Повышение терапевтического эффекта 177 lu dota m 5 a в сочетании с ингибитором белка теплового шока 90 оналеспиба при ксенотрансплантациях колоректального рака

Background

Currently, the prognosis and treatment for patients (pts) with CA is primarily dictated by AJCC TNM staging criteria, which includes tumor extent (T), lymph node involvement (N), and detectable metastasis (M). However, recent studies have highlighted the prognostic and predictive value of circulating tumor (ct)DNA-based detection of molecular residual disease (MRD) post-curative-intent surgery. Here, we evaluated whether MRD status can further refine staging in pts with CA.

Methods

Results

In the GALAXY cohort, MRD-positive pts were observed to be significantly more likely to recur compared to MRD-negative pts across all TNM stages (24-month DFS; range: 0% — 50%, Table). MRD-negative pts had a high 24-month DFS probability compared to MRD-positive pts, independent of the TNM stage (range: 56.1% — 95.9%, Table). Among MRD-positive pts, advanced TNM stages (IIIC, IV) had significantly inferior outcomes compared to earlier stages, while the TNM stage was not prognostic in the MRD-negative cohort. These results were validated in the other cohorts and will be presented. Table: 4MO

Stage	MRD status	# Patients	HR (95% CI)	P	24-month DFS (95% CI), %
I	— +	294 2	39.0 (7.3-208.6)	<0.0001	95.9 (92.3 — 99.9) 50.0 (12.5 — 100.0)
IIA	— +	629 39	31.9 (17.3 — 58.8)	<0.0001	96.1 (94.2 — 97.9) 35.1 (21.3 — 58.0)
IIB	— +	103 13	10.8 (4.4 — 26.6)	<0.0001	86.9 (79.6 — 95.0) 28.9 (11.8 — 70.3)
IIC	— +	31 5	9.3 (1.9 — 46.6)	0.007	88.8 (77.5 -100.0) 40.0 (13.7 -100.0)
IIIA	— +	80 9	16.3 (5.2 — 51.4)	<0.0001	88.4 (78.9 — 99.0) 22.22 (6.6 — 75.4)
IIIB	— +	606 115	11.1 (7.7 — 15.9)	<0.0001	88.8 (85.8 — 91.9) 32.7 (24.1 — 44.4)
IIIC	— +	171 72	9.4 (5.7 — 15.5)	<0.0001	80.1 (72.4 — 88.5) 17.0 (9.0 — 32.2)
IVA	— +	34 24	5.5 (2.6 — 11.4)	<0.0001	56.1 (39.5 — 79.5) 12.1 (3.7 — 39.8)
IVB/C	— +	14 73	13.9 (3.0 — 63.6)	<0.0001	83.6 (10.8-64.9) 0.0 (N/A)

Conclusions

Legal entity responsible for the study

Funding

Has not received any funding.

Disclosure

Наименование отраслей науки по профилю журнала в соответствии с Номенклатурой специальностей:

3.1.6. Онкология, лучевая терапия (медицинские науки)

3.1.25. Лучевая диагностика (медицинские науки)

3.1.1. Рентгенэндоваскулярная хирургия (медицинские науки)

3.1.6. Онкология, лучевая терапия (биологические науки)

«Онкологический журнал: лучевая диагностика, лучевая терапия» — ежеквартальный научно-клинический рецензируемый журнал. Основан в 2018 г. Является специализированным медицинским изданием, информирующим неограниченный круг читателей наиболее полно и объективно о медицине, онкологии, рентгенологии, радиологии, лучевой диагностике. Содержит большое количество высококачественных полноцветных иллюстраций, обязательно сопровождающих статьи по лучевой диагностике и лучевой терапии.

С 2019 года «Онкологический журнал: лучевая диагностика, лучевая терапия» включен в научную электронную библиотеку и Российский индекс научного цитирования (РИНЦ).

С 2019 года журнал включен в CrossRef, все статьи индексируются с помощью цифрового идентификатора DOI.

С 2021 года журнал включен в перечень рецензируемых научных изданий ВАК, в которых должны быть опубликованы основные научные результаты диссертаций на соискание ученой степени кандидата наук, на соискание ученой степени доктора наук.

С 2023 г. журнал получил итоговую категорию К2 по результатам итогового распределения журналов перечня ВАК.

Официальный основной журнал межрегиональной общественной организации содействия развитию ядерной медицины «Общество ядерной медицины» и «Общества интервенционных онкорадиологов».

Целевая читательская аудитория: журнал предназначен для врачей, ученых, аспирантов, специалистов, работающих в области онкологии.

Контент: в журнале публикуются статьи по всем разделам лучевой диагностики и лучевой терапии в онкологии. Статьи могут быть экспериментальными или клиническими, теоретическими или концептуальными, обзорными по материалам литературы, дискуссионного характера, информацией о проблемах медицинской радиологии. Принимаются оригинальные статьи, краткие сообщения, аналитические обзоры, клинические случаи, дискуссионные материалы, рецензии, лекции, нормативные документы.

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Текущий выпуск

Том 7, № 2 (2024)

ЯДЕРНАЯ МЕДИЦИНА 

ЛУЧЕВАЯ ДИАГНОСТИКА 

ИНТЕРВЕНЦИОННАЯ РАДИОЛОГИЯ 

ПРОФЕССИОНАЛЬНОЕ ОБРАЗОВАНИЕ 

КЛИНИЧЕСКИЕ СЛУЧАИ 

Abstract

Purpose

Methods

Results

Conclusion

Study Registration: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1

Methods

Study design and patient population

Key study milestones are shown in Fig. 1.

Key study milestones and dates

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Study ethics

The investigational review board or local ethics committee at each participating site reviewed and approved the study protocol, and the rights, safety, and well-being of all participants were further protected by the regulations of Advanced Accelerator Applications, Italy, and by the strict monitoring and reporting requirements stipulated by Agenzia Italiana del Farmaco (AIFA).

Protocol and report writing, project management, statistics and data analysis, and regulatory and monitoring activities of the study were carried out by the contract research organisation (CRO), OPIS S.r.l., Desio, Italy.

Study objectives and endpoints

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Inclusion and exclusion criteria

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Study measures

Patient baseline clinical characteristics and demographics are collected and recorded in an electronic case report form (eCRF), including complete medical history, primary diagnosis, and disease status, the radiographic imaging technique used for tumour assessment, information from surgery/biopsy specimens (including chromogranin-A (CgA) and synaptophysin expression if available), SSTR expression levels, prior treatments, and concomitant medications.

Disease status includes disease stage according to the European Neuroendocrine Tumour Society (ENETS) Tumour Node Metastasis (TNM) classification, tumour grade (according to Ki-67 index or/and mitotic count), presence and site(s) of metastases, Karnofsky Performance Status (KPS) score, and any relevant clinical signs and symptoms.

Laboratory assessments, electrocardiograms (ECGs), physical assessment, vital signs, and KPS will be monitored per clinical practice and the summary of product characteristics (SmPC) and any clinically relevant laboratory abnormality will be recorded.

All data collected in the eCRF are loaded into the study database by the investigator and/or study coordinator using a fully-validated electronic data capture (EDC) software system; the investigator/study coordinator is also responsible for quality control. The designated CRO is responsible for reviewing the data for completeness, accuracy, and to ensure database quality processes.

Treatment procedure

Statistical analysis

Any discrepancies or missing values will be recorded by the EDC system, and imputations, if deemed appropriate, will be reported. Statistical significance will be considered as a two-sided alpha level of 0.05. No inferential analysis will be performed. Analysis of pooled and summarised data, including continuous and categorical data, will be performed by the CRO. All statistical analyses will be performed using SAS® version 9.4 or later (SAS Institute, Inc, Cary, NC, USA).

Results

The interim analysis was performed in the enrolled population at the end of the enrolment period. The cut-off date was extended from 2 March 2022 to 28 April 2022, to ensure that the planned sample size of 150 patients was achieved.

Baseline demographics

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Baseline KPS was assessed in 130 patients; the median score was 90.0 (range, 60.0–100.0), indicating that most patients could carry on with normal activities and had only minor signs or symptoms of disease. One hundred and thirty-five patients (83.8%) appeared ‘normal’ at physical examination.

At the time of this interim analysis, 46 (28.6%) patients had completed treatment, 106 (65.8%) were receiving ongoing treatment, and 9 (5.6%) had discontinued treatment. Reasons for discontinuing treatment included the occurrence of an AE (n = 3; one event each of hypoglycaemic coma, respiratory failure, and pulmonary embolism), death (n = 2), disease progression (n = 2), physician decision due to occurrence of thrombocytopenia (n = 1), and patient withdrawal (n = 1).

At the end of study enrolment, 154 patients (95.7%) were receiving ongoing treatment, and 7 (4.4%) had discontinued treatment due to death (n = 2), disease progression (n = 2), patient withdrawal (n = 2), or physician decision due to occurrence of thrombocytopenia (n = 1). Most patients (90.1%) had ≥ 1 previous or concomitant disease or previous surgery (Supplementary Table S2, Online Resource 1).

Tumour characteristics

Tumour grade (according to the Ki-67 index and/or mitotic count) was evaluated in 86 (53.4%) patients at study entry. The Ki-67 index was most frequently between 3.0–20.0% (n = 61, 70.9%) and was < 3.0% in 24 (27.9%) patients. The mitotic rate was available in 21/86 patients, with a median value of 2.0 (range, 0–16.0).

Most patients (90.7%) had stage IV disease at study entry, with histopathological grade 1 and 2 disease in 70.9% and 27.9% of patients, respectively. According to the Response Evaluation Criteria in Solid Tumours (RECIST) Criteria, version 1.1, 110 (68.3%) patients at study entry had ≥ 1 target lesion, 89 (55.3%) had ≥ 1 non-target lesion, 42 (26.1%) had ≥ 1 nodal target lesion, and 82 (50.9%) had ≥ 1 non-nodal target lesion.

Somatostatin receptor expression

SSTR expression was evaluated in 152 (94.4%) patients, predominantly using a ⁶⁸Ga-DOTATOC-positron emission tomography (PET)/computed tomography (CT) scan (96.7%; Table 4). Standardised uptake value (SUV) was performed in 113 (74.3%) patients. The mean maximum SUV was 45.0 ± 36.1 and the median SUV was 29.4 (range, 3.8–167.0). Among 39 (25.6%) patients with a Krenning score evaluation, 29 (74.4%) patients had a Krenning score of 4, and 4 patients each (10.3%) had scores of 2 and 3.

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Prior procedures and treatments for GEP-NETs

Health-related quality of life

Baseline HRQoL was assessed in 155 (96.3%) patients and is summarised in Table 5. Briefly, when HRQoL was assessed using the EORTIC QLQ-C30 questionnaire, mean functional, symptom, global health, and single-item scale scores indicated high levels of functioning, low levels of symptoms and high QoL. Notably, median scores were 100 for role, cognitive, and social functioning scales. Symptoms such as fatigue, nausea, and vomiting were absent, and approximately 50.0% of patients were symptom-free at baseline.

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Evaluation of baseline HRQoL using the NET-specific EORTC QLQ-G.I.NET-21 questionnaire revealed only a small impact on disease symptoms, treatment side effects, body image, disease-related worries, social functioning, communication, and sexuality. Higher mean scores were reported for disease-related worries and social function.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgements

We thank Ray Hill, an independent medical writer who provided medical writing support on behalf of Springer Healthcare and Nireshnee Ramchundar, PhD of Springer Healthcare Communications who provided editorial support before submission. This was funded by Advanced Accelerator Applications (a Novartis Company), Italy.

Funding

The REAL-LU study, editorial assistance for the preparation of this article, and the Article Processing Charge (APC) were funded by Advanced Accelerator Applications (a Novartis Company), Italy.

Author information

Authors and Affiliations

Contributions

Conceptualization: Secondo Lastoria, Sergio Baldari, and Ettore Seregni. Methodology: Ettore Seregni and Antonio D’Agostini. Formal analysis and investigation: Secondo Lastoria and Sergio Baldari. Writing—review and editing: Secondo Lastoria, Sergio Baldari, Francesco Dondi, Germano Perotti, Alberto Signore, Ettore Seregni, and Giovanni Storto. Supervision: Sergio Baldari. All authors read and approved the final manuscript. Protocol and report writing, project management, statistics and data analysis, and regulatory and monitoring activities of the study were carried out by the contract research organisation, OPIS S.r.l., Desio, Italy.

Corresponding author

Correspondence to
Sergio Baldari.

Ethics declarations

Ethics approval

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

Competing interests

Secondo Lastoria has received fees for participating on Advanced Accelerator Applications (AAA) advisory boards. Ettore Seregni has received speaker fees and fees for bureau services from AAA. Anna Rita Cervino participated in editorial project for Advanced Accelerator Applications (AAA). Angelina Filice participated in editorial projects for Advanced Accelerator Applications (AAA). All remaining authors declare no competing interests.

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Cite this article

• Received29 November 2023

• Accepted18 April 2024

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