Visual Abstract
Abstract
177Lu-DOTATATE has emerged as a viable treatment strategy for advanced well-differentiated grade 1/2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Few retrospective studies have shown concomitant 177Lu-DOTATATE with radiosensitizing low-dose capecitabine to be effective in advanced NETs. However, this has not been validated in prospective randomized-controlled trials. Methods: In this investigator-initiated, parallel-group, open-label, phase 2 trial, patients with grade 1/2 GEP-NETs, having progressive somatostatin receptor–positive, locally advanced, or metastatic disease on 68Ga-DOTANOC PET/CT, were randomly assigned in a 1:1 ratio to 177Lu-DOTATATE plus capecitabine (experimental arm) or 177Lu-DOTATATE only (control arm). 177Lu-DOTATATE was administered at approximately 7.4 GBq/cycle intravenously, for up to 4 cycles, at 8 wk intervals, whereas capecitabine was given at 1,250 mg/m2/d orally from day 0 to day 14 of each cycle of 177Lu-DOTATATE. The primary endpoint was the objective response rate. Secondary endpoints included the disease control rate, progression-free survival, overall survival, and adverse events. Results: Seventy-two patients (median age, 53 y; range, 18–79 y) were enrolled. The objective response rate was 33.3% (95% CI, 18.6–50.9%) in the experimental arm versus 30.6% (95% CI, 16.4–48.1%) in the control arm (P = 0.800). The disease control rate was 88.9% (95% CI, 73.9–96.9%) and 91.7% (95% CI, 77.5–98.2%) in the experimental and control arms, respectively (P = 1.000). The estimated median progression-free survival in the experimental arm was 29 mo (95% CI, 22–29 mo) versus 31 mo (95% CI, 29–32 mo) in the control arm (P = 0.401). The median overall survival was not reached in either arm (P = 0.876). Overall, adverse events of at least grade 3 were noted in 7 patients in the experimental arm versus 6 patients in the control arm (P = 0.759). Conclusion: Based on the results of this trial, the addition of low-dose capecitabine to 177Lu-DOTATATE in advanced grade 1/2 GEP-NETs did not lead to superior radiographic responses. Further studies are needed to evaluate its potential role in high-grade NETs.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare group of malignancies which have shown an increased burden in recent times (1). Treatment options for advanced metastatic GEP-NETs include somatostatin analogs, peptide receptor radionuclide therapy (PRRT), targeted drugs, and cytotoxic chemotherapies (2–4). Increased somatostatin receptor (SSTR) expression in GEP-NETs, as demonstrated by high-grade uptake on SSTR-targeted imaging, provides the rationale for the use of PRRT (5). The PRRT agents bind to the SSTRs on the tumor cell membrane, resulting in the delivery of β- or α-emitting radionuclides, thus causing cellular damage (6). PRRT with the β-emitting somatostatin analog 177Lu-DOTATATE has demonstrated improved survival outcomes in advanced midgut NETs progressing on somatostatin analogs in the pivotal NETTER-1 trial (7,8). Comparative analyses also demonstrate its efficacy and safety vis-à-vis everolimus and sunitinib in pancreatic NETs (9,10). Nevertheless, objective radiographic responses with 177Lu-DOTATATE remain modest, with the NETTER-1 trial reporting only 18% of the midgut NET patients having complete or partial radiographic responses (7). Thus, there exists an unmet need to further improve the treatment outcomes.
Few observational and single-arm studies have shown combination therapies of PRRT with capecitabine to be effective in advanced NETs (11–14). In a single-center retrospective study by Ballal et al., patients treated with concomitant 177Lu-DOTATATE and low-dose capecitabine showed higher objective response rate (ORR), longer progression-free survival (PFS), and longer overall survival (OS) compared with those treated with 177Lu-DOTATATE alone (13). Capecitabine, administered in suboptimal doses in this setting as a radiosensitizer, acts through inducing inappropriate progression through the S-phase cell cycle checkpoint into the radiosensitive G2/M phase and inhibiting DNA damage repair, thereby suggesting it has a synergistic role with PRRT (15,16). A few other studies have also demonstrated the safety of this combination approach (17,18). However, to the best of our knowledge, no prospective randomized controlled study has yet been conducted to establish the added benefit associated with this combination approach over standalone PRRT. In this phase 2 trial, we intended to compare the activity of concomitant 177Lu-DOTATATE plus capecitabine and 177Lu-DOTATATE alone in patients with advanced well-differentiated GEP-NETs.
MATERIALS AND METHODS
Study Design and Patient Population
This was an investigator-initiated randomized, parallel-group, open-label, phase 2 trial, prospectively registered at the Clinical Trials Registry-India (CTRI/2020/01/022636). Between January 2020 and May 2023, patients with advanced well-differentiated grade 1/2 GEP-NETs were enrolled at a tertiary care referral center. The trial protocol is available as supplemental material (supplemental materials are available at http://jnm.snmjournals.org) (19–28). Patients were considered eligible if they had progressive, locally advanced, or metastatic disease on a recent 68Ga-DOTANOC PET/CT scan (within 12 wk), with significant SSTR expression, defined as the avidity of lesions being greater than that of a normal liver. The patients were required to have Eastern Cooperative Oncology Group performance score of no more than 2 and adequate hematologic, renal, and liver function reserve. All patients also underwent an 18F-FDG PET/CT at baseline (within 2 wk of the 68Ga-DOTANOC PET/CT), and those with discordant lesions (SSTR negative but 18F-FDG positive) were excluded (detailed inclusion and exclusion criteria listed in the trial protocol in Supplemental Table 1). Informed written consent was obtained from the patients before inclusion. The study was approved by the Institute Ethics Committee (INT/IEC/2019/002803) and was conducted according to guidelines in the Helsinki Declaration.
Randomization and Masking
Eligible patients were randomly assigned in a 1:1 ratio to the experimental arm, 177Lu-DOTATATE plus capecitabine, or the control arm, 177Lu-DOTATATE alone. Random allocation was accomplished using a computer-generated block randomization sequence (block size of 2). Allocation concealment was done using sequentially numbered opaque sealed envelopes. However, the interventions were not masked to either the patients or the trial staff.
Intervention Procedures
The patients in both arms were administered up to 4 cycles of 177Lu-DOTATATE (approximately 7.4 GBq/cycle) intravenously over 30 min at 8 wk intervals. Pretreatment with 8 mg of intravenous ondansetron and 8 mg of dexamethasone was performed. To ensure nephroprotection, an intravenous amino acid infusion comprising 26.8 g of lysine and 9.6 g of arginine in 2 L of solution was given over 4 h, starting 30 min before the infusion of 177Lu-DOTATATE as per established department protocol (29,30). Patients were monitored for 24 h for any immediate adverse event (AE), and a posttherapy scan was acquired at 24–48 h. Additionally, in the experimental arm, oral capecitabine was given as a radiosensitizer at a dose of 1,250 mg/m2/d from days 0 to 14 of each cycle of 177Lu-DOTATATE. This dose and schedule of radiosensitizing capecitabine was adapted from the studies by Claringbold et al. and Ballal et al. and was based on our own previous clinical experience (11,13,29,30). In both treatment arms, patients were allowed to receive long-acting or short-acting octreotide if they experienced functional symptoms (e.g., diarrhea or flushing). Patients who showed radiographic progression on follow-up or experienced persistent grade 3 or greater toxicities (in the case of thrombocytopenia, grade ≥2, and for nephrotoxicity, grade ≥2, with estimated glomerular filtration rate of <50 mL/min/1.73 m2) were discontinued from the study and were treated with other options as per established guidelines.
Treatment Endpoints
Patients were followed every 3 wk with complete hemogram, liver, and renal function tests. Radiographic response was assessed by 2 masked reviewers using contrast-enhanced CT images of the whole-body 68Ga-DOTANOC PET/CT at around 8 wk after every 2 cycles of 177Lu-DOTATATE and every 24 wk thereafter until disease progression. The primary endpoint was the ORR, which was calculated as the proportion of patients achieving complete response and partial response per RECIST 1.1 (31). Secondary endpoints included disease control rate, PFS, OS, and toxicity profile. Disease control rate was defined as the proportions of complete response, partial response, and stable disease per RECIST 1.1 (31). PFS was estimated from the start of the treatment until radiographic progression or death due to any cause. OS was estimated from the start of the treatment until the occurrence of death due to any cause. Treatment-related toxicity was evaluated using Common Terminology Criteria for Adverse Events, version 5.0.
Statistical Analysis
The sample size of 72 patients was calculated to detect a 30% absolute improvement in ORR with concomitant 177Lu-DOTATATE plus capecitabine while assuming an ORR of 20% with 177Lu-DOTATATE alone, a power of 80% at 2-sided α-level of 5%, and an allocation ratio of 1:1. The assumed response rate with 177Lu-DOTATATE alone was based on prior literature, whereas the assumption of 30% absolute improvement with the addition of capecitabine was based on the study by Ballal et al. (7,13). The primary analysis was by intention to treat and included all the randomized patients. Per-protocol analysis for the primary endpoint was also done comprising patients who completed all 4 cycles of the allocated treatment. The categoric variables were expressed as numbers and percentages. For interarm comparison, a χ2 test or a Fisher-exact test was used for testing significance of any difference. Risk ratios and their 95% CIs were also used for overall and subgroup analyses of the primary endpoint. The continuous variables were expressed as median and interquartile range (IQR). A Mann–Whitney U test was used for testing the significance of difference between the arms. A prespecified interim survival analysis was done using the Kaplan–Meier curve method and the Cox proportional hazards regression model. A log-rank test was used to compare the median PFS and OS durations between the treatment arms. The median follow-up duration was calculated using the reverse Kaplan–Meier estimator. Statistical analyses were done using IBM’s SPSS Statistics for Windows, version 20.0, and R Statistical Software (The R Project for Statistical Computing). The Kaplan–Meier curves were plotted using MedCalc for Windows, version 22.026. A 2-tailed P value of less than 0.05 was considered statistically significant.
RESULTS
Clinical Characteristics
Of the 91 patients assessed for eligibility, 72 patients with advanced grade 1/2 GEP-NETs were included, comprising 36 patients in each arm (Fig. 1). The patients’ characteristics were observed to be similar in both the arms (Table 1). The median age of the patients was 53 y (IQR, 41–61 y). Gastrointestinal NETs accounted for most of the primary tumors (45/72, 62.5%) with small bowel being the most frequent primary site (32/72, 44.4%). Most of the patients had lower-grade tumors, with a Ki-67 index less than 10% in 53 of 72 patients (73.6%). The most common sites of metastases included lymph nodes (47/72, 65.3%) and liver (58/72, 80.6%). Overall, 45 of the 72 patients (62.5%) had Krenning score of 4 on the 68Ga-DOTANOC PET/CT, with the rest having a Krenning score of 3.
CONSORT flow diagram describing study enrollment process.
Demographic and Clinical Characteristics of Patients in the Study
Treatment Characteristics
Sixty of the 72 patients (83.3%) completed all 4 cycles of 177Lu-DOTATATE, receiving a cumulative activity of 29.6 GBq. These included 32 patients in the experimental arm and 28 patients in the control arm. The reasons for not completing 4 cycles of 177Lu-DOTATATE in the remaining 12 patients were progressive disease (radiographic progression, n = 2; clinical progression, n = 1), disease-related deaths (n = 2), coronavirus disease 2019 pandemic (n = 2), loss of SSTR expression (n = 1), and treatment-emergent AEs (n = 4). No event of capecitabine discontinuation during the cycles of 177Lu-DOTATATE was observed in the experimental arm.
Radiographic Response
Two patients, 1 in each arm, died before their first radiographic follow-up. Of the 36 patients, 12 in the experimental arm (Fig. 2A) and 11 in the control arm (Fig. 2B) achieved partial response. No event of complete response was observed in either arm. In the intention-to-treat analysis, the ORR was 33.3% (95% CI, 18.6–50.9%) in the experimental arm and 30.6% (95% CI, 16.4–48.1%) in the control arm (risk ratio, 1.09; 95% CI, 0.56–2.14; P = 0.800). In the per-protocol analysis, the ORR was 11 of 32 (34.4%; 95% CI, 18.6–53.2%) and 10 of 28 (35.7%; 95% CI, 18.6–55.9%) in the experimental and control arms, respectively (risk ratio, 0.96; 95% CI, 0.48–1.92; P = 0.914). Overall, the disease control rate was 32 of 36 (88.9%; 95% CI, 73.9–96.9%) in the experimental arm compared with 33 of 36 (91.7%; 95% CI, 77.5–98.2%) in the control arm (P = 1.000). The median percentage changes in the sums of largest dimensions of the target lesions in the evaluable patients were −12.0% (IQR, −36.6 to −2.8%) and −8.6% (IQR, −36.6 to −2.1%) in the experimental and control arms, respectively (P = 0.842). No significant difference in the risk ratios for ORR was observed between the 2 arms across the different subgroups (Fig. 3).
Waterfall plots showing radiographic responses in experimental (A) and control (B) arms. x-axis represents individual patients, and y-axis represents maximum percent change in sum of largest dimensions (SLD) from baseline. ●Appearance of new lesions. #Patient died before radiographic assessment. *Nonmeasurable disease. CAP = capecitabine; Lu-TATE = 177Lu-DOTATATE.
Forest plot for objective radiographic response across different subgroups for experimental arm versus control arm. Squares represent risk ratio (RR), and horizontal lines represent 95% CIs. CAP = capecitabine; GI-NET = gastrointestinal NET; Lu-TATE = 177Lu-DOTATATE; p-NET = pancreatic NET.
Survival Analysis and Follow-up
At the first data cutoff date of May 23, 2024 (median follow-up, 27.5 mo; 95% CI, 23.9–30.5 mo), a total of 25 events of disease progression or death had occurred in the study cohort: 14 events in the experimental arm and 11 events in the control arm. The estimated median PFS duration in the experimental arm was 29 mo (95% CI, 22–29 mo) compared with 31 mo (95% CI, 29–32 mo) in the control arm (unadjusted hazard ratio, 1.39; 95% CI, 0.63–3.06) (Fig. 4A). The estimated PFS rates at 12 and 24 mo were 86.1% (95% CI, 74.6–97.6%) and 62.5% (95% CI, 43.8–81.2%), respectively, in the experimental arm versus 86.1% (95% CI, 74.6–97.6%) and 72.7% (95% CI, 55.5–89.9), respectively, in the control arm (P = 0.401). The median OS was not reached in either arm (unadjusted hazard ratio, 1.11; 95% CI, 0.30–4.13; P = 0.876) (Fig. 4B).
Kaplan–Meier curves showing PFS (A) and OS (B) between 2 arms. CAP = capecitabine; Lu-TATE = 177Lu-DOTATATE.
Toxicity
Overall, AEs of any grade were observed in 29 patients (80.6%; 95% CI, 63.9–91.8%) in the experimental arm and 31 patients (86.1%; 95% CI, 70.5–95.3%) in the control arm (P = 0.527). AEs of at least grade 3 were noted in 7 patients (19.4%; 95% CI, 8.2–36.0%) in the experimental arm compared with 6 patients (16.7%; 95% CI, 6.4–32.8%) in the control arm (P = 0.759). The most commonly encountered symptomatic AEs in either arm was nausea or vomiting, which was mainly attributable to the amino acid infusion and promptly relieved after its completion. Most of these toxicities were grade 1/2 events. Among the laboratory parameters, anemia, leukopenia, neutropenia, and thrombocytopenia of at least grade 3 were recorded in 3 (8.3%), 3 (8.3%), 1 (2.8%), and 1 patients (2.8%), respectively, in the experimental arm. The corresponding figures for the control arm were 2 (5.6%), 1 (2.8%), 0 (0%), and 3 (8.3%), respectively. There was no reported case of nephrotoxicity of grade 3 or greater in either arm. Long-term AEs such as myelodysplastic syndrome and leukemia were not observed in this cohort until the time of follow-up. The toxicity profiles of both the treatment arms are summarized in Table 2.
Toxicity Profile of Patients in the Study as Evaluated with CTCAE Version 5.0
DISCUSSION
177Lu-DOTATATE has shown remarkable clinical and survival benefits in advanced progressive GEP-NETs. Nevertheless, radiographic response rates remain modest (7,8). We hypothesized that the addition of low-dose capecitabine as a radiosensitizer to 177Lu-DOTATATE could potentially lead to superior radiographic responses. Few observational and single-arm studies reported that the addition of oral capecitabine as a radiosensitizer to 177Lu-DOTATATE therapy in patients with inoperable and metastatic, progressive, well-differentiated NETs was safe and achieved high tumor control (11–14,17,18). In a retrospective comparative analysis, Ballal et al. reported the combination of 177Lu-DOTATATE and low-dose capecitabine to be safe with significantly higher rates of objective response (∼27% absolute difference) compared with 177Lu-DOTATATE therapy alone (13). However, the results of these observational studies are limited by their single-arm or retrospective study designs and are not supported by those of our current phase 2 randomized controlled trial.
In the current study, we randomized patients with advanced grade 1/2 GEP-NETs to 177Lu-DOTATATE plus low-dose capecitabine or 177Lu-DOTATATE alone. The ORR was 33% in our combination arm versus 31% with 177Lu-DOTATATE monotherapy, with the difference being neither clinically nor statistically significant. Per-protocol analysis as well as subgroup analyses across the different strata also did not show any significant difference in the ORRs between the 2 arms. Further, the median PFS was also similar between the 2 arms. Our results, therefore, suggest that the addition of low-dose capecitabine to 177Lu-DOTATATE in advanced grade 1/2 GEP-NETs may not be clinically relevant in the absence of any significant additive or synergistic effect. Since capecitabine acts on the S-phase of the cell cycle, the low proliferation index in grade 1/2 NETs could thus be the reason behind its apparent lack of benefit in such cases (15,16).
Our results regarding the similar efficacy of 177Lu-DOTATATE with or without capecitabine in advanced grade 1/2 GEP-NETs are supported by the initial findings from the Australasian CONTROL-NET trial. Here, patients with grade 1/2 midgut NETs were randomized to either 177Lu-DOTATATE plus capecitabine and temozolomide (n = 33) or 177Lu-DOTATATE alone (n = 14). The ORR was 34.4% in the combination arm versus 23.1% in the monotherapy arm (P > 0.5). The PFS rates at 36 mo were also similar between the 2 arms (60.4% vs. 61.5%, respectively) (32).
One interesting observation in the current trial was the ORR of 31% in the 177Lu-DOTATATE monotherapy arm. This was considerably higher than the 18% ORR reported in the landmark NETTER-1 trial (7). Two essential differences between the 2 trials need to be highlighted. Although the NETTER-1 trial included only midgut NETs, the current trial included all GEP-NETs. More importantly, only patients with a Krenning score of 3/4 were included in this trial, whereas the NETTER-1 trial also included those with a Krenning score of 2. These differences in patient selection could explain the relatively higher ORR with 177Lu-DOTATATE alone in our study.
Despite the lack of additive or synergistic action in grade 1/2 GEP-NETs, concomitant capecitabine was well-tolerated in our patients. AEs of at least grade 3 were observed in a similar proportion of patients with or without capecitabine. This high safety margin has important ramifications for treatment strategies in high-grade NETs (Ki-67 index, >20%), wherein combination chemotherapy and PRRT can potentially lead to better outcomes. In a retrospective study evaluating the combination therapy of 177Lu-DOTATATE with capecitabine plus temozolomide in SSTR-expressing, grade 2/3 NETs after progression with PRRT or chemotherapy alone, Yordanova et al. reported a clinical benefit rate of 55% and a median OS of nearly 25 mo (33).
This study has certain limitations, notably, the open-label design, lack of stratified randomization, and unavoidable delays in treatment administration and follow-up in few patients during the coronavirus disease 2019 pandemic. Further, the estimated sample size was powered for the primary endpoint of ORR and not for other observations. Nevertheless, to our best knowledge, the current study remains one of the first and largest controlled trials evaluating the role of combined PRRT and chemotherapy in advanced grade 1/2 GEP-NETs and fills an important gap in the literature. The randomized, parallel-group design, masked radiographic assessments, and adequate uniform follow-up are its major strengths.
CONCLUSION
The LuCAP trial provides the first randomized phase 2 data showing that the addition of capecitabine to 177Lu-DOTATATE in advanced grade 1/2 GEP-NETs does not result in clinically or statistically significant improvements in radiographic responses and, hence, may not be routinely warranted. Future research exploring the potential synergy between PRRT and capecitabine-based chemotherapy may be directed toward higher-grade GEP-NETs or those with SSTR- and 18F-FDG–discordant lesions.
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Does the addition of capecitabine to 177Lu-DOTATATE improve radiographic responses in patients with advanced grade 1/2 GEP-NETs?
PERTINENT FINDINGS: In this randomized phase 2 trial, 72 patients with progressive, advanced grade 1/2 SSTR-positive GEP-NETs were randomly assigned in a 1:1 ratio to treatment with 177Lu-DOTATATE plus capecitabine or 177Lu-DOTATATE alone. The ORR rate was 33.3% in the combination arm versus 30.6% in the monotherapy arm, a nonsignificant difference.
IMPLICATIONS FOR PATIENT CARE: The addition of capecitabine to 177Lu-DOTATATE in advanced grade 1/2 GEP-NETs did not lead to superior radiographic responses and, hence, may not be routinely warranted.
ACKNOWLEDGMENTS
This work was selected for oral presentation at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Mid-Winter and American College of Nuclear Medicine (ACNM) Annual Meeting, 2024. The authors thank Mr. Ashish Kumar and Ms. Ramandeep Kaur for their assistance in the data entry and storage of records.
Footnotes
Published online Jan. 8, 2025.
- © 2025 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication August 15, 2024.
- Accepted for publication December 5, 2024.