Prospective observational study of ¹⁷⁷Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Peptide receptor radionuclide therapy (PRRT) has been used successfully in patients with neuroendocrine tumours (NETs) for two decades [1‐5]. ¹⁷⁷Lu-DOTA-octreotate [5‐9], different ⁹⁰Y–labelled peptides [10‐14] and combinations of both have been used. ¹⁷⁷Lu-DOTA-octreotate has usually been administered according to a standard protocol with four cycles of 7.4 GBq [5, 8, 9]. When PRRT became available in Sweden, the legal demand for individualized planning of radiotherapy necessitated the development of dosimetry procedures suitable for use under clinical conditions [15‐20]. The organs at risk are the kidneys and bone marrow, with a growing body of data demonstrating higher nephrotoxicity with ⁹⁰Y–labelled peptides using several schedules [11, 14, 21] than with ¹⁷⁷Lu-DOTA-octreotate [5, 22‐24]. The physical properties of lutetium-177 are well suited to following the distribution of the radionuclide for dosimetry during therapy. For ¹⁷⁷Lu-DOTA-octreotate, a cumulative absorbed dose of 23 Gy to the kidneys was taken from external beam radiation [25], a cautious cut-off value in the setting of PRRT [26, 27]. A 2-Gy cut-off value for the bone marrow was based on experience with radioiodine therapy [28]. From dosimetry data compiled in our department we concluded that about 50% of patients might be undertreated and able to receive more than 4 × 7.4 GBq of ¹⁷⁷Lu-DOTA-octreotate before reaching either 23 Gy to the kidneys or 2 Gy to the bone marrow [17].

The present study was designed to investigate the efficacy of treatment with ¹⁷⁷Lu-DOTA-octreotate guided by dosimetry in patients with advanced NETs who either have progressive disease or are not suitable for standard care protocols. The primary aims were to evaluate the feasibility of individualized dosimetry in a routine setting, the applicability of dosimetry as a stop criterion for therapy aiming at an absorbed dose of 23 Gy to the kidneys and a maximum of 2 Gy to the bone marrow, and the side effects of PRRT performed under these conditions. Secondary endpoints were objective response according to RECIST 1.1 [29], progression-free survival (PFS) and overall survival (OS).

A total of 200 patients with NETs with somatostatin receptor expression higher than in normal liver (Krenning score 3 or 4 [30]) based on somatostatin receptor scintigraphy were enrolled after providing written informed consent (EudraCT no. 2009-012260-14). The local ethics and radiation ethics committees approved the study and the study was performed in accordance with the principles of the Declaration of Helsinki. Inclusion criteria were: metastatic NETs progressive on standard of care therapy, and proven intolerance or contraindications to other therapies. Patients with rectal NETs or bronchopulmonary carcinoids were accepted for first-line treatment, since no standard therapy has been established for metastatic disease. Life expectancy had to be more than 3 months, white blood cell count (WBC) >3.0 × 10⁹/L, platelet count >100 × 10⁹/L, bilirubin <40 μmol/L, albumin >25 g/L, creatinine <110 μmol/L or, if higher, glomerular filtration rate (cystatin-C) >50 ml/min/1.73 m². Exclusion criteria were pregnancy, tumour amenable to surgery or radiofrequency ablation, and inability to stay isolated for 24 h. Of the 200 patients, 55% had small intestinal NETs (SI-NETs); for other tumour types see Table 1. After amendments to the initial study protocol, 16 patients (8%) diagnosed with grade 3 disease (Ki-67 index >20%) were accepted, and included those with a Ki-67 index up to 40%. All patients were receiving somatostatin analogues (SSA), and 43 (21.5%) had received higher than standard doses. SSA treatment was continued in all patients during PRRT. Patient characteristics are shown in Tables 1 and 2. The largest group of patients (84, 42%) were Swedish citizens; the remainder were referred from institutions in several other countries.

Patients were treated with 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate per cycle with an intended interval of 6 to 8 weeks. The peptide was a kind gift from Prof. Eric Krenning. Lutetium-177 was purchased from IDB, Holland BV, and labelling was performed in-house. Kidney protection was provided by infusion of 2 L of an amino acid mixture (Vamin, 14 g N/L, electrolyte-free; Kabi Fresenius) over 8 h, starting half an hour before infusion of the radiopeptide. One hour before therapy, 8 mg of betamethasone and 8 mg of ondansetron or 250 μg palonosetron were given intravenously as antiemetic. Before every treatment cycle, WBC had to be >3 × 10⁹/L, granulocytes >1.5 × 10⁹/L and platelets >100 × 10⁹/L. Therapy was terminated if these criteria were not met within 6 months. As an exception, in some patients the activity was decreased by 30% instead of delaying treatment.

Cycles of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy (Table 3). A cumulative absorbed dose of 2 Gy to the bone marrow was intended to act as a stop criterion, but was not reached in any of the patients during the initial treatment. In 14 patients (7%) with a favourable tumour response, salvage therapy aiming at a cumulative absorbed dose to the kidneys of 45 Gy was offered upon progression, given normal bone marrow and kidney function.

Dosimetry for solid organs and bone marrow was performed as previously described in detail [15‐17]. For solid organs, dosimetry was based on the small volume method performed on single photon emission tomography with low-dose CT (SPECT/CT) at 1, 4 and 7 days after therapy. Volumes of 4 cm³ were drawn on representative regions with homogeneous uptake. The activity concentrations were fitted to a monoexponential function. To calculate absorbed doses to the kidneys, the time-integrated activity concentrations were multiplied by the appropriate dose concentration factor considering only self-dose:where D_O is the absorbed dose to the organ, and DCF is the dose concentration factor converting C_cumO to absorbed dose by self absorption. Similarly, doses to the liver, spleen and representative tumours were calculated (data not shown). For complete bone marrow dosimetry, the dose from the blood activity (self-dose) was calculated from integrated blood activity curves derived from blood samples obtained at 0.5, 1, 2.5, 4, 8 and 24 h. This self-dose derived from the blood was complemented with the photon dose from resident activity in tumours, organs and the remainder of the body in order to calculate the total bone marrow dose. The photon dose was based on consecutive whole-body scans (WBS) at 1, 4 and 7 days after therapy. Regions of interests delineating the kidneys, liver, spleen, tumours and the whole body were drawn on geometrical mean images at 24 h and transferred to the images at 4 and 7 days. For calculation of the absorbed dose to bone marrow, the contribution of other source organs was added to the self-dose derived from the blood measurements as follows:where D_BM is the absorbed dose to the bone marrow, C_cumBM is the time-integrated activity concentration in the bone marrow, DCF is the factor converting C_cumBM to absorbed dose by self-absorption, A_cumT is the time-integrated activity in tissue T (solid organs, tumour and the remainder of the body), and DF_BM ← T is the factor converting A_cumT to absorbed dose in the bone marrow (cross-fire).

Complete dosimetry was always performed during the first treatment, whenever large changes in tumour volume had occurred, after delay, and at least every fourth cycle. A short dosimetry protocol was performed for all other cycles after 24 h including a SPECT/CT scan over the abdomen and one WBS. The absorbed dose to the kidney was then calculated assuming an unchanged effective half-life, the amplitude for the area under the curve was adjusted for the actual measured activity concentration derived from the SPECT/CT scan at 24 h [16]. The self-dose from blood and the total bone marrow dose were calculated for each treatment with complete dosimetry and extrapolated for the remaining cycles by assuming the higher figure of two measurements for the adjacent unknown values. Radiological response was assessed using RECIST 1.1 criteria [29]. Whenever available, the biochemical response of biomarkers was monitored.

The dosimetry protocol applied was feasible. All patients underwent initial dosimetry. Most patients were able to leave hospital after 1 day, with patients who had to travel long distances staying in a hotel during weekdays when complete dosimetry was performed.

To our knowledge, this is the first prospective study to explore the outcome of PRRT with ¹⁷⁷Lu-DOTA-octreotate in patients with NET applying systematic, individualized dosimetry of the kidneys and bone marrow. The study provides evidence supporting our assumption that about half of the patients can tolerate more than four cycles of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate [17]. The question to be answered is whether outcome is improved in the substantial proportion of patients who would receive a higher activity than given using the widely accepted Rotterdam protocol of four cycles of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate. In Table 6, the number of cycles per patient during the initial treatment is given, along with information as to whether 23 Gy to the kidneys was reached and the number of surviving patients at the time of analysis.

Data so far published are not easily compared since the studies were inhomogeneous regarding tumour type, risk factors and previous therapy as well as endpoints. In the present study, several risk factors were more prevalent than in the majority of other larger studies (Table 7). In 8% of patients the Ki-67 index was >20% and in 29% >10%, a level found to affect survival [7]. PFS was significantly lower in patients with a Ki-67 index >20% (Fig. 2), but a median PFS of 14 months (95% CI 10–21 months) and a median OS of 31 months (95% CI 19–39 months) in our 16 patients still compares well with previous published data on patients with high-grade NETs [31, 32]. This confirms that patients with a high-grade tumour and sufficient somatostatin receptor expression may benefit from PRRT, as described in previous case reports [33‐35]. In these patients, higher accumulated activities and an individualized protocol may be of special importance, and fractionation may partially explain improved tumour-to-background ratios as previously discussed [35]. The response rates in patients with a Ki-67 index >20% were higher than in those reported by Ezziddin et al., who aimed at four cycles of 7.9 GBq ¹⁷⁷Lu-DOTATATE with an intended interval of 10 to 14 weeks [34]. Among their seven patients with a Ki-67 index >20%, only one had PR and SD (14%), respectively, while five patients (71%) progressed. In our study, 43.8% of patients received more than four (five to seven) cycles of 7.4 GBq with an intended interval of 6 to 8 weeks. PR was seen in 5 of 16 patients (31%) and SD in 69%, and no progression at first follow-up examination.

Few observations of a dose-response relationship in PRRT have been reported [36, 37]. To prescribe tumour doses in PRRT, as in external beam radiation, is not possible, but the present results indicate that the absorbed dose to the kidneys can serve as a substitute for tumour dose and the tolerance of the individual patient. Bodei et al. found a positive correlation between objective response and cumulative activity, that was in turn related to higher absorbed tumour doses [6].

The relationships among absorbed dose, objective tumour shrinkage and survival are not easy to determine in patients with NETs undergoing PRRT, since the time from the start of therapy to best response varies and can be several years [5], in our study up to 54 months. Based on best response, patients with CR or PR had a significantly longer OS than those with SD (Fig. 2). Kwekkeboom et al. found no significant difference in survival between patients with CR or PR and those with SD based on their radiological response 3 months after therapy [5], which may be attributable to the earlier time point for evaluation. In a recent update, the Rotterdam group have also reported longer survival in patients with CR or PR as best response than in those with SD [9]. On the other hand, we found no difference between these groups in terms of PFS. One explanation for this may be that at the time of progression, patients become amenable to further treatment after previous substantial tumour regression. An example of this is presented in Fig. 5 that shows the WBS findings in a patient with massive liver metastases of a VIPoma. After the first cycle of ¹⁷⁷Lu-DOTA-octreotate, she developed a hormonal crisis with life-threatening diarrhoea requiring intensive care. After three cycles, vasoactive intestinal peptide levels normalized and the diarrhoea stopped completely. The best morphological result was a PR with a decrease by 45% according to RECIST 1.1 after cycle 5. By 40 months after the start of therapy, the tumour had progressed and salvage therapy was given with another two cycles. At this time-point, the tumour burden was still lower than at the start of therapy, and the patient’s general condition had improved. In the current series, 14 patients were able to receive salvage therapy, of whom 9 (64.2%) were alive at the time of analysis.

There is a relationship between objective responses and decrease of tumour markers, which is in turn related to OS, and according to Khan et al. [38] is also associated with improvement in quality of life. In this study, decreases in tumour markers by more than 50% from increased baseline levels in 65% of 85 patients were associated with longer survival with a median OS of 60 months (95% CI 42 months, NR) versus 35 months (95% CI 17–52 months; p = 0.01). Furthermore, more patients in whom the absorbed dose to the kidneys reached 23 Gy showed a decrease in tumour markers.

In agreement with other studies, in the present study the objective response rate was lower in patients with SI-NETs than in those with other NETs [4, 14], but the survival rate was not lower (Tables 4 and 5, Fig. 1). In the present study, 24% of patients obtained an objective response (RECIST 1.1 CR/PR), with better results in those with pancreaticoduodenal NETs (42.9%) and rectal NETs (45.4%) than in those with SI-NETs (12%). In the NETTER-1 study, four cycles of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate was compared with an increased dose of SSA in a group of patients with grade 1 and grade 2 SI-NETs, and a higher objective response rate with PRRT (18.8% versus 3%) was found with an estimated PFS rate of 65.2% (95% CI 50–76.8%) at 20 months [8]. This is comparable to 68% (95% CI 59–75%) found in the present study (parametric Weibull fit, supported by Kaplan-Meier analysis), despite the fact that 31.5% of the patients had increased doses of SSA on enrolment and risk factors such as liver and bone metastases being more frequent in our study (liver metastases 84% versus 97%, bone metastases 11% versus 49%). Table 8 compares patient groups with similar inclusion characteristics from the NETTER-1 study [8], the recent update from the Rotterdam group (table adapted from Brabander et al. [9]) and the present study.

We conclude that an absorbed dose of 23 Gy is generally well tolerated by all patients in whom this limit can be reached, regardless of the number of cycles. The only case of grade 4 nephrotoxicity observed was found to be related to hypertensive nephrosclerosis before this dose had been reached, at cumulative doses of 15.2 and 16 Gy to the right and left kidney, respectively. Therapy was stopped because of an increase of about 50% between cycle 1 and cycle 2, so that further damage was avoided. We interpreted this toxicity as primarily caused by the patient’s hypertension, but probably worsened by the treatment. A grade 2 kidney toxicity was seen in eight patients (4%) at the time of progression as part of general deterioration, and was probably unrelated to the treatment. and seven of these patients had cardiovascular risk factors and/or diabetes mellitus. On the other hand, risk factors for kidney toxicity (cardiovascular disease including arterial hypertension and diabetes mellitus) were present in 79 patients (39.5%), and in 43 of these patients (54%) the absorbed dose to the kidneys reached 23 Gy, with 37 of these 43 patients receiving more than four cycles (five to seven) without toxicity. This demonstrates that even in the presence of risk factors, the limit of 23 Gy to the kidneys is generally safe, and patients with risk factors need not automatically be excluded from the attempt to reach this goal with higher activities if they show clinical benefit. Kidney dosimetry can help reveal abnormal dose changes and levels and minimize damage. Figure 6 illustrates the range of absorbed doses to the kidneys that were observed per cycle and patient and the changes over time.

Even higher cumulative absorbed doses to the kidneys (with maximum absorbed doses to the right and left kidney of 46.6 and 43.3 Gy, respectively) were reached in 14 patients (7%) who underwent retreatment without nephrotoxicity worse than grade 1. This implies that higher absorbed doses from ¹⁷⁷Lu-DOTA-octreotate may be possible in patients without risk factors. The tolerability of higher biological effective doses (BED) to the kidneys is currently being studied [39]. The relationship between absorbed doses (as reported in the current study) and BED is discussed by Cremonesi et al. [40] and in a recent report from our group [41].

The Rotterdam protocol of four cycles of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate has been widely accepted. In patients who received four cycles during initial treatment, those in whom the absorbed dose to the kidneys reached 23 Gy showed a significantly longer survival (median OS 60 months) than those in whom it did not (median OS 19 months, p < 0.0006; Fig. 4). The majority of patients in whom the dose to the kidneys did not reach 23 Gy had progression or bone marrow suppression. Still, the comparison implies that a cut-off defined by four cycles of 7.4 GBq will exclude patients who might benefit from further therapy. This view is supported by the finding that differences in survival between the patient groups could still be observed when patients who stopped treatment because of tumour progression or deterioration for other reasons were excluded. In the remaining patients therapy was stopped due to kidney dosimetry, slow bone marrow recovery without other complications, decrease in tumour burden and the patient’s wish to stop after four cycles (Table 3).

Although more than half of our patients had bone metastases, the morphological response rate was similar or superior to that in other studies (Table 7) and the subacute haematotoxicity was not higher in this group (Table 3). Unlike in other studies, the diagnosis of bone and bone marrow metastases was based on posttreatment scans during therapy, which has to be regarded as more sensitive than somatostatin receptor scintigraphy, and this may be one possible explanation for this high figure. Although in none of our patients was an absorbed dose of 2 Gy to the bone marrow reached, 22% had to stop therapy due to bone marrow-related events.

In agreement with others [22, 30, 40], we found a considerable interindividual variation in calculated bone marrow doses, and similar median values in patients with and without therapy-limiting bone marrow toxicity (Table 3). Although a correlation between absorbed dose and bone marrow toxicity has previously been shown by applying a dosimetry method based on planar imaging supported with SPECT/CT [42], our finding emphasizes that bone marrow dosimetry at the current state of our knowledge cannot be used to predict bone marrow toxicity in the individual patient. In line with the view of these authors, both their method and the method used in the current study will underestimate bone marrow doses in patients with bone marrow metastases. Also, the interindividual variation mentioned above will contribute to uncertainty in predicting toxicity.

The incidence of bone marrow malignancies in four patients (2%) is in line with reports from other centres [43]. Of previously documented risk factors, all had bone metastases and one had extensive liver metastases. Three patients (75%) had received the alkylating agent temozolomide, and one had also received streptozotocin. In this series, temozolomide is over-represented among patients with bone marrow malignancies despite the fact that streptozotocin (in combination with 5-fluorouracil) was the predominant alkylator used in 23.9% of all patients compared with 15.3% who had received temozolomide. This finding is an isolated observation and must be interpreted with caution. Still, as a comparatively new agent in the therapeutic arsenal of NETs, this toxicity should be observed more closely. As discussed by Bodei et al. [43], bone marrow malignancy is a fairly infrequent finding in larger PRRT series, even though one recent study showed a much higher incidence of bone marrow malignancies in a small group of heavily pretreated patients (20%, 4 of 20 patients) [44]. The present study, in line with several others, showed favourable tumour responses and survival data that compare well with alternative treatments. Especially in rectal NETs and bronchopulmonary carcinoids [23], the outcome is most encouraging.

In our opinion, this study provides important findings in favour of an individualized, dose-driven PRRT protocol. A prospective randomized study comparing the treatment protocol involving four cycles of 7.4 GBq of ¹⁷⁷Lu-DOTA-octreotate with a protocol based on kidney dose might answer the question as to whether the observed superior outcome in patients in whom the absorbed dose to the kidneys reached 23 Gy was a result of optimization of the tumour dose or depended on individual patient and tumour characteristics.