PReCedeNT trial: Phase III randomized-controlled trial of Lutetium − 177 DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) plus Chemotherapy versus PRRT alone in FDG-avid, Well-differentiated Gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Abstract

Background

Peptide receptor radionuclide therapy (PRRT) with Lutetium-177 DOTATATE is the standard of care for well-differentiated metastatic or locally advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, tumor heterogeneity, particularly in FDG-avid tumors, can limit treatment effectiveness. The PReCedeNT trial aims to evaluate the efficacy of combining PRRT with capecitabine and temozolomide (CAPE-TEM) chemotherapy compared to PRRT alone in patients with FDG-avid, well-differentiated GEP-NETs.

Methods

This single-center, randomized, open-label, phase III trial will enroll patients with FDG-avid, well-differentiated GEP-NETs. Participants will be randomized in a 1:1 ratio to receive either PRRT alone or PRRT plus CAPE-TEM chemotherapy. The primary endpoint is progression-free survival (PFS), with secondary endpoints including objective response rate, overall survival, toxicity, and quality of life parameters. The sample size of 162 patients was calculated based on the assumption that the addition of chemotherapy would improve PFS by an absolute value of 15% compared to the PRRT arm of the NETTER-1 trial.

Discussion

The combination of PRRT and chemotherapy may enhance treatment efficacy by targeting both somatostatin receptor-positive and FDG-avid tumor cells. By addressing the lack of prospective data on the efficacy of PRRT combined with chemotherapy in NETs, this trial aims to provide valuable insights into the benefits and risks of this combination. The results of this study have the potential to significantly impact the treatment strategies for patients with aggressive NETs, potentially improving the outcomes and quality of life of this patient population.

Trial Registration

This trial is registered with the Clinical Trials Registry of India (CTRI/2019/07/027255) and ClinicalTrials.gov ID: NCT07185672.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-025-15111-x.

Background

Neuroendocrine tumours (NETs), better defined as neoplasms (NENs), are a heterogeneous group of neoplasms that range from well-differentiated tumours to more aggressive carcinomas [1]. In the most recent SEER register (SEER-17), more than half of all NENs, i.e. 61%, were gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [2]. A condition once thought to be slow-progressing has seen an increase in cases due to improved access to cross-sectional imaging and the development of PET imaging with somatostatin receptors (SSTR) targeting radiotracers [3]. According to the SNMMI appropriate use criteria guidelines, SSTR PET with Ga-68 DOTA ligands is preferred imaging modality for initial diagnosis and selection of patients for peptide receptor radionuclide therapy (PRRT) [4]. Peptide receptor radionuclide therapy (PRRT) with Lutetium-177 DOTATATE is the established standard of care for patients with well-differentiated metastatic or locally advanced GEP-NETs. It has demonstrated a significant improvement in outcomes compared to Octreotide LAR, both as a first-line and second-line treatment approach [5, 6]. ENETS guidelines recommend the use of Ga-68 labeled DOTANOC/TOC/TATE imaging only for WHO Grade 1 NET whereas FDG PET is the preferred modality for WHO Grade 3 NEN and NEC [7]. EANM guidelines recommend including FDG PET in the diagnostic pathway for higher G2 (Ki67: 10–20%), G3 NET, and NEC [8], whereas ESMO guidelines offer broader recommendations, suggesting the evaluation of both FDG PET/CT and SSTR-PET for all G2-G3 NETs [9]. Studies have also shown FDG positivity in G1 NETs, which makes FDG PET an essential marker of heterogeneity across all grades [10]. FDG PET positivity has been shown to be an independent predictor of shorter progression-free and overall survival in NET patients undergoing PRRT [11]. Sansovini et al. studied a prospective cohort of 60 patients, of whom 55 underwent FDG-PET before PRRT; 32 (58%) showed increased FDG uptake. The FDG-negative cohort showed a median progression-free survival of 68.7 months compared with 21.1 months in the FDG PET-positive group. The gap in outcomes needs to be addressed by the addition of therapy for the heterogeneous FDG-avid component [12]. Consequently, it is imperative to address FDG-avid tumors by integrating PRRT with chemotherapy. Strosberg et al. have demonstrated an exceptionally high and durable response rate with the combination of capecitabine and temozolomide in metastatic well-differentiated or moderately differentiated pancreatic neuroendocrine tumors [13]. Nicolini et al. in a prospective cohort of 37 patients of metastatic NET treated with combination of PRRT and Capecitabine showed partial response (PR) in 10 patients (30%), stable disease (SD) in 18 patients (55%), with a DCR of 85% [14]. Kashyap et al. conducted a retrospective cohort study involving 52 patients who were selected for treatment based on somatostatin-receptor imaging, with the exclusion of those exhibiting spatially discordant FDG-avid disease. Following a median follow-up period of 36 months, the median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 48 months [15]. These findings further substantiate the efficacy of the combined approach of PRRT and chemotherapy, which has become the standard practice and serves as the foundation for our hypothesis. Given the absence of a prospective study to establish this treatment regimen, we designed a phase 3 randomized controlled trial to evaluate the combination of PRRT and CAPE-TEM-based chemotherapy in patients with FDG-positive metastatic well-differentiated NETs.

Hypothesis

Based on the encouraging results obtained with combination therapy in retrospective and single-arm phase 2 studies, we hypothesized that PRRT and CAPE-TEM would improve PFS in patients with well-differentiated FDG-avid metastatic or locally advanced GEP-NETs.

Study design

This study is a single-center, investigator-initiated, phase 3 open-label, parallel-group, prospective randomized controlled trial registered under the Clinical Trials Registry of India (CTRI/2019/07/027255) and ClinicalTrials.gov (ID: NCT07185672). It is performed in a tertiary care oncology center with a dedicated multidisciplinary neuroendocrine tumor clinic. The study is currently in the recruitment phase and includes patients with metastatic, locally advanced or progressive well-differentiated NET, showing SSTR expression on Ga-68 DOTANOC PET/CT (Krennings score − 3/4) and GLUT-receptor expression on FDG PET/CT (uptake more than or equal to normal liver uptake), with both scans performed within an interval of two weeks. As per institutional protocol, both studies will be performed with use of intravenous contrast, unless contraindicated. Patients with histology of WHO Grade 1 and Grade 2 (Ki-67 of 3–5%), disease progression within 6 months of first-line treatment with somatostatin analogs (SSA), and upfront WHO Grade 2 and 3 will be included. Other inclusion criteria are an Eastern Cooperative Group Performance Score (ECOG PS) of not more than 2, adequate hematological, renal, and liver functional parameters as per the EANM guidelines, and a life expectancy greater than 6 months. The detailed inclusion and exclusion criteria are presented in Table 1. Patients with concurrent malignancy and prior treatment with chemotherapy/PRRT will be excluded from the study. The study is approved by the Institutional Ethics Committee (TMH/IEC/2019/003258) and was conducted according to the guidelines of the Helsinki Declaration. The detailed study protocol is available as Supplementary Material.

Table 1.

Inclusion and exclusion criteria

Inclusion Criteria	Exclusion Criteria
Male or female, age greater than 18 years	Serum creatinine level of more than 1.6 mg/dl or a creatinine clearance of less than 50 ml/min
Well-differentiated G1 (< 3%) or G2 (3–5%) with disease progression in last 6 months	Hemoglobin level of less than 8.0 g per deciliter
Well differentiated G2 (Ki67 : >5–20%) OR G3 (Ki67- greater than 20–55%),	Red blood cell count less than 300,000/cubic millimeter
Positive Ga-68-DOTANOC PET/CT, Krennings score >/=3	White cell count of less than 2000 per cubic millimeter
Positive FDG PET/CT scan grade 3 or 4 uptake	Platelet count of less than 75,000 per cubic millimetre
Locally advanced/inoperable disease or metastatic disease	Total bilirubin level of more than 3 times the upper limit of the normal range
Karnofsky performance-status score of at least 60 or ECOG performance status </= 2	Serum albumin level < 3.0 g/dl
Life expectancy greater than 6 months	Treatment with more than 30 mg of octreotide LAR within 4 weeks before randomisation.
	Peptide receptor radionuclide therapy and chemotherapy at any time before randomisation
	Pregnancy and Lactation
	Patients with concurrent malignancies

Screening, consenting, and randomization

Patients with biopsy-proven well-differentiated GEP-NET will be discussed in the institutional NET multidisciplinary clinic. Patients with Ki-67 ≤ 5% who have shown disease progression on imaging with DOTA PET after primary treatment and those with grade 2 (Ki-67 of 6–20%) and grade 3 histology will undergo FDG PET. Patients with a Krenning score of ≥ 3 and FDG positivity will be screened for trial eligibility by the study team. Participants will receive a detailed explanation of the study and an information sheet composed in accessible language. Participants will have the opportunity to address any concerns or questions within a 24- to 48-hour period, after which they may proceed to sign the consent form. Upon providing consent, participants will be randomly allocated in a 1:1 ratio to either the experimental group, receiving PRRT with Lu-177 DOTATATE plus CAP-TEM, or the control group, receiving Lu-177 DOTATATE PRRT alone. Randomization will be conducted using computer software employing a permuted block design. Notably, the interventions will not be blinded to either the participants or trial staff.

Interventions

Patients in both groups will receive up to four cycles of Lu-177 DOTATATE PRRT (approximately 7.4 GBq per cycle) administered intravenously over 30 min at intervals of 8–12 weeks. The PRRT treatment protocol is described in Table 2. Lutetium-177 DOTATATE is indigenously produced by Board of Radiation and Isotope technology (BRIT) and supplied in doses of 7.4 GBq. To ensure nephroprotection, an intravenous amino acid infusion containing 25 g of lysine and 25 g of arginine in 2 L of solution will be administered over four hours, following the established department protocol. Patients will be discharged from the hospital after a post-therapy scan is conducted four hours after the infusion ends. They will be contacted again at 24 h to check for any immediate side effects and for a post-therapy scan. In the study arm, oral capecitabine and temozolomide will be administered. Two weeks after completing PRRT, patients will be prescribed oral capecitabine at 1500 mg/m2 in two divided doses within 15 min of eating for 14 days. Oral temozolomide at 200 mg/m2 will be administered daily for five days as a single dose with a glass of water at bedtime, on an empty stomach at least 30 min before or two hours after a meal. This will be followed by a two-week rest period. Two cycles of the CAPE-TEM regimen will be administered between PRRT cycles and at the end of the fourth PRRT cycle.

Table 2.

PRRT administration protocol: (in sequence)

One-day prior		Tablet Dexamethasone 4 mg BD oral
Day of therapy (Day 1)	Premedication	Tablet Aprepitant 125 mg oral Intravenous Dexamethasone 8 mg Intravenous Palonosetron 0.25 mg
	Amino Acid infusion to be started (1 h after premedication)	Intravenous infusion of lysine and arginine diluted in 500 ml of normal saline over 1 h
	PRRT with Lu-177 DOTATATE	Intravenous infusion of 200 mCi of Lu- 177 DOTATATE diluted in 100 ml normal saline over 30 min
	After PRRT infusion, start amino acid infusion	Intravenous infusion of lysine and arginine diluted in 1500 ml of normal saline over 3 h
Day 2		Tablet Aprepitant 80 mg oral, in morning Oral Dexamethasone 4 mg BD
Day 3		Tablet Aprepitant 80 mg oral, in morning Oral Dexamethasone 4 mg BD

Toxicity assessment and dose modification

Toxicity will be graded according to the NCI CTCAE version 5.0. Toxicities of severity grade 1 will not lead to any dose reduction or cycle delay. The same holds true for adverse reactions without any potential for serious or life-threatening complications, according to the judgment of the physician (e.g., alopecia). If toxicity is unequivocally caused by only one drug, dosage modification of the other drugs is not necessary. If more than one type of toxicity occurs concurrently, the most severe grade will determine the modification. In the case of a necessary dose reduction, the lower dose level will be applied throughout the rest of the therapy without re-escalation, if not stated otherwise. In the case of acute allergic reactions of grade 3 or 4, the respective agent should be discontinued permanently; in the case of grade 1 or 2, it is up to the physician to continue treatment without dose modification if this is in the best interest of the patient. Each dose modification or treatment delay must be documented in the Case Record Form or source document, including the respective reason. Due to logistic reasons arising out of non-availability of Lu-177-DOTATATE (PRRT), CAP-TEM regimen can be started till the availability of radio-pharmaceutical for study arm. Dose modification strategies for PRRT and CAPE-TEM are mentioned in the supplementary material.

Study assessments

In the experimental and standard arms, the following assessments will be performed at baseline and within 2 weeks prior to the start of PRRT or oral chemotherapy: two-dimensional echocardiography, routine hemogram, liver function, renal function, and serum electrolytes. Glomerular filtration rate with Tc-99 m DTPA renogram and tubular functional assessment with Tc-99 m EC renogram will be carried out. Following assessments will be carried out on the next day, at two weeks and six weeks following PRRT: complete hemogram, liver function tests and serum electrolytes. FDG PET and DOTA PET will be performed after 2 cycles of PRRT in the standard arm, and after 2 cycles of PRRT and 4 cycles of CAPE-TEM in the study arm. End of treatment FDG PET and DOTA PET will be performed at 4 cycles of PRRT in the standard arm, and after 4 cycles of PRRT and 8 cycles of CAPE-TEM in the study arm. The study assessment schema is presented in Table 3.

Table 3.

Study assessments

	Pre-therapy	Cycle 1	15–21 days after PRRT	Pre therapy	Cycle 2	15–21 days after PRRT	Pre therapy	Cycle 3	15–21 days after PRRT	Pre therapy	Cycle 4	15–21 days after PRRT	Follow up
PRRT		X			X			X			X
CAPE-TEM			X			X			X			X
PS	X			X			X			X			X
Hb	X			X			X			X			X
WBC	X			X			X			X			X
RBC	X			X			X			X			X
LFT
Platelet	X			X			X			X			X
GFR	X			X			X			X			X
EC scan	X			X			X			X
ECG/2D ECHO	X			X			X			X
DOTA PET	X						X						X
FDG PET	X						X						X
EORTC QLQ- C30	X			X			X			X			X
EORTC GI.NET 21	X			X			X			X			X

Follow-up assessments

After completion of treatment in both the standard and experimental arms, patients will be clinically followed up every 3 months through a scheduled outpatient visit or by telephonic follow-up. Patients will undergo DOTA PET, FDG PET, complete hemogram, renal and liver functional parameters assessment at every 6 months for the first two years. Subsequently, patients will be followed up clinically every 6 months and once symptomatic, relevant imaging will be performed after discussion in a multi-disciplinary clinic.

Quality of life assessment

QOL analysis will be conducted using EORTC QLQ-30 and EORTC G.I.NET-21 with appropriate language translations at baseline, one week before start of every session of PRRT/PRRT and at every 6 months for first two years when the patient comes for DOTA and FDG PET imaging. According to the EORTC QOL scoring manual, for domains with several questions, if more than half but not all of the questions are answered during a visit, that visit is considered valid for that domain. The average of the answered questions will be used in the analysis. Visits in which less than half of the questions for a specific domain were answered will be excluded from the analysis.

Treatment end-points

Primary endpoint

Progression-free survival (PFS) is defined as the time duration from the date of randomization to the date of tumor progression or death from any cause. Patients alive at last follow-up will be censored at the date of last follow-up visit.

Secondary endpoints

Objective Tumor Response (complete + partial response) based on a Ga-68-DOTATOC and FDG PET/CT scan compared to baseline (pre-treatment) evaluation, and graded by RECIST 1.1 criteria and by Metabolic Criteria (EORTC). As per institutional protocol, PET/CT studies for patients with neuroendocrine tumors were performed with administration of intravenous contrast, unless contraindicated; hence contrast-enhanced CT scan of PET/CT study was used for assessment of therapeutic response by RECIST 1.1 criteria. Quality of Life parameters using EORTC QLQ C-30 and EORTC G.I.NET21 questionnaires. Overall Survival (OS) is defined as the time duration from the date of randomization to the date of death from any cause. Patients alive at last follow-up will be censored at the date of last follow-up visit. Once the patient has ceased therapy (either Arm A or Arm B), due to progressive disease, intolerable side effects or patient choice, further therapy is as per physician choice. Patients who have temporarily ceased therapy (for a minimum of 2 months) (Arm A or Arm B) due to adverse events can be considered for restarting the same regimen after a delay/break based on discretion of the treating physician. The cessation of therapy will be labelled as an ‘event’ if not progression, and the date of cessation will be taken for the calculation of event-free survival (Fig. 1).

Fig. 1.

Trial schema

Statistical analysis

The sample size was calculated based on the outcome of NETTER-1 trial, wherein PFS rate in the PRRT arm was 65.2% at 20 months. We assumed that addition of chemotherapy in the experimental arm will improve the PFS by an absolute value of 15%. With a type 1 error (one-sided) of 5% and Type 2 error of 20%, with 10% patients lost to follow-up, a sample size of 162 patients was derived. For any statistical test performed, significance level will be set to 5%.

Discussion

PRRT with Lu-177 DOTATATE has shown excellent improvement in progression free survival and disease control in well-differentiated metastatic NENs. The pivotal NETTER-1 trial provided the first high-level evidence of PRRT’s efficacy, with a median PFS of 28.4 months in the PRRT group compared to 8.5 months in the control group [5]. NETTER-2 trial further established the utility of PRRT as first line therapy in metastatic well-differentiated Grade 2 (>10–20%) and Grade 3 (>20%) NENs [6]. Although grade is a crucial determinant of outcomes and serves as the primary focus of both studies, it is widely acknowledged that the Ki-67 index, when obtained from a single biopsy site or resected specimen, frequently fails to accurately represent the entire tumor burden. Whole-body FDG PET detects areas of poor differentiation and is recognized for influencing outcomes in a large cohort of patients eligible for PRRT. Zhang et al. conducted a study involving 495 patients with metastatic NENs who underwent PRRT with Lu-177/Y90 DOTATATE. Among these patients, 382 (77.2%) had positive FDG PET/CT results, whereas 113 (22.8%) had negative results prior to PRRT. Those with negative results exhibited shorter PFS (18.5 months vs. 24.1 months) and OS (53.2 months vs. 83.1 months) [16]. FDG PET serves as a direct indicator of glycolytic activity within tumors, functioning as a surrogate marker for tumor hypoxia and neovascularization, which contribute to dedifferentiation [17]. As a result, FDG positivity is more commonly observed in higher-grade neuroendocrine neoplasms (NENs) and neuroendocrine carcinomas (NECs), and this specific subset is generally treated with chemotherapy [18]. Consequently, the selection of patients for this study was contingent upon FDG positivity and the Ki-67 index. Patients classified as G1 and those in the early stages of G2 (ranging from 3 to 5%) were included in the study only if they showed evidence of disease progression. The threshold for G2 was determined based on the findings of Binderup et al., [19] which revealed that individuals in the Ki5 group (Ki-67 less than or equal to 5%) had a reduced risk of mortality and disease progression compared with those in the Ki20 group (Ki-67 5%–20%). Although there is no standardized treatment protocol or extensive data on chemotherapy for neuroendocrine neoplasms (NENs), the phase 2 ECOG-ACRIN E2211 study [20], which included patients with progressive pancreatic lower-grade NETs with a Ki67 index of ≤ 20%, showed a 40% response rate when treated with a combination of capecitabine and temozolomide, the same regimen used alongside PRRT in this study. The rationale for combining PRRT with chemotherapy lies in their complementary mechanisms of action: PRRT delivers targeted radiation via somatostatin receptor-binding radiolabeled peptides, whereas chemotherapy exerts cytotoxic effects through systemic pathways. Interestingly, the chemotherapeutic combination of capecitabine and temozolomide (CAPTEM), frequently employed in this context, may enhance the effects of PRRT by increasing DNA damage. Claringbold et al. were among the pioneers in prospectively investigating the combination of PRRT (177Lu-DOTATATE) and CAPE-TEM in metastatic NETs. In their phase I/II study involving 35 patients, the most common toxicities observed were transient nausea, with grade 2 occurring in 18% and grade 3 in 3% of patients, thrombocytopenia of grade 2 in 24%, and neutropenia of grade 3 in 6%, with no grade 4 events reported. The study reported an objective response rate (ORR) of 24%, with a disease control rate (DCR) of 97%. Toxicity was manageable, with few grade 3/4 hematologic events. In a follow-up study in 2016 with 50 patients, similar results were observed, with an ORR of 44% and median progression-free survival (PFS) of 31 months. The CONTROL NETS was the first randomized trial to study the combination regimen of PRRT and CAPE-TEM in a phase 2 design [21]. The final results showed significantly improved PFS with the PRRT-CAPE-TEM combination versus CAPE-TEM in pancreatic NET (61.1 vs. 33.3% at 27 months) and modest benefit in mid-gut NETs with PRRT-CAPE-TEM combination versus CAPE-TEM (60.4 vs. 61.5% at 36 months). These findings support the hypothesis that CAPTEM may act synergistically with PRRT, particularly in pancreatic NETs. The highlight of our study is to include the entire cohort of GEP-NETs, and the plan to ‘sandwich’ two cycles of CAPE-TEM between subsequent cycles of PRRT was based on our institutional publication by Parghane et al. [22] The recently published phase 2 results of LuCap trial has yielded a non-significant difference in ORR (33.3 versus 30.6%) in the PRRT monotherapy versus the PRRT-capecitabine arm [23]. This further emphasis the need for a study wherein the sample size is powered for primary end-point of PFS [24]. While this study objectively addressed heterogeneity by grading uptake on FDG and DOTA PET, the only limitation is that the congruency of dual uptake was not accounted for. In conclusion, the PReCedeNT trial protocol aims to generate level 1 evidence for the use of combination therapy in addition to PRRT in NETs.

Authors’ contributions

Author Names and Contributions: ADP- Conceptualization, Methodology, Writing Original Draft. ID- Patient screening, Consenting and Writing - Review & Editing. SY- Project administration. VR, AA, SB, SVS - Supervision. VC, MB, SP, RP, PB- Clinical assessment and follow up. MB, Subhash Y - Pathological assessment. AR, VO, PB- Chemotherapy assessment and follow up. NCP, SS, SG, SC, MV- Imaging assessment.

Funding

Open access funding provided by Department of Atomic Energy. This study was funded by Terry Fox Research Institute, Canada.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study has been approved by Institutional Ethics Committee at Tata Memorial Hospital. The approval letter and informed consent form in English language is provided in Supplementary Material.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.