Treatment of bronchopulmonary/thymus neuroendocrine tumors, interpretation of the 2021 CSCO guidelines

*Only for medical professionals to read for reference, Professor Duan Jianchun will give you a comprehensive understanding of the treatment strategies for lung-derived neuroendocrine tumors! On April 23-24, the 2021 CSCO Guide will be held in Beijing in a combined online and offline manner.

This update of the CSCO guidelines combines the latest evidence-based medicine at home and abroad.
The purpose is to promote more standardized clinical treatment of oncology in China.
There will be a total of 11 special sessions in this conference, and well-known experts in various oncology fields in China will give lectures and reports.
Interpret the guidelines for various cancers.

Among them, Professor Duan Jianchun from the Cancer Hospital of the Chinese Academy of Medical Sciences shared the "Treatment of Bronchial Lung/Thymic Neuroendocrine Tumors".

Neuroendocrine tumors can occur in various parts of the body.
The most common are digestive system neuroendocrine tumors such as stomach, intestine, and pancreas, accounting for about 2/3 of all neuroendocrine tumors.

Pulmonary bronchial neuroendocrine tumors are second only to the above tumors.
According to their malignancy, mitotic phase and Ki-67 index, they can be divided into small cell neuroendocrine tumors (small cell lung cancer), large cell neuroendocrine tumors, atypical carcinoids and tumors.
cancer.

According to the American Cancer Council (AJCC) TNM staging of tumors, if there is a chance of radical surgical resection, radical surgical resection should be the first choice.

According to different pathological types, stages, and whether the tumor is accompanied by related clinical symptoms caused by the secretion of biologically active hormones, it is decided whether to follow up systemic treatment.

The treatment principle of resectable bronchopulmonary neuroendocrine tumors is stage I~II and operable stage IIIA patients.
The recommended treatment plan is lobectomy or other anatomical resection + mediastinal lymph node dissection or sampling, and stage IIIA patients can be operated on stage II.
The recommended treatment plan is that if the postoperative pathology is atypical carcinoid (medium grade), observation is recommended; or chemotherapy with cytotoxic drugs.The principle of treatment of resectable thymic neuroendocrine tumors is that for patients with stage I to II, surgical resection is recommended for grade I; for patients with radical resection of stage IIIA to IIIB with negative margins, the recommended treatment for grade I is recommended.
For regular follow-up.

For patients with palliative resection and/or positive margins, the grade I recommended treatment plan is recommended observation, and the grade III recommended treatment plan is reverse therapy ± chemotherapy; for atypical carcinoids, more aggressive treatment is required than for typical carcinoids.

The treatment of local bronchial/thymic unresectable neuroendocrine tumors requires the use of octreotide or lanreotide based on whether the patient’s tumor is positive for somatostatin receptors and/or hormonal symptoms, and whether platinum-containing chemotherapy or radiotherapy is required according to the grade of the tumor.

The treatment of distant metastatic bronchopulmonary/thymic neuroendocrine tumors needs to be stratified according to tumor load and type.
For asymptomatic patients with typical carcinoids, observation can be selected.
Follow-up medication should be considered when the disease has progressed significantly.

For patients with clinically significant tumor burden and typical carcinoid or advanced signs or atypical carcinoid, some patients can choose to observe or choose a more active systemic treatment plan; if the disease progresses in the first-line treatment, it is recommended to change the follow-up treatment plan.

The incidence of multiple pulmonary nodules or micro tumors and multiple congenital pulmonary neuroendocrine cell growth is relatively lower, and the degree of malignancy is also lower.

This part of the patients is recommended to observe, check chest CT every 12 to 24 months, if new symptoms appear, follow-up treatment options can be used.

The exploration of immunotherapy in neuroendocrine tumors The SWOG DART study is a basket trial of CTLA-4 inhibitor ipilimumab combined with PD-1 inhibitor nivolumab in the treatment of rare tumors.

The primary study endpoint is the objective response rate (ORR).

The 32 patients who received treatment were all those who had failed previous treatment with more than 2 lines.

Among them, 18 cases were high-grade poorly differentiated neuroendocrine tumors (NECs); 15 cases were of gastrointestinal origin, and 6 cases were of lung origin.

The overall ORR is 25%.

The CA209-538 trial is a multicenter, non-randomized, open-label Phase II study of ipilimumab and nivolumab against rare cancers.

The trial included patients in 3 tumor groups (rare upper gastrointestinal tumors, rare gynecological tumors, and neuroendocrine tumors), and the endpoint of the study was disease control rate (DCR).

The study included 29 patients with neuroendocrine tumors (NENs) who had failed previous treatments, including 16 well-differentiated neuroendocrine tumors (NETs) and 13 NECs.

The lung is the main source of 39%, and 25% is from the pancreas.

The DCR was 72%, the ORR was 24%, the effective rate of typical bronchial carcinoid was 33%, and the median progression-free survival (PFS) and overall survival (OS) were 4.
8 months and 14.
8 months, respectively.

The prospective phase II study DUNE trial explored the efficacy of CTLA-4 inhibitor trimelimumab combined with PD-L1 inhibitor duvalizumab for NENs that failed standard treatment.

The trial included a total of 123 patients, 27 in the lung cohort, and the DCR at 9 months was 7.
4%.

The efficacy of the lung carcinoid/atypical carcinoid cohort was related to the expression of PD-L1.
The immune-related objective response rate (irORR) of PD-L1 positive patients was 16%, while that of negative patients was 0% (P=0.
033).

Carcinoid syndrome assessment and treatment The assessment and treatment of carcinoid syndrome have not been updated compared to last year's guidelines.

Biochemical testing and echocardiography or impact assessment are still needed to determine the patient's disease progression.

Treatment of large cell neuroendocrine tumorsLarge cell neuroendocrine tumors (LCNEC) are a type of tumor with a relatively high degree of malignancy between carcinoid and small cell lung cancer (SCLC).
The overall treatment principle is based on the patient's TNM stage, I~ The recommended treatment plan for stage III patients is surgical resection.
Postoperative chemotherapy can refer to the SCLC chemotherapy for small cell lung cancer.

For stage IV inoperable patients, the chemotherapy regimen for SCLC patients is mainly referred to.

There are different molecular subtypes of LCNEC, including small cell-like LCNEC and non-small cell-like LCNEC, which are mainly classified according to the deletion and mutation of RB1, TP53 and KRAS genes.

At present, there are still controversies regarding the choice of treatment strategies for patients with advanced and advanced LCNEC.
The American Society of Clinical Oncology recommends both SCLC and NSCLC treatment options for LCNEC.

However, a recent genome-based study showed that RB1 wild-type and/or LCNEC expressing RB1 protein are treated with NSCLC chemotherapy regimens, and OS is significantly better than SCLC chemotherapy regimens.

For LCNEC, the role of chest radiotherapy or preventive brain irradiation is still unclear, and there is no evidence that radiotherapy can benefit such patients.

Immunotherapy can prolong the survival of patients with stage IV LCNEC.
A retrospective analysis included 37 patients with advanced LCNEC who were diagnosed at Davidoff Cancer Center from 2014 to 2019.
Among them, 23 received immune checkpoint inhibitor (ICI) treatment, 14 Case did not receive ICI treatment.

In addition, the information and efficacy of non-LCNEC NSCLC patients who received nivolumab monotherapy from 2015 to 2016 were collected at the same time (N=270).
The results of the study showed that patients with advanced LCNEC received immunotherapy can observe survival benefits ( ICI vs No ICI: 14.
5 months vs 10.
3 months) and the efficacy of immunotherapy was similar to that of the NSCLC population (P=0.
23).

In 2020, a real-world retrospective study of four cancer centers in Israel and the United States showed that ICI can significantly improve the OS of patients with advanced LCNEC.

Compared with advanced LCNEC who did not receive ICI treatment, the median OS of patients who received ICI was significantly prolonged (12.
5 months vs 8.
4 months).
It can be seen from different stratified analyses that the efficacy of patients with different types may be different.

For the future treatment of neuroendocrine tumors, Professor Duan Jianchun believes that immunotherapy is a direction worth exploring.
In view of the low incidence of these tumors, some basket studies are needed to explore the efficacy of immunotherapy for these patients.