Recommendations for bone‐directed therapy in patients with neuroendocrine tumour skeletal metastases at the New Zealand National Neuroendocrine Tumour Multidisciplinary Meeting

Abstract

The role of anti‐resorptive agents in patients with bone metastases from neuroendocrine neoplasms is unclear. Our aim was to review bone‐specific treatment recommendations by the New Zealand National Neuroendocrine Tumour Multidisciplinary Meeting (MDM). Recommendations for bone‐specific treatment were given at 29/365 MDMs (7.9%); 44.8% were confirmed to have received the recommended therapy. Bone‐specific treatment recommendations were infrequent; there is a need for more data on the role of anti‐resorptive agents in this group.

Approximately 18% of patients with metastatic neuroendocrine neoplasms (NENs) develop bone metastases. ¹ Bone metastases can result in skeletal‐related events (SREs) (i.e. pathological fracture, spinal cord compression and pain requiring treatment with surgery or external beam radiotherapy (EBRT)) and are associated with reduced overall survival compared to those without bone metastases. ²

Anti‐resorptive agents, such as zoledronic acid and denosumab, reduce SREs and improve survival in multiple cancer types, and the use of these agents is well established in patients with breast and prostate cancers. ³ , ⁴ , ⁵ There are no randomised controlled trials of these agents in NEN patients and retrospective studies reporting on anti‐resorptive therapy (ART), and outcomes are limited. ⁶

The European Neuroendocrine Tumour Society (ENETS) consensus guideline states, ‘Patients with bone metastases should be considered for treatment with bisphosphonates which can be administered either orally or intravenously’ and recommends analgesia for bone metastases while considering external beam radiotherapy for pain management and prophylactically to prevent pathological fractures. ⁷ Surgery is advised as a palliative measure for mechanical indications (spinal cord compression or high risk of pathological fracture). ⁷

Our aim was to assess the recommendations of the national New Zealand Neuroendocrine Tumour Multidisciplinary Meeting (NETMDM), a weekly hybrid in‐person/online meeting, with a focus on how often bone‐specific treatments are recommended in clinical practice.

NETMDM records from June 2019 until June 2023 were reviewed. Inclusion criteria: any patient with a histologically confirmed NEN, including neuroendocrine carcinoma and ≥1 bone metastasis. Demographic and disease‐specific data were collected from the electronic medical record, including age at diagnosis, age at death, gender, ethnicity (according to the electronic clinical record), primary site and tumour grade. Presence of symptoms related to the bone metastases was recorded if they were noted in the MDM documentation. The indication for bone‐directed treatment was recorded based on the information presented in the NETMDM referral document, or if documented in the NETMDM outcome. Bone‐specific treatments included zoledronic acid, denosumab, surgery to bone or EBRT to bone. Patients could have multiple bone‐specific treatments recommended and it was recorded whether the bone‐specific treatment was administered (if known). Systemic therapy (e.g., peptide receptor radionuclide therapy (PRRT), chemotherapy) was not considered bone‐specific therapy. Data were recorded in an Excel spreadsheet. Analysis was performed using IBM SPSS Statistics version 30.0.0.0. Continuous variable comparisons were made using the Mann–Whitney U test. Categorical variables were compared using the chi‐squared test. The null hypothesis was rejected at a P‐value of <0.05.

Ethical approval was granted by the Central Health and Disability Ethics Committee (2024 EXP 19472).

From the 4‐year study period, of the 1934 NETMDM outcomes reviewed, 182 patients met the inclusion criteria. Patients were often discussed more than once, giving a total of 365 NETMDM outcome recommendations available for analysis. Of the 182 patients included, 57.1% were male, 66.5% New Zealand European/other European and 18.7% Māori. Median age at NEN diagnosis was 59 years (interquartile range (IQR) 49–68 years) for patients who developed bone metastases, and as of June 2024, 44% of the study population were deceased, with a median age at death of 65.5 years (IQR 60–75.8 years). The median time from NEN diagnosis to death was 2 years (IQR 0.25 years to 6.75 years). The median age at death was younger for Māori compared to non‐Māori (60.5 vs 68 years P = 0.03), but the time from diagnosis to death was similar (median 1 year, IQR 0–5 years, vs 2.5 years, IQR 1–7.25 years, P = 0.3). The most frequent primary sites were small intestine (41.8%) and pancreas (20.9%). Tumour grade was well‐differentiated grade 1 and 2 in 26.9% and 35.7% respectively, with 8.1% neuroendocrine carcinoma and the remainder composed of lung (typical carcinoid 3.3%, atypical carcinoid 7.1%) and neuroendocrine tumours without a generally accepted grading system (e.g. paraganglioma, medullary thyroid carcinoma). There was a greater proportion of phaeochromocytoma/paraganglioma among Māori compared to non‐Māori (52.6% vs 14.7% P ≤ 0.001). Those with phaeochromocytoma/paraganglioma were younger at the age of diagnosis than other NEN diagnoses (median age 44 years vs 61 years P ≤ 0.001).

Recommendations for bone‐specific therapy were infrequent, only occurring in 29 from 365 MDM outcomes (7.9%) (Fig. 1). The indications for bone‐specific treatment are recorded in Table 1. The 29 recommendations were made for 21 patients (14 patients had one recommendation, six patients had two bone‐specific treatments recommended, and one patient had three bone‐specific treatments recommended (EBRT once and surgery twice). In total, zoledronic acid was recommended twice (0.5%) but on both occasions this was for the same patient, EBRT 18 times (4.9%), and surgery in nine (2.5%). Denosumab was never recommended, likely due to this not being funded for patients with bone metastases. Symptoms were reported in the NETMDM referral or NETMDM outcome in 33/365 (9.0%) of our study cohort. Symptoms related to bone metastases were reported in 8/18 (44.4%) of those recommended EBRT and 5/9 (55.6%) of those recommended surgery. There was no difference in the rate of bone‐specific therapeutic recommendations between Māori and non‐Māori (P = 0.52). Other MDM recommendations for people with bone metastases included chemotherapy (40.7%), PRRT (42.9%), imaging (39.6%), surveillance (23.6%) and other (45.6%), noting that each patient may have had more than one recommendation made.

Figure 1.

Percentage of patients recommended to receive bone‐specific treatment at the New Zealand National Neuroendocrine Multidisciplinary Meeting and, if a recommendation was made, which therapy was recommended.

Table 1.

Bone‐specific treatment recommended and indications

Treatment	Number of MDM recommendations (individual patients)	Indication	Recommended treatment received¶
Zoledronic acid	2 (1)†	Extensive asymptomatic bone metastases—2	Yes—0 No—2
Denosumab	0		Not applicable
External beam radiotherapy	18 (18)‡	Pain—5 Pathological fracture—2 Cord compression—5 Pain and cord compression—1 Pathological fracture and cord compression—2 Indication not provided—3	Yes—11 No—6 Unknown—1
Surgery	9 (8)‡ , §	Pathological fracture—2 Cord compression—5 Pathological fracture and cord compression—1 Indication not provided—1	Yes—2 No—7

^†One patient was recommended zoledronic acid on two separate occasions;

^‡Includes five patients recommended both surgery and external beam radiotherapy within the same multidisciplinary meeting;

^§One patient was recommended surgery at two separate multidisciplinary meetings. ‘Pathological fracture’ encompasses both confirmed and at high risk of developing fracture associated with a bone metastasis. ‘Cord compression’ encompasses both confirmed or threatened spinal cord compression due to bone metastasis.

^¶Reasons for treatment not being received included external beam radiotherapy instead of surgery (2), peptide receptor radionuclide therapy instead of surgery (1), patients moved overseas (2), non‐attendance/failure of engagement with the service (2), and unknown for the remainder.

Discussion

The New Zealand national NETMDM infrequently recommended bone‐specific treatment. There are likely several reasons for this, including the efficacy of systemic therapy for bone metastases (e.g. PRRT), the infrequent presence of bone metastases without extensive visceral disease that requires other systemic therapy and NETMDM referral patterns (e.g. the NETMDM is the first step in the referral pathway for the national PRRT service) that favour systemic therapy recommendation. There was also likely a selection bias of patients included for assessment. Patients presented at the national NETMDM likely do not represent the full population of patients with NENs in NZ, with those presented potentially being more complex, with more advanced disease suggested by the shorter than expected median survival (~2 years in this cohort vs >5 years ⁸ in the literature). This could have influenced the preference to recommend non‐bone‐specific treatments and management strategies, and there may be an assumption that bone‐specific treatments may have already been administered or considered by their local team.

An important factor influencing treatment recommendations from the NETMDM may be the reporting of symptoms. In our study, for the patients with bone metastases, only 9.0% of the MDM documentation reported symptoms related to bone metastases. This is significantly lower than the international literature, which shows that 60%–80% of NEN patients with bone metastases have symptoms ⁹ and may reflect a limitation of the referral proforma used which does not explicitly request details of current symptoms. The low reporting of symptoms may explain why the rate of radiotherapy is lower than in the international literature and may have also been contributed to by the absence of a radiation oncologist at most of the NETMDMs. It is also possible that patients had already received the maximum locally available treatment such as EBRT before being referred to the NETMDM. A change to the NETMDM referral proforma that explicitly requests information on previous EBRT and symptoms may clarify this.

Zoledronic acid was rarely recommended (only suggested twice, in the same patient out of 182 patients). This is despite being both indicated and funded for the prevention of skeletal‐related events in patients with advanced malignancies with bone metastases. ¹⁰ In comparison, in a retrospective study from two North American centres, bone‐directed therapy was administered to 67/82 (82%) of NEN patients with skeletal metastases: 50% received radiation, 45% bisphosphonates, 5% denosumab and 18% surgery; 46% had more than one intervention. ² High rates of bone‐directed therapy were also reported by a German ENETS centre – nearly two‐thirds of patients received bisphosphonates and 25.9% received radiotherapy. ¹¹ On the other hand there is a lack of randomised, controlled trial data showing the benefit of ART in patients with NEN and data from other cancer types cannot necessarily be directly extrapolated to NEN. Bone metastases in NEN are predominantly osteoblastic, unlike in breast cancer, in which they are predominantly osteolytic. Prostate cancer metastases are osteoblastic; however, men with prostate cancer have other treatment factors (androgen deprivation therapy) that have an impact on bone. Furthermore, the relatively longer survival in patients with metastatic NEN, compared to other advanced malignancies, may leave them vulnerable to the side effects of ART, particularly osteonecrosis of the jaw, compared to patients with other cancer types.

The New Zealand national NETMDM infrequently recommended bone‐specific treatment. Further research is needed as to whether bone‐specific therapy, particularly with anti‐resorptive agents such as zoledronic acid, is efficacious in reducing SREs in NEN patients, and a randomised controlled trial in this area is recommended.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.