Accurate bone marrow dosimetry is mandatory for safe PRRT. All methods available have certain disadvantages: aspiration of bone marrow is costly and time consuming, and it is an invasive procedure associated with a high level of discomfort for the patients. Calculating the dose to the red marrow from the accumulated activity concentration in the blood deals with the assumption that no specific binding of the radiolabelled somatostatin analogue occurs in the bone marrow. Also, it neglects the contribution of other radiation sources in the body, such as organs and tumours, thereby underestimating the true radiation absorbed dose to the bone marrow. Alternatively, the determination of the radioactivity in the remainder of the body (needed for the MIRD scheme) depends on accuracy in urine collection, which is subject to errors. Apart from these considerations, it should be realized that at present none of the diverse models to estimate the dose to the bone marrow has been actually confirmed with toxicity data, be it the incidence of thrombocytopenia or the occurrence of MDS. Apart from the risk of patients developing MDS, the essential issue of bone marrow dosimetry is to predict, or better to avoid, severe haematological toxicity caused by PRRT.
The dose to the red marrow, however, is only one of several factors influencing the haematological toxicity after PRRT. A high interpatient variability in the haematological response after PRRT has been found and also previous therapies can highly influence the results [2
]. Using different radiopharmaceuticals, some investigators have found a correlation between haematological toxicity and injected dose of radioactivity [32
], whereas others have not found such a correlation [34
]. It is possible that additional factors such as age and sex of the patients might influence the haematological toxicity as well, although in a trial with radiolabelled antibodies there was only a minor influence of these factors [35
]. As early as the year 2000, Blumenthal et al reported that plasma levels of FLT3-L help to predict haematological toxicity after radioimmunotherapy [36
]. In 2003 this was confirmed by Siegel et al. for radioimmunotherapy with iodinated anti-CEA antibodies [37
]. However, no studies taking this into account have been published for PRRT. Nevertheless, the importance of introducing biological parameters into treatment planning is indisputable [38
We found a high correlation between the radioactivity concentration in the blood and in the bone marrow aspirate during PRRT with [177Lu-DOTA0,Tyr3]octreotate. The most probable explanation for the high congruence between the radioactivity measured in the blood and in the bone marrow aspirate is that the amount of stem cells in a bone marrow aspirate is low and that most of the aspirate consists of blood. On the other hand, the high volume of blood in the bone marrow aspirate reflects the fact that the blood contributes most of the self-dose to the bone marrow. Taking into consideration that the path lengths of the common therapeutic radionuclides are in the millimetre range and the structure of the bone marrow it is evident that the radiation from the blood will reach all bone marrow structures.
Promising results for predicting the haematological response were obtained by using an ROI surrounding a section of the thoracic spine for determining the absorbed dose to the red marrow. In these studies the absorbed dose was calculated with the positron emitter 86
Y before treatment with 90
Y can be regarded as the ideal surrogate for 90
Y and offers a high resolution when using a PET scanner. However, imaging with 86
Y is currently only available in specialized centres because besides the need for a cyclotron to produce 86
Y, the reconstruction of the PET data requires sophisticated correction algorithms. There is certain evidence in literature that imaging with 86
Y might overestimate doses, particularly if the bone marrow is close to dense tissue such as the spine [40
]. Besides, dosimetry using 86
Y will be a gold standard only for treatments with 90
Y because in PRRT the radionuclide used influences the receptor affinity and consequently the biodistribution of the compound [42
]. Moreover, the relatively short physical half-life of 86
Y (14.7 h) does not allow the radioactivity to be followed over several days which is important for planning of the treatment with 90
Y. However, these results have not yet been confirmed by another group.
To date one group has found interesting results when calculating the absorbed radiation dose to the bone marrow from scans for radiolabelled antibodies using an integrated SPECT/CT camera [30
]. The results have also not been confirmed by other groups, and no results using this method with radiopeptides have been published so far. Remarkably no bone marrow dosimetry was feasible on SPECT scans in our setting because no or only very faintly visible uptake in the bone marrow was present on the scans (Fig. ).
Our results indicate the radioactivity in the blood is a very accurate surrogate for the radioactivity present in the bone marrow. However, we also showed that the radioactivity in the remainder of the body as well as the radioactivity in source organs and tumours significantly contributes to the absorbed radiation dose to the bone marrow. With that, our tacit hope that the cumbersome collection of 24-h urine and time-consuming calculations of cross-radiation from tumours and organs could be circumvented, and that bone marrow absorbed doses could be derived from blood radioactivity levels only, evaporated. Also, the bone marrow absorbed dose after treatment with [177
]octreotate showed considerable variation between patients. This is in contrast with the findings of a previous pilot study in six patients that showed the biodistribution of the radiopharmaceutical [43
]. These patients, however, all had a very limited tumour load. The present series of patients more truly represented the practice of PRRT in our institution, where the tumour load in patients is highly variable, and so the contribution of the cross-dose to the bone marrow is variable as well. This finding implies that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary. The results shown in Table indicate that the remainder of the body as well as organs and tumours significantly contribute to the absorbed dose to the bone marrow. Since the contribution to this dose from the remainder of the body, organs and tumours from the β-emission of 177
Lu is virtually negligible, it appears that the γ-radiation from tumours, organs and the remainder of the body contributes to the absorbed bone marrow dose.
We determined the degree of correlation between the absorbed dose to the red marrow and the decrease in platelet count after 6 weeks. We focused on platelets only since platelets show the most pronounced reaction after PRRT. The degree of correlation between the calculated absorbed doses to the red marrow and the decrease in platelet count was disappointing. A number of reasons may have accounted for this. The absorbed doses were compared with only one posttreatment platelet count. This platelet count, 6 weeks after treatment, may not have reflected the nadir in each patient. Another explanation could have been the relatively small number of patients studied. Moreover, probably the most important reason could have been that the response of an individual patient to PRRT is not only related to the radiation absorbed dose in the bone marrow but also to the pretreatment status of the bone marrow. Especially previous, potentially haemocytotoxic treatments can influence the response after the treatment.
No conclusions can be drawn concerning the relationship between the calculated radiation absorbed dose in the bone marrow and the risk of developing MDS. However, developing MDS is probably also related to the pretreatment status of the bone marrow and previous treatments.
Bone marrow dosimetry is a difficult topic. Beside all factors mentioned above that may influence the dosimetry of an individual patient, many other considerations have to be faced. The bone marrow is not a solid organ and simply the determination of the mass is virtually impossible. As for all internal radiotherapy treatments, the dose rate in PRRT is low. Most values that deal with the maximum tolerated dose of healthy organs are derived from external beam radiation with a much higher dose rate. The influence of such physical properties is not well understood and may highly influence the results of internal dosimetry as much as the biological response.
In conclusion, our results show that: (1) after PRRT with [177Lu-DOTA0,Tyr3]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) there is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) the contribution of the cross-dose from source organs and tumours to the bone marrow dose is significant; (4) there is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary.