In the current study, we investigated possible predictive markers for peptide receptor radionuclide therapy (PRRT) outcome in patients with advanced neuroendocrine neoplasms (NENs). A favorable response (partial response vs stable disease) after two PRRT treatments was predictive of a higher rate of partial response after completion of PRRT treatment, as demonstrated by multivariate model controlled for patients’ age, grade and NEN type. In addition, a pancreatic NEN (PNEN) primary was associated with a higher rate of partial response compared with small intestine NEN (SiNEN) during and after PRRT treatment.
Previous studies have demonstrated the importance of functional imaging as a predictive factor for PRRT outcome. Baseline tumor avidity on 68Ga-DOTATATE PET/CT before PRRT treatment is predictive of response [22], and in addition, reduction in the standardized uptake value on 68Ga-DOTATATE PET/CT after 1st PRRT treatment is also associated with prolonged PFS [17]. However, to the best of our knowledge, this is the first study to evaluate and demonstrate that mid-treatment partial response is predictive of continued partial response at treatment’s end. One should note that no formal guidelines recommend imaging during PRRT as a decision tool for continued treatment. The NETTER-1 trial, the first clinical trial to demonstrated efficacy of PRRT for mid-gut NEN, included imaging every 12 weeks in order to assess response [10], and the European Neuroendocrine Society (ENETS) guidelines only suggest evaluation by clinical response or imaging (somatostatin analogue PET/CT or SPECT) during PRRT [13]. While further research with a larger sample size and follow-up time is required to validate our results, adding imaging assessment during PRRT should be considered, as it might aid the clinical decision of whether to continue PRRT in the case of a patient with a borderline hematologic parameter during treatment.
An additional finding in this study is that a pancreatic tumor origin is also predictive of continued partial response during PRRT compared with small intestine origin. A favorable response to PRRT in PNEN was previously describe by Hasegawa et al [21], demonstrating that pancreatic origin is a favorable factor for lesion shrinkage after PRRT, while rectal NEN is associated with resistance to tumor reduction. Pancreatic NEN differ from SiNEN in several aspects, first, hormonal secretory syndromes differ markedly between the two, as carcinoid syndrome is prevalent in 20–30% of SiNEN with liver metastases [23] while under 1% of carcinoid syndromes are of PNEN origin [11]. Second, a larger proportion of PNEN develop as part of multiple neoplasia syndromes compared to rare reports in SiNEN [24]. In addition, the somatic genetic landscape of PNEN comprise an almost three times higher mutation rate in PNEN vs. SiNEN with specific driver mutations in PNEN (most commonly inactivation of MEN1 and ARTX/DAXX), while SiNEN show mainly chromosomal alterations (loss of parts of chromosome 8 and 18, gains of 4, 5 and 20) [24, 25]. Overall, the striking difference in genetic stability between PNEN and SiNEN might lead to a better response to PRRT seen in PNEN, as a higher mutation rate and genomic instability renders the tumor more susceptible to certain pharmacological treatments [26, 27].
This study has several limitations. First, it is a retrospective study that includes only patients with metastatic disease and very few patients with lung NEN, thus results of this study might not be applicable to locally advanced NENs or to lung NEN. Second, due to the relatively small cohort, we were not able to statistically assess the validity of mid-treatment response as a predictor for long-term (six months from PRRT completion or at last follow-up) response. Finally, high-grade NEN were not represented in this study but for a few cases. However, as there is no published randomized controlled trials demonstrating PRRT efficacy in G3 NEN yet, the low proportion of high-grade NEN in this study is in fact predictable.
To conclude, mid-treatment response to PRRT might serve as predictor for PRRT outcome. This finding is important as it is a readily available tool for disease evaluation and decision-making during treatment, thus providing data to either support or cease continued PRRT treatment.