Although the anti-tumour effects of therapy with ¹⁷⁷Lu-octreotate are promising and serious side effects are rare, further studies are needed to find treatments that are more effective and still have acceptable side effects. One option for improvement is to use combinations of a radiolabelled somatostatin analogue with chemotherapeutic agents as radio-sensitiser. Candidate drugs for this purpose are 5-fluorouracil (5-FU) and capecitabine, which is an oral prodrug of 5-FU. For 5-FU, the additional effect to radiation therapy has been demonstrated: The combination of external beam radiation therapy with 5-FU resulted in better anti-tumour effects than external beam radiation therapy alone in patients with cancers of stomach, pancreas, large bowel, rectum, head and neck and oesophagus (mostly with cisplatin added as well). Moreover, chemoradiotherapy with 5-FU is also successfully used in anal and bladder cancers (see [2] for review). External beam radiation therapy with capecitabine was as effective as external beam radiation therapy with intravenous 5-FU in patients with locally advanced rectal carcinoma, but treatment with capecitabine is more convenient for patients, as it is an oral drug [3, 4]. Most common specific side effects of capecitabine are hand-foot syndrome and stomatitis. These side effects occur frequently when capecitabine is used in a dose of 2,500 mg/m² per day in chemotherapy regimens, either as single agent or in combination with other chemotherapeutic agents. When using capecitabine as radio-sensitiser, lower doses (1,600–2,000 mg/m² per day) are administered, and hand-foot syndrome and stomatitis are less frequent. Another known, but rather infrequent, side effect of capecitabine and related drugs is cardiac ischaemia. This can result in myocardial infarction, also in patients without a previous history of cardiac disease [5].

Most data on the combination of radiation therapy and 5-FU or capecitabine were derived from studies using external beam radiation therapy. Few data have been published about 5-FU or capecitabine in combination with radionuclide-derived radiation therapy with radiolabelled peptides or antibodies. Wong et al. [6] reported that treatment with ⁹⁰Y-labelled antibodies and 5-FU was safe in patients with metastasised colorectal cancer. PRRT with [¹¹¹In-DTPA⁰]octreotide in combination with 5-FU resulted in symptomatic improvement in 71% of patients with neuroendocrine tumours [7]. This is much more than 13 out of 38 patients (34%) with symptomatic improvement published by Valkema et al. [8] who had not used 5-FU during PRRT with [¹¹¹In-DTPA⁰]octreotide. We were therefore interested in combining ¹⁷⁷Lu-octreotate with capecitabine in treating patients with GEP NETs, as this might result in better treatment outcomes. A possible drawback could be an increase in side effects. We therefore started a pilot study to investigate this combination.

Twenty-six treatment cycles were given: Six patients received four cycles; in one patient, treatment was stopped after two cycles because of clinically progressive disease. Side effects within 24 h after administration were: nausea with vomiting, reported by one patient after one cycle. Two patients had an increase in diarrhoea (3 of 26 cycles). Increase in pain was not reported by any of the patients. Patients also reported subacute side effects in the weeks after the treatment: Five patients had nausea at home (7 of 26 cycles), two patients vomited (5 of 26 cycles). Two patients noticed an increase in pain in tumour-involved areas (2 of 26 cycles). Six patients experienced some fatigue after a treatment cycle (7 of 26 cycles). Mild alopecia was observed in four patients.

The patients were also asked to report any side effects that are more specific for capecitabine: None of the patients had signs or symptoms of hand-foot syndrome. One patient mentioned that after the second treatment, the oral mucosa was a bit more sensitive than usual, but no mucosal abnormalities were seen (grade 1 stomatitis). None of the other patients had complaints of stomatitis (Table 1). None of the patients had chest pains. One patient with a serotonin producing metastasised midgut carcinoid developed mild oedema of the lower extremities. This was due to severely progressive tricuspid valve insufficiency proven by a cardiac ultrasound. Another patient developed oedema of the legs caused by compression of the inferior vena cava. None of the other patients had symptoms of heart failure.

Haematological toxicity is summarised in Table 2. Grade 3 or 4 leukopenia or neutropenia did not occur. One patient had grade 3 anaemia (Hb 4.9 mmol/l) after the second cycle, which resolved to grade 2 spontaneously 1 week later. In this patient, treatment was stopped after two cycles because of clear clinical progression of disease. Grade 4 anaemia did not occur. One patient had grade 2 thrombocytopenia (72×10⁹/l) after the fourth treatment. In one patient, platelet count dropped to 36×10⁹/l (grade 3 toxicity) after the third cycle. After recovery of platelet count to 93×10⁹/l, therapy was resumed with half a dose of ¹⁷⁷Lu-octreotate (3.7 GBq) and the normal dose of capecitabine. Subsequently, platelet count again dropped to 37×10⁹/l. Treatment with ¹⁷⁷Lu-octreotate was then stopped (cumulative dose 25.6 GBq) because the patient was deteriorating clinically and progression of disease was documented on CT scan. Grade 4 thrombocytopenia did not occur.

The course of haematological parameters and serum creatinine levels are shown in Fig. 2. Platelet counts at 4 weeks after treatment were consistently lower than baseline counts or counts at 6 weeks after the same treatment. No changes were noted in serum creatinine levels (no grade 2 or higher toxicity). No changes in liver function tests occurred that could be attributed to the treatment. Liver function tests deteriorated in the patient with progressive disease despite two treatment cycles.

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.