Abstract:

The oncological diseases are still a challenge to clinicians and inspire the search for new diagnostic and therapeutic procedures. Lately radioisotope therapy with 90Y-labelled compounds has been introduced in the treatment of neuroendocrine tumours and non-Hodgkin’s lymphomas. 90Y is the emitter of beta radiation of the energy high enough to directly influence the tumour biology. Its properties enable the treatment without necessity of the patient’s hospitalisation. For the successful therapy an appropriate ligand should be chosen to carry the isotope to the place of its action. Ligands influence both the course and the side effects of the treatment. Yttrium connected by chelating agent Tiuxetan to the monoclonal antibody against antigen CD20+ expressed on the surface of type B lymphocytes is used in the non-Hodgkin lymphomas therapy. It enables the direct action of the radiation not only on the tumour, but on the adjacent neoplasmatic cells not expressing the antigens on their surface as well (so called cross-fire effect). In the treatment of neuroendocrine tumours the somatostatin analogue labelled with radioactive isotope is utilised. Ligand - chelator - [DOTA, Tyr3] complex is characterised by the greatest affinity to somatostatin receptor type 2, which is expressed in most of the NETs. The radioisotope therapy of NETs is used in the patients with disseminated disease or ; with inoperable primary tumour with positive results of the pre-therapeutic scintigraphy with labelled somatostatin analogues. Radioimmunotherapy is an alternative method of treatment of lymphomas resistant to the standard treatment. The aim of the study was to assess the effectiveness of the therapy with 90Y combined with the different types of ligands in two groups of patients: with neuroendocrine tumours and with non-Hodgkin lymphomas, as well as the side effects of the treatment depending on the exposure of the critical organs. 32 patients (19 females and 13 males - 59,37% and 40,63% of the study subgroup respectively) aged 37-75 years (mean age 58,03±10,75 years) with histopathologically confirmed NET treated in Endocrinology Department of the University Hospital in Krakow between 2001 and 2007 were included in the study. 90,6% of patients were diagnosed with disseminated disease. In 3 patients the tumour was inoperable. Radioimmunotherapy was instituted in 30 patients (16 females and 14 males - 53,33% and 46,67% of the study subgroup respectively) aged 41-82 years (mean age 58,73 ± 11,26 years) diagnosed with non-Hodgkin lymphoma CD20+ of III and IV stage according to Ann Arbor classification. All patients were followed-up by the Haematology Department of the University Hospital in Krakow. The isotope therapy (1) was the first line of the treatment, (2) was initiated af ; ter achieving partial remission after the first or second line of the treatment or (3) was commenced in recurrent disease after non-successful immunotherapy or chemotherapy. Before implementation of the treatment in the patients of the NET subgroup, receptor scintigraphy was performed to confirm the somatostatin receptors expression in the tumour, as well as the computed tomography (CT) of the involved area. Both procedures were essential to the treatment implementation. In every patient the serum level of AlAT, creatinine and chromogranin A together with completed blood count was estimated. Glomerular filtration rate (GFR) was also estimated. In every patient in the non-Hodgkin lymphoma (NHL) subgroup CT of the abdomen and chest, complete blood count and bone marrow trepanobiopsy were performed to qualify the patient to the therapy. The serum AlAT and creatinine were also assessed. The dose of the 90-DOTA-TATE in NET patients was calculated according to the body surface area (BSA). The maximum dose did not exceed 7,4 GBq/m2 (200 mCi/m2) of BSA. In all patients the implementation of the therapeutic dose divided into 4 - 5 cycles were planed. 22 patients received planed treatment, 2 patients received the therapy divided into 3 cycles, the other 1 patient received 7 cycles. The most often instituted dose was 100 mCi per treatment cycle. The cycles were repeated every 4 to 9 wee ; k, most commonly every 6-7 week. Two hours before the injection of the labelled somatostatin analogue, the infusion of amino-acids formula was given to every patient for nephroprotection. The infusion time of the pre-prepared somatostatin analogue preparation labelled with radioisotope (manufacturer: Research and Development IAE Radioisotope Centre Otwock-Świerk) was 30 minutes. It was followed by 6-hour infusion of the amino-acids. The NHL patients received the dose of 90Y-Ibritumomab-tiuxetan (Zevalin) calculated based on the platelet count and body mass. If the platelet count (PLT) exceeded 150 000 per µl, the patient was administered 15 MBq (0,4 mCi) per kg of the body mass. If the PLT was within the range 100 000 – 150 000 per µl, the dose of 11 MBq (0,3 mCi) per kg of the body mass was given. The maximum dose was 1200 MBq (32 mCi). The radioimmunotherapy was preceded by Rituximab injection (250 mg per m2 of the BSA) administered one week earlier. Rituximab injection (the dose of 250 mg per m2 of the BSA) was repeated again 4 hours before the treatment with Zevalin. The preparation was labelled with Yttrium isotope in Nuclear Medicine Unit of the Endocrinology Department of University Hospital in Krakow. The radiochemical purity of the pharmaceutical was assessed after the labelling procedure, Zevalin was injected only when its purity was higher than 95%. Every patient w ; ith mantle cell lymphoma was given every 21 days 3 to 6 cycles of FCM+/-Rituximab chemotherapy. After first 3 cycles of the therapy the patient was qualified for radioimmunotherapy (RIT). If the patient did not fulfill the criteria for RIT, next 3 cycles of the therapy were given. Additional bridging dose of Rituximab was administered if the rise of neutrophil count or PLT count was not observed. The 90Y-Ibritumomab tiuxetan was not implemented in patients not meeting the criteria of the qualification. Statistical analysis was performed using STATISTICA PL (version 6.0) package. After the treatment in subgroup of NET patients no statistically important changes in creatinine level and GFR were observed. After 5 months an increase in creatinine level was noticed (from 73,37 µmol/l to 86,63 µmol/l). A slightly higher rise in creatinine levels was observed in a small subset of patients with longer, 24-month follow-up period. Mean creatinine level was 101,66 µmol/l. None of the patient showed the signs and symptoms related to the deterioration of the kidney function. However, literature data on the delayed nephrotoxicity suggest that the prolonged observation after the treatment with labelled somatostatin analogues is needed. Only minor changes in complete blood count (CBC) were seen after completion of the therapy. Mean haemoglobin level decreased after subsequent therapy cycles. ; The lowest mean values of haemoglobin (11,65 g/dL) were found during the 4 month after initiation of the treatment (mean pre-therapy level was 12,4 g/dL). Increase in haemoglobin level was observed 1 month after nadir values were reached. Normal haemoglobin levels or mild anaemia were present in most of the patients. 2 persons developed severe anaemia (3rd grade of toxicity) after 1 month after initiation of the treatment and after 3 cycle respectively. Similarly, after subsequent cycles of the therapy decrease in the PLT count was seen, but the mean values were within normal range. Only in 1 patient single measurement of PLT was assessed as the 3 grade toxicity according to WHO.The lowest values of white blood cell count (WBC) were seen after 3 and 4 cycle of the treatment. In the subgroup of NET patients WBC decreased by at least one toxicity grade according to WHO in 20 patients. No 4 grade toxicity was observed. Three patients developed 3 grade toxicity. In 1 patient with WBC-1360/µl Neupogen was implemented during the 3 month after implementation of the therapy. The influence of the chemotherapy on the CBC and creatinine level in NET patients was analysed. The preceding chemotherapy resulted in lower basal and post-therapeutic WBC and PLT count as well as higher creatinine levels compared to the chemotherapy-naïve patients. Some of the differences were statistically sign ; ificant. Concomitant diseases such as diabetes mellitus or diabetes mellitus did not influence the kidney function after the radioisotope treatment. The chromogranin A was assessed in 22 NET patients before and after the treatment with labelled somatostatin analogue. However no statistically significant difference in chromogranin A was found in all 22 patients, in 16 th of them mean values of chromogranin A was lower. The treatment with labelled somatostatin analogue did not result in the worsening of the liver function. In 13 patients increase in AlAT levels was observed during single measurements performed in different time after the treatment. In NHL subgroup the changes in CBC after the RIT were more pronounced than in NET subgroup, particularly in neutrophils, WBC count and PLT count. Mean PLT count was less than 100000/mm3 in 4 week after the therapy, reached its nadir in the 6 week (mean values of PLT - 48000/mm3), and gradually increased after that time. However mean values of PLT count were significantly lower than the basal values, although they approached the lower normal limits.Fourth grade toxicity was observed in 15 patients (50% of the subgroup) and lasted in most patients for 2-3 weeks and in 1 patient for 8 weeks. Third grade toxicity developed in 5 patients (16,6%) and in 2 of them lasted for 5 weeks and in 1 patient 11 weeks. The platelets concentrate transf ; usion was necessary after therapy the in 12 patients (40%) due to haemorrhagic diathesis signs and symptoms. Normal values of PLT count after the treatment were seen in 3 patients. Leucopaenia was developing during the first week after RIT. The nadir values of 1680/mm3 were observed in 8 week after the therapy and increased to 3890/mm3 during subsequent weeks. Fourth grade toxicity was noticed in 8 persons (26,6%) and lasted up to 3 weeks. 11 patients (36,6%) developed 3 grade toxicity, which persisted in 3 patient for 5 weeks and in 1 person for 10 weeks.Nadir values of neutrophil count (ANC) were observed during 6 week after the therapy, mean values of ANC at that time reached 1010/mm3. After 4 weeks mean ANC values increased to 1810/mm3. Fourth grade toxicity according to WHO was noticed in 12 patients (40%), 3 grade toxicity in 4 persons (13,3%). The median duration time of the 4 grade toxicity was 2-3 weeks. In 6 patients (20%) Neupogen was administered due to leucopaenia and granulocytopaenia, 8 persons were treated with antibiotics due to the upper respiratory tract infection. Three patients were admitted to the hospital because of the severe infections (pneumonia, neutropaenia accompanied by fever), which however were not life-threatening. Decrease in mean haemoglobin levels was noticed from the 1 weeks after the therapy reaching nadir values in 8 week after initiatio ; n of the treatment and rising in subsequent months. The mean haemoglobin values returned to normal, low limit 6 month after beginning of the therapy. Third grade toxicity in respect to haemoglobin was observed in 7 patients (23,3%), 4 grade toxicity in 1 person. Red blood cell concentrate transfusion was necessary in 10 patients (33,3%). Low haemoglobin levels lasted for 2 weeks in all but 1 patient, in whom it persisted for 3 weeks.RIT did not influence creatinine and AlAT levels. In most of the patients with NET stabilization or partial remission was observed. Due to the isotope labelled somatostatin analoque treatment expected life prolongation and shrinkage of the non-operative tumour was possible in patients with disseminated disease. This treatment caused complete relief or tone down clinical symptoms accompanying disease in all patients with stabilization of partial remission of the neoplasmatic process, improving quality of life. In patients who received full planned treatment partial remission was observed in 44%, stabilization of the disease in 30% and progression of the disease in 26 % of patients. The mean time to progression was 17,7 month. 7 patients died before the completion of the planned treatment. After the completion of the planned treatment only 2 patients in whom the progression of the disease was found died. In the whole group, regardless full, or not c ; omplete planned treatment received, progression of the disease was observed in 43%, partial remission in 34% and stabilization in 23% of the patients. In NHL subgroup CR was obtained in 52%, PR in 14% and PD in 34% of patients. In 10 subjects progression of disease was observed. Mean time to progression was 11,5 months, in patients with partial remission - 10,5 months, in patients with complete remission 16,4 months. Longer time to progression could be observed in subjects with complete remission. The treatment with 90Y-DOTA TATE in patients with NETs did not result in significant nephrotoxicity and the decrease in CBC parameters was transient. In comparison to other methods of the treatment relatively high percentage of partial remission was obtained after completion of therapy. In NHL patients 3 and 4 grade of toxicity regarding CBC was also transient and the parameters normalised gradually in subsequent weeks after therapy. RIT proved to be safe method of therapy enabling complete remission achievement in most of the treated patients. According to presented results it seems that 90Y-Ibritumomab tiuxetan therapy should be implemented in early stage of disease as the first line of the treatment to achieve high percentage of complete remissions and longer time to progression.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

onkologia ; radiologia ; endokrynologia

Degree grantor:

Wydział Lekarski

Promoter:

Hubalewska-Dydejczyk, Alicja

Date issued:

2008

Identifier:

oai:dl.cm-uj.krakow.pl:1030

Call number:

ZB-107988

Language:

pol

Access rights:

nieograniczony