PRRT with 177
Lu-octreotate as single agent is effective in patients with somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours. However, strategies to increase the efficacy of such treatment should be investigated. One possible way to improve these effects is combining 177
Lu-octreotate with chemotherapeutic agents as radio-sensitiser. Capecitabine is often used as radio-sensitiser with external beam radiation therapy. It has attractive features for combining with radiation therapy: Capecitabine is an oral prodrug of 5-FU and has to be converted to its active form after three enzymatic converting steps. The third step is by the enzyme thymidine phosphorylase (TP). Several types of malignant cells have high expression of TP, and this can result in higher concentrations of the active form (i.e. 5-FU) in tumour cells compared to non-malignant cells [10
]. Moreover, TP expression is induced by radiation [11
], which can again result in higher concentrations of 5-FU in irradiated cells. These features are also attractive for combining capecitabine with radionuclide-derived radiation therapy, like PRRT.
To our knowledge, no studies have so far been published that describe the combination of capecitabine with a somatostatin analogue labelled with a beta-emitting isotope, like 177Lu-octreotate, with regard to side effects. Based on the findings from a pilot study to evaluate the safeness and feasibility of this combination, we intended to make a decision to start or reject a randomised clinical trial comparing 177Lu-octreotate as single agent with 177Lu-octreotate in combination with capecitabine.
Haematological toxicity was infrequent. One patient had grade 2 thrombocytopenia after the fourth cycle. In one patient, WHO grade 3 thrombocytopenia occurred after the third and fourth cycles. In another patient, haemoglobin was 4.9 mmol/l on one occasion (WHO grade 3 anaemia) after the second cycle, which improved within 1 week to grade 2 anaemia.
No acute renal toxicity was observed in these patients based on measured serum creatinine levels. Of course, some subtle side effects on glomerular filtration rate or tubular function, which may only be demonstrated with more sensitive methods, like 99mTc-DTPA or 99mTc-MAG3, cannot be ruled out. However, based on serum creatinine levels alone, we may conclude that there was no clinically relevant acute renal toxicity.
None of the patients had hand-foot syndrome, and one patient had a more sensitive oral mucosa, but grade 2 or more stomatitis was not noted. The low frequency of these side effects of capecitabine in our group can be explained by the relatively low dose (approximately 825 mg/m2 bid) used in this and other radio-sensitising studies. This is an important characteristic, as ideally, we do not want to provoke side effects that have a serious impact on quality of life in these patients who usually have a life expectancy of several years. Furthermore, nausea, vomiting and hair loss were observed, but percentages in the group treated with the combination are similar to those after treatment with 177Lu-octreotate alone. None of the patients had symptoms of cardiac ischaemia or heart failure that could be attributed to capecitabine.
Of note is that so far, only acute and subacute side effects could be registered. No data are known yet about long-term side effects. The patients treated with the combination of 177Lu-octreotate and capecitabine will therefore also be closely monitored in the future to reveal potential late toxic effects, e.g. on kidney function and bone marrow. The patients will undergo blood tests every 6 months and will also collect urine for 24 h to determine creatinine clearance and proteinuria.
Based on these findings, we conclude that the combination of 177Lu-octreotate with capecitabine is safe and feasible in patients with GEP NETs with regard to short-term side effects. We recently started a randomised controlled clinical trial comparing treatment with 177Lu-octreotate alone to treatment with 177Lu-octreotate and capecitabine. Ultimately, the results of that study will provide final data about differences in anti-tumour effects and toxicity profiles between these treatments, also on the longer term.