After sequential PRRT and [166Ho]-radioembolization, additional short-term lymphopenia was observed in 55% of the treated patients with well-differentiated (grade 1–2) NET, 32% had grade 3–4 lymphopenia. After 12 months, additional lymphopenia was present in only two patients. Other hematologic parameters (i.e. thrombocytes, neutrophils, leukocytes and hemoglobin) were mainly limited to grade 1–2 toxicity. Additionally, trends indicated that after a radiation boost to the liver using [166Ho]-radioembolization, patients recovered from additional radioembolization-related toxicity, and partially from pre-existent PRRT-related hematologic toxicity within 1 year of follow-up. In the current study, no baseline factors could be identified that correlated with an increased risk of hematologic toxicity. Most notably, the NLR and TLR at 3-weeks follow-up after [166Ho]-radioembolization seem to be predictors of response at 3 months after treatment according to RECIST 1.1. Specifically, an increase of NLR or TLR compared to baseline improved the chance of objective response in our population. This observation was independent of pre-existing lymphopenia, indicating that lymphopenia is not a contra-indication for [166Ho]-radioembolization.
Multiple studies assessed the toxicity profiles after yttrium-90 [90Y]-radioembolization monotherapy in patients with hepatic NET metastases. In a study by Zuckerman et al., using glass microspheres (TheraSphere™, Boston Scientific), grade 3 lymphopenia occurred in 14/59 patients (23.7%), similar to the number of patients with grade 3 lymphopenia in the current study [13]. Thrombopenia was mainly limited to grade 1 or 2 toxicity, further confirming our findings. In another study, performed by Tomozawa et al., 52 patients with hepatic NET metastases were followed 1 year after [90Y]-radioembolization using resin microspheres (SIR-Spheres; Sirtex Medical Ltd), of whom 11 were followed 4 years. Within 1 year, hematologic toxicity occurred rather infrequently, with no grade 3 hematologic toxicity, and grade 1–2 anemia, grade 1–2 thrombopenia, and grade 1–2 leukopenia in only a limited number of patients. However, the WHO grade was not reported and only late (6–12-months) follow-up was presented, while in the current study hematologic toxicity occurred after 3 weeks. In a previously published study by Braat et al., 244 patients with well-differentiated (grade 1–3) NET treated with resin [90Y]-radioembolization were included in a retrospective international multicenter study [14]. Toxicity during follow-up was very comparable with this study, with grade 1–2 lymphopenia occurring in 52% of patients, grade 1–2 thrombopenia in 17%, and grade 1–2 anemia or leukopenia in less than 8%. Lymphopenia was the most frequent cause for grade 3–4 toxicity. However, hematologic toxicity was only analyzed up to 3 months after treatment. The current study showed similar toxicity profiles compared to previously published studies on [166Ho]-radioembolization [15, 16]. Lymphocyte levels showed the most significant toxicity. Overall, given the available toxicity profiles after radioembolization, there seems to be only limited added hematotoxicity from radioembolization when given sequentially after PRRT.
In earlier publications, the value of NLR and TLR was studied in different fields of medicine and for different types of tumors [6, 8]. It is well established, that baseline NLR can predict the OS, PFS and disease-free survival for many cancers, including colorectal cancer, breast cancer, hepatocellular carcinoma, gastric cancer, esophageal cancer and NET [17,18,19,20,21,22]. A high NLR is thought to be an indicator of systemic inflammatory response, and can be used as an index for severity of disease in cancer patients [23]. From the acknowledged hallmarks of cancer, inflammatory response can be seen as both a cause for as well as a result from tumor growth [24,25,26]. Thus, a high NLR is thought to reflect a more severe disease phenotype. In most studies, for a wide variety of treatments, both systemic (such as chemotherapy) and locoregional (such as radiotherapy), NLR is used as a baseline index for the systemic inflammatory status of patients, their capability to induce reduction in tumor growth, and therefore response to treatment and survival [6,7,8, 10]. In the current study, an increase in NLR or TLR shortly after treatment appeared to be indicative of response at 3 and 6 months, which contrasts earlier publications, even though the currently presented relation is between change in NLR and TLR and response, rather than baseline NLR and TLR. For example, Estrade et al. found that in HCC patients, lymphopenia 3 months after radioembolization, and therefore an increased NLR, was associated with poor survival (14.3 months vs 23.4 months) [27]. The difference might be due to the effect of radioembolization on short-term systemic availability of lymphocytes, granulocytes and thrombocytes. Therefore, the observed increase in NLR and TLR must be seen more as a treatment effect, than as a disease effect. It is also noteworthy that the short-term NLR and TLR trends (i.e. change within one month after radioembolization) have not been studied before. Furthermore, there may be certain unknown confounders that explain the observed relationship. The pre-[166Ho]-radioembolization NLR and lymphocyte counts seems to be in accordance with ranges found earlier in NET patients, so a bias in patient selection seems unlikely [22, 28].
Another marker recently studied in NET is the inflammation-based index (IBI), based on c-reactive protein and albumin levels [29]. It was demonstrated by Black et al. to show prognostic value in hepatocellular patients, and was proposed as a selection tool for PRRT in NET patients [30,31,32]. In the study, an increased IBI was found to be a significant prognosticator for decreased overall and progression-free survival, while NLR and TLR at baseline were not found to be significant prognosticators. This approach may be analogous to measuring NLR and TLR at baseline, as both markers represent the inflammatory status of the patient. However, the role of the inflammatory status of the patient in patient selection is not yet fully understood. As both PRRT and radioembolization may be beneficial even in patients with a high inflammatory status, it is unfeasible to withhold therapy from these patients. Therefore, this study proposes these inflammatory markers to be used during follow-up as well, as these parameters may be predictive of response.
For [90Y]-radioembolization, it was shown that an increase in baseline NLR or TLR was indicative of a worse prognosis in patients with primary or secondary liver malignancies [10]. In the study by D’emic et al., patients with hepatocellular carcinoma, colorectal cancer, breast cancer, bile duct cancer or NET, OS and PFS were significantly worse in patients with higher NLR and TLR at 20 days post-treatment in univariate analysis. In multivariate analysis, a post-treatment increase in TLR was most significantly associated with worse OS and PFS [10]. However, the study population was very heterogeneous, with a wide variety of tumor types included, among which only 8 (6.8%) patients with NET. Contrary to the study by D’emic, the current study focused on response in relation to the relative change in NLR and TLR after [Ho166]-radioembolization, in patients with NET. A temporary increase in NLR at 3 weeks post-treatment was associated with objective response at 3, 6, 9, and 12 months, which may seem contrary to previous findings. However, we could not find a relation with overall survival. It is important to note that our study is the first study to focus solely on the relation between NLR and TLR and response in neuroendocrine tumor patients. This is essentially different from studies focusing on the prognostic value of baseline NLR and TLR, as the change in NLR and TLR after treatment may reflect the effect of the treatment on the disease, rather than baseline NLR and TLR, which reflect the disease status of the patient prior to treatment. This is also essentially different from NLR and TLR several months post-treatment, which may potentially be obscured by disease progression and subsequently increased systemic inflammation. Although the prognostic value of NLR (and TLR) has been evaluated in multiple studies, it is rarely used in clinical practice.
There are some limitations in this study. First, the sample size for prognostic studies in general should preferably be larger. Unfortunately, multivariate prognostic models are difficult to build in small samples, as frequently encountered in NET studies. Second, there was some missing data, as not all patients completed follow-up. However, toxicity data up to and including the 3 weeks follow-up visit and response after three months was available in all patients. Third, our study consists of both grade 1 and grade 2 NET, which tend to have a very different course of disease over the years. Because of this heterogeneity, survival analysis is less accurate. Finally, all patients in the study were treated with a mean target liver volume absorbed dose of 60 Gy, which was calculated using the MIRD model which assumes the injected activity to be distributed evenly throughout the healthy liver tissue and tumor tissue. Toxicity in patients treated with [166Ho]-radioembolization can be further reduced by calculating the therapeutic activity using the so-called partition or multicompartment model [33].
Patients who are initially treated with PRRT can be safely referred for additional [166Ho]-radioembolization, as a boost in treatment of liver metastases [3]. In clinical practice, a significant treatment boost can safely be pursued in patients with bulky NET liver disease. Based on this study, measurement of NLR and TLR at baseline and during short-term follow-up visits may provide early information on response to treatment. In the future, prospective studies on the benefit of monitoring inflammatory markers on overall and progression-free survival should be conducted, because much is still unclear. Especially in patients with NET, predictive and prognostic markers may be difficult to find due to the heterogeneous nature of the tumor.
In conclusion, no clinically significant or permanent additional hematologic toxicity was observed after sequential treatment with PRRT and [166Ho]-radioembolization, while inflammatory markers such as NLR or TLR may provide early information on treatment response.