Research ArticleClinical (Oncology: Lung)

Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study

Lamiaa Zidan, Amir Iravani, Kira Oleinikov, Simona Ben-Haim, David J. Gross, Amichay Meirovitz, Ophra Maimon, Tim Akhurst, Michael Michael, Rodney J. Hicks, Simona Grozinsky-Glasberg and Grace Kong
Journal of Nuclear Medicine February 2022, 63 (2) 218-225; DOI: https://doi.org/10.2967/jnumed.120.260760

Abstract

The purpose of this study was to assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR)–positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1–4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6–43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18–28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%–35%) and 44% (95% CI, 30%–59%); stable disease, 68% (95% CI, 52%–80%) and 44% (95% CI, 30%–59%); and progressive disease, 12% (95% CI, 5%–27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21–0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28–64), hazard ratio 0.2 (95% CI, 0.1–0.6), P < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

Well-differentiated lung neuroendocrine tumor (NET) or “lung carcinoid,” classified into typical carcinoid (TC) and atypical carcinoid (AC), is a heterogeneous disease with variable clinical behavior and prognosis (1). TC rarely metastasizes and generally has a favorable prognosis, whereas AC is more likely to be metastatic at presentation and has a worse prognosis (1).

Surgery is the treatment of choice in patients with localized disease, whereas management of inoperable locally advanced and metastatic disease is complex and requires a multidisciplinary approach (1). For metastatic disease, the European Neuroendocrine Tumors Society (ENETS) guidelines recommend the mammalian target of rapamycin inhibitor everolimus as the first-line therapy for progressive lung NET; however, in patients with tumor of a low proliferative index, a somatostatin analog (SSA) can be considered as first-line therapy, especially when the uptake on somatostatin receptor (SSR) imaging is strongly positive (2). In the LUNA phase 2 trial, pasireotide (an agonist for SSR subtypes 1–3 and 5) alone or in combination with everolimus showed evidence of activity and safety (3). Chemotherapy is only considered in rapidly progressive metastatic pulmonary carcinoids and when no other treatment options are available. According to the National Comprehensive Cancer Network guidelines, platinum-based regimens or temozolomide can be used in stage IV AC with a high proliferation index (4).

Although lung NET frequently expresses SSR subtype 2 (SSR-2), the role of SSR-2–targeted peptide receptor radionuclide therapy (PRRT) with 177Lu DOTA-0-Tyr3-Octreotate (177Lu-DOTATATE) remains to be determined (5). Limited retrospective studies showed the efficacy of PRRT in lung NET, comparable to the results of the NETTER-1 trial, reflecting the generalizability of PRRT for any SSR-positive NET (6–8). Because of the lack of comparative studies, after progression on SSA the selection of the next systemic treatment modality including everolimus, chemotherapy, or PRRT is at the discretion of physicians and depends on the access, expertise, and practice patterns of different institutions in the world. Besides, the efficacy of 177Lu-DOTATATE in patients previously untreated with either chemotherapy or everolimus is unclear. This dual-center study aims to assess the safety and efficacy of patients with lung NET who received 177Lu-DOTATATE.

MATERIALS AND METHODS

Patients

This is a retrospective review of all consecutive patients with biopsy-proven, well-differentiated lung NET (TC or AC), who received PRRT. Data are extracted from 2 ENETS centers of excellence—Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia, and Hadassah-Hebrew University Medical Center (HHUMC), Jerusalem, Israel—during the period from 2006 to 2019. This series shares a single patient with the series of Lim et al. (8). This shared patient underwent PRRT at PMCC but was comanaged at another institution involved in that publication. We consider it valuable to include this patient’s data given the additional response assessment analyses and longer follow-up in our series.

Eligibility criteria for 177Lu-DOTATATE therapy included positive SSR imaging in all lesions, with either imaging progression or uncontrolled symptoms related to the unresectable disease. Positive 68Ga DOTA-0-Tyr3-Octreotate (68Ga-DOTATATE) PET/CT or SSR imaging was defined as lesion uptake higher than liver and subgrouped to less than spleen or higher than spleen on the basis of tomographic imaging (modified Krenning score 3 and 4, respectively). Further eligibility criteria are listed in the supplemental materials (supplemental materials are available at http://jnm.snmjournals.org).

This study was conducted after receiving approval from the institutional ethics committee at the PMCC (Peter Mac project no. 19/214R) and the HHUMC (approval no. 0072-16). Details of access to PRRT at respective institutions are summarized in the supplemental materials.

Therapy

Each cycle of 177Lu-DOTATATE was administered with premedication granisetron (2 mg), dexamethasone (8 mg), and renoprotective amino-acid infusion (25 g lysine and 25 g arginine in 1 L of normal saline) commencing 30 min before 177Lu-DOTATATE and continuing for 3 h thereafter (9). Dexamethasone was used as an antiemetic medication per institutional protocol only at PMCC. The treatment regimen typically included up to 4 cycles of 177Lu-DOTATATE given 6–10 wk apart. At PMCC, 177Lu-DOTATATE was usually given with radiosensitizing chemotherapy unless contraindicated, based on prior experiences showing enhanced efficacy without additional toxicity (10–12). Further details of radiosensitizing chemotherapy are described in the supplemental materials. Patients at HHUMC did not receive concurrent chemotherapy.

Follow-up

Patients were clinically reviewed before, and after, each cycle of 177Lu-DOTATATE and typically at 3 mo after the last cycle of treatment. Evaluation at 3 mo included assessment of symptoms; laboratory tests including full blood counts, renal function, hepatic function, and serum chromogranin A (supplemental materials); and imaging by CT or 68Ga-DOTATATE PET/CT with or without 18F-FDG PET/CT. Ongoing follow-up occurred at intervals of 3 to 6 mo. CT response was defined by RECIST 1.1 (13). Where available, contrast-enhanced CT images were directly compared. Otherwise, nonenhanced CT from the PET/CT component of the study was assessed, using 68Ga-DOTATATE uptake as a guide to follow the dominant lesions. RECIST response was used to define the main outcomes and 68Ga-DOTATATE PET/CT and 18F-FDG PET response were used for exploratory outcome measures. Response assessments were performed blinded to the patient outcome.

A descriptor for pathologic uptake on 68Ga-DOTATATE PET/CT was adapted from a semiquantitative visual scoring system originally designed for planar 111In octreotide imaging known as the Krenning score. Scores were from 0 to 4 as follows: 0 = no uptake; 1 = uptake < liver; 2 = lesion uptake similar to liver; 3 = uptake > liver and < spleen; 4 = uptake ≥ spleen (14). Response by 68Ga-DOTATATE PET/CT is described in Table 1.

View this table:
TABLE 1.

68Ga-DOTATATE PET/CT Response Criteria

In patients who underwent baseline 18F-FDG PET/CT, positive lesion was defined as uptake above the liver, and metabolic responses were assessed on the 18F-FDG PET images qualitatively according to the PMCC criteria (supplemental materials) (15,16).

Time to next treatment has been included to capture the timing of the next treatment from start of 177Lu-DOTATATE. All hematologic and renal toxicities occurring from the time of the first 177Lu-DOTATATE administration were recorded and defined according to the Common Terminology Criteria for Adverse Events (CTCAE; version 5.0).

Statistical Analysis

The continuous variables are summarized using the median (interquartile range [IQR] or range), and categoric variables are summarized using basic proportions. The concordance between RECIST and 68Ga-DOTATATE PET/CT response was assessed by Cohen’s κ statistics. Fisher’s exact was used to evaluate the difference between response rates in different groups. Progression-free survival (PFS) was calculated from the start of 177Lu-DOTATATE to clinical or imaging progression, new oncologic treatment, or death. Overall survival (OS) was recorded as the duration from the start of 177Lu-DOTATATE to last follow-up or death. The patients who were alive at the last follow-up were censored on that date. The cutoff follow-up date was August 31, 2019. The Log-rank test and Cox regression model were used to compare survival of different groups. A Kaplan–Meier curve was used to depict the survival. Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software).

RESULTS

Patient Characteristics

Of 51 consecutive patients with lung NET (22 from PMCC and 29 from HHUMC), 3 patients were removed from the analysis as they received at least 1 cycle of 90Y-DOTATATE. Forty-eight patients were included for final analysis, including 43 (90%) with AC and 5 (10%) with TC. The median Ki-67 of the entire population was 10% (range, 1%–30%), and most patients (90%) had metastatic disease in the liver, bone, or multiorgan involvement. Most patients (83%) received SSAs, and 10 (20%) had prior everolimus, chemotherapy, or both. Almost all patients (47/48, 98%) were treated due to radiographic disease progression and 1 patient for uncontrolled symptoms (back pain correlated to sites of osseous metastasis). Most (94%) demonstrated high avidity on SSR imaging, with a Krenning score of 4. Of 25 patients who underwent baseline 18F-FDG PET/CT, 16 (64%) had concurrent 18F-FDG–avid disease (Table 2). The median cumulative activity of 177Lu-DOTATATE was 27.4 GBq (range, 7.1–43.4 GBq) administered over a median of 4 cycles (range, 1–4). Sixteen patients (33%) had radiosensitizing chemotherapy (5FU or capecitabine with or without temozolomide) (Table 3).

View this table:
TABLE 2.

Patient Characteristics

View this table:
TABLE 3.

Treatment Parameters

Imaging Response

Of 40 patients with RECIST-measurable disease at 3 mo, 8 patients (20%; 95% CI, 10%–35%) had partial response and 27 patients (68%; 95% CI, 52%–80%) had stable disease resulting in a disease control rate (DCR) of 88% (95% CI, 73%–95%). Five patients (12%; 95% CI, 5–27) had progressive disease (Fig. 1). Five patients were lost to follow-up, 1 died early, and 2 had no available follow-up CT data (Supplemental Table1).

FIGURE 1.
FIGURE 1.

Waterfall plot of RECIST response at 3 mo after completion of PRRT. SOT lesions = sum of target lesions diameters.

Of 39 patients with available 68Ga-DOTATATE PET/CT at 3 mo, 17 patients (44%; 95% CI, 30%–59%) had partial response and 17 patients (44%; 95% CI, 30%–59%) had stable disease with a DCR of 88% (95% CI, 73%–95%) (Table 4 and Fig. 2). Five of those 39 patients (12%; 95% CI, 5%–27%) had progressive disease. Of the 9 patients with no available 68Ga-DOTATATE PET/CT, 5 were lost to follow-up, 1 died, and 3 had Octreoscan as their posttreatment molecular imaging. In 39 patients with both RECIST-assessable disease and available 68Ga-DOTATATE PET/CT results, only a moderate concordance in response categories of the 2 modalities was noted, weighted κ of 0.51 (95% CI, 0.21–0.68). Most patients with partial response or progressive disease by RECIST were also categorized similarly by 68Ga-DOTATATE PET/CT, 4 of 5 (80%) and 7 of 8 (87%) patients, respectively. The discordant response categories were noted in stable disease by RECIST: in this category, 10 of 26 patients were classified as partial response and 1 patient as progressive disease by 68Ga-DOTATATE PET/CT due to the development of new avid lesions.

View this table:
TABLE 4.

Response to Treatment

FIGURE 2.
FIGURE 2.

A representative patient with metastatic atypical lung carcinoid with partial response on 68Ga-DOTATATE PET/CT and CT at 3 mo after PRRT. Maximum-intensity-projection PET (top), PET/CT (middle), and CT (bottom) at baseline (A) and 3-mo follow-up (B) show marked response to treatment in liver (brackets), bones (arrowheads), and lymph nodes (arrows).

Follow-up 18F-FDG PET/CT was available in 12 of 48 patients. Although RECIST and 18F-FDG PET/CT responses were in agreement in most cases, 3 cases with stable disease by RECIST were grouped as partial response by 18F-FDG PET/CT.

In 30 patients from the AC cohort, although the rate of partial response was numerically higher in patients with a Ki-67 of >10% than in those with a Ki-67 of ≤10%, the difference did not reach statistical significance (36% and 16%, respectively; P = 0.4). Similarly, there was no significant difference in the rate of partial response in patients who received radiosensitizing chemotherapy, although a trend toward higher response rate was noted (36% and 12%, respectively; P = 0.1).

Survival Outcome

At a median follow-up of 42 mo, there were 16 (33%) deaths. The median PFS and OS of the entire cohort were 23 mo (95% CI, 18–28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively (Figs. 3A and 3B). The OS was not significantly different between the 2 institutions. The OS of the AC patients with Ki-67 ≤ 10% versus Ki-67 >10% and patients who received radiosensitizing chemotherapy versus those who did not receive chemotherapy were not significantly different (P = 0.7 and 0.4, respectively) (Supplemental Figs. 1A and 1B).

FIGURE 3.
FIGURE 3.

Kaplan–Meier plot depiction of OS (A) and PFA (B) of entire cohort.

Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had longer OS than those with no response (NR vs. 52 mo [95% CI, 28–65]; hazard ratio, 0.2 [95% CI, 0.1–0.6]; P < 0.001) (Fig. 4). Baseline 18F-FDG PET/CT–positive disease (available for 25/48 patients) and follow-up 18F-FDG PET/CT response (available for 12/48 patients) did not correlate with OS (P = 0.2 and 0.3, respectively).

FIGURE 4.
FIGURE 4.

Of the patients with stable disease by RECIST, those with partial response (PR) on 68Ga-DOTATATE PET/CT had longer OS than nonresponders (non-PR) on 68Ga-DOTATATE PET/CT, as demonstrated by Kaplan–Meier plot.

During follow-up, 27 patients received further treatment. The median time to next treatment was 23 mo (range, 7–56). Fifteen patients received further PRRT, and 12 patients received other treatments, including everolimus (n = 4), liver-directed therapy (n = 3), or change or increase in the dosage of SSA (n = 3) or chemotherapy (n = 2). One patient who did show progressive disease at 3 mo after PRRT received no treatment but did not show any further progression up to 24 mo, possibly indicating pseudoprogression.

Toxicity

177Lu-DOTATATE was well tolerated with acceptable toxicity, and most CTCAE grade 3/4 hematologic toxicity during treatment reversed to CTCAE grade 1/2 or baseline (Table 5). The most common hematologic toxicity included thrombocytopenia and lymphopenia. There was no incidence of myelodysplasia/leukemia or renal toxicity on long-term follow-up.

View this table:
TABLE 5.

Hematologic Adverse Events of 177Lu-DOTATATE

DISCUSSION

PRRT is an effective treatment option for patients with advanced gastroenteropancreatic NET, with sufficient SSR expression after progression on SSA (4,7). We have recently reported that only a proportion of lung NET expresses SSR at sufficient levels to potentially benefit from PRRT (17). Although lung NETs were not included in the NETTER-1 trial, limited clinical studies have shown promising results (6,7). By pooling the patients from 2 ENETs centers of excellence, we have shown that 177Lu-DOTATATE is an effective and safe treatment modality in lung NETs with high SSR expression after progression on SSA with a radiographic response of 20%, DCR of 88%, and favorable median PFS and OS of 23 and 59 mo, respectively. These results are largely consistent with those of previous studies, indicating the efficacy of this treatment (Supplemental Table 2) (8,18–27).

Effective treatment options for advanced progressive lung NET are limited, with no available data to guide the sequencing of therapy. Furthermore, the limited patient tolerability remains of serious consideration when deciding on further lines of treatment with the aim of preserving the quality of life. In the subcohort of 90 patients with lung NET in the RADIANT 4 trial, in 57 patients randomized to the everolimus arm a 50% reduction in risk of disease progression or death was reported compared with placebo (28). Although 58% of the patients achieved any tumor shrinkage, only 2% were evaluated as partial response by RECIST. The median PFS was 9.2 mo (95% CI, 6.8–10.9), with a 5.6-mo improvement compared with placebo (28). The phase II LUNA trial involving 112 patients, the majority with lung NET, supported the efficacy of pasireotide, everolimus, or their combination, with a radiographic DCR at 9 mo of 39%, 33%, and 58%, respectively (3). In line with the RADIANT-4 trial, the rate of partial response in the LUNA trial was 2% in all 3 groups. Adverse events (AEs) requiring dose adjustment or interruption were reported in 24%, 52%, and 61% of patients in the pasireotide, everolimus, and the combination arm, respectively (3). Chemotherapy remains an option as palliative therapy in lung NET, with a combination of various chemotherapeutic drugs showing a <30% objective response and median OS of 24.3 mo in a small retrospective series (29). Although PRRT is usually considered after progression on everolimus or chemotherapy, most patients (80%) in this study were untreated with either of those treatments. Although our result cannot be compared with prior trials or extrapolated to all patients with lung NET, the stringent patient selection based on sufficient SSR expression on pretreatment scanning remains a major advantage of this targeted treatment. Furthermore, attention to tumor heterogeneity of SSR expression is important as we have recently shown that up to 50% of patients with lung NET may demonstrate inter- and intrapatient heterogeneity on dual imaging by 68Ga-DOTATATE and 18F-FDG PET/CT (17).

PRRT has also shown an acceptable safety profile, with largely reversible short-term and limited long-term treatment-related AEs, with no cases of myelodysplasia or renal toxicity in our cohort, which is consistent with other studies (18–21). In a study by Sabet et al., grade 3 hematotoxicity was reported in 13.6% of patients at 3–10 wk after at least 1 cycle of PRRT with no grade 3 or higher nephrotoxicity (19). Mariniello et al. reported a <5% hematotoxicity after 90Y-DOTATOC and no hematologic or renal AEs after 177Lu-DOTATATE (21). In an Australian multicenter study, Lim et al. reported 2 of 48 (4%) patients with acute myeloid leukemia after PRRT; 1 patient was heavily pretreated including alkylating chemotherapy and the other patient was treated with SSA only (8).

Although previous studies and clinical trials have typically used CT or MRI for response assessment, it appears that the outcome of the patients with NET may not be adequately captured by RECIST 1.1 alone (19–22,26,27,30). In addition to standard RECIST, by combining the functional information provided by PET and morphologic change by CT, we also explored the use of 68Ga-DOTATATE PET/CT for response assessment and found a moderate concordance between 2 modalities. Interestingly, the response by 68Ga-DOTATATE PET/CT further stratified the OS of the patients who were otherwise grouped as stable disease by RECIST (Fig. 4). Such patients constituted almost two thirds of our cohort. The recent update on appropriate-use criteria indicated the use of SSR PET as appropriate for restaging after completion of PRRT(31). On the basis of our experience, response should include the disappearance or significant reduction of 68Ga-DOTATATE avidity such as a decline in the Krenning score of the known lesions without structural progression on CT or MRI. The response monitoring of nonmeasurable lesions such as osseous disease is also another advantage of SSR PET/CT. However, the exact role of 68Ga-DOTATATE PET/CT in response monitoring remains to be determined without currently established or validated criteria but warrants further evaluation.

The retrospective methodology of this study imposes some limitations, including potential selection bias, which we hope has been mitigated by combining the patients from the 2 institutions. Despite a relatively long follow-up time, death occurred only in around one third of patients, limiting the statistical power to robustly evaluate the prognostic implications of multiple clinical and imaging factors. In addition, the relatively low number of patients included further restricted the strength of statistical inference and precluded multivariate analysis. The use of different treatment protocols between the sites is also another limitation. For instance, dexamethasone was used as an antiemetic, and most patients at PMCC also received concurrent radiosensitizing chemotherapy. However, use of different procedures appears not to have had a major impact on outcomes, with comparable survival demonstrated at both centers. Lastly, 10% of patients had only locoregional disease, which may have better outcomes compared with those with bone, liver, or multiorgan involvement. We did not remove these patients from the analysis as this may have further reduced the statistical power of this study.

CONCLUSION

In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe, with a high DCR and encouraging PFS and OS. Further prospective studies comparing 177Lu-DOTATATE with other systemic options are warranted.

DISCLOSURE

Grace Kong is supported by a Clinical Fellowship Award from the Peter MacCallum Foundation. Rodney J. Hicks is recipient of a National Health and Medical Research Council Practitioner Fellowship (APP1108050). No other potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

We thank the nuclear medicine and nursing staff at the Peter MacCallum Cancer Centre and Hadassah-Hebrew University Medical Center for their commitment to providing excellent care for the patients.

KEY POINTS

QUESTION: What is the role of 177Lu-DOTATATE in patients with SSR-positive metastatic lung NET?

PERTINENT FINDINGS: In this retrospective study of 48 patients from 2 ENETS centers of excellence, 177Lu-DOTATATE was safe and achieved a high disease control rate, with an objective response in one fifth of patients. In patients who achieved stable disease by RECIST at 3 mo after completion of 177Lu-DOTATATE, the response by 68Ga-DOTATATE PET/CT may have prognostic implication.

IMPLICATIONS FOR PATIENT CARE: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE should be considered as an early effective and safe treatment modality.

Footnotes

  • Published online May 28, 2021.

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  • Revision received April 21, 2021.
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