroid cancers [1]
Gemcitabine resulted in a detrimental effect on tumour growth
The animals treated with a combination of both 177Lu-octretoate and gemcitabine showed no statistically significant difference in tumour volume compared with the animals treated with gemcitabine only (p = 0.430 at day 16)
Summary
Medullary thyroid cancer (MTC) accounts for about 1–2% of all thyroid cancers [1] It originates from the calcitonin-producing parafollicular C-cells of the thyroid and occurs either sporadically or as a hereditary form in the multiple endocrine neoplasia type 2 syndrome, often caused by mutations in the RET proto-oncogene [2,3,4]. For distant metastases from the more common papillary and follicular thyroid cancer, systemic therapy with radioiodine (131I) is a well-established treatment technique with high response rates [8]. High receptor-specific binding of radiolabelled SST analogues, e.g. 111In-octreotide or 177Lu-octreotate, can be achieved in MTC [10, 11]. Treatment with radiolabelled SST analogues is one type of peptide receptor radionuclide therapy (PRRT). In a clinical phase II trial, PRRT with 90Y-octreotide for patients with metastatic MTC was associated with long-term survival benefit [12]. There is a clear need for optimisation and one option could be to combine PRRT with another drug [13]
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