Radiation therapy of the primary tumour and/or metastases of digestive metastatic cancers.

Metastatic gastrointestinal cancer is not an uncommon situation, especially for pancreatic, gastric, and colorectal cancers. In this setting, few data are available on the impact of the treatment of the primary tumour. Oligometastatic disease is associated with longer survival in comparison with more advanced disease. Metastasis-directed therapy, such as stereotactic body radiotherapy, seems related to better outcomes, but the level of evidence is low. In most tumour locations, prospective data are very scarce and inclusion in ongoing trials is strongly recommended.

Combination of Immunotherapy and Radiation Therapy in Gastrointestinal Cancers: An Appraisal of the Current Literature and Ongoing Research.

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Radiotherapy in the management of rare gastrointestinal cancers: A systematic review.

The aim of this analysis is to assess radiotherapy's role and technical aspects in an array of rare gastrointestinal (GI) cancers for adult patients. Collection data pertaining to radiotherapy and digestive rare cancers were sourced from Medline, EMBASE, and Cochrane Library. Preoperative chemoradiotherapy improved outcomes for patients with esophageal undifferentiated carcinoma compared with esophageal salivary gland types of carcinomas. For rare gastric epithelial carcinoma, perioperative chemotherapy is the common treatment. Adjuvant chemoradiotherapy showed no benefice compared with adjuvant chemotherapy for duodenal adenocarcinoma. Small bowel sarcomas respond well to radiotherapy. By analogy to anal squamous cell carcinoma, exclusive chemoradiotherapy provided better outcomes for patients with rectal squamous cell carcinoma. For anal adenocarcinoma, neoadjuvant chemoradiotherapy, followed by radical surgery, was the most effective regimen. For pancreatic neuroendocrine tumors, chemoradiotherapy can be a suitable option as postoperative or exclusive for unresectable/borderline disease. The stereotactic body radiotherapy (SBRT) is a promising approach for hepatobiliary malignancy. Radiotherapy is a valuable option in gastrointestinal stromal tumors (GIST) for palliative intent, tyrosine kinase inhibitors (TKIs) resistant disease, and unresectable or residual disease. Involved field (IF) radiotherapy for digestive lymphoma provides good results, especially for gastric extranodal marginal zone lymphoma (MALT). In conclusion, radiotherapy is not an uncommon indication in this context. A multidisciplinary approach is needed for better management of digestive rare cancers.

Organ and Function Preservation in Gastrointestinal Malignancies.

Radiation plays an important role in organ preservation for gastrointestinal malignancies, with a watch and wait strategy enabling surgery to be avoided in patients who are not suitable or who are refusing surgery. Brachytherapy boost allows the radiation dose to be escalated, which plays a pivotal role in the successful outcome of achieving organ preservation. Here we describe the role of brachytherapy in two common gastrointestinal malignancies (oesophagus and rectum). Their indications and how the brachytherapy procedures are carried out, together with the dose and fractionation commonly used are discussed. The use of brachytherapy needs to be included in the training curriculum at all academic centres so that its use is developed by the newer generation of radiation oncologists. Its current non-use due to bias, lack of training and availability is no longer justified, given the overwhelming published evidence for the role of brachytherapy to improve organ preservation for both radical treatment and palliation in gastrointestinal malignancies.

Intraoperative Radiation Therapy for Gastrointestinal Malignancies.

Despite improvements in definitive therapy, many patients with gastrointestinal malignancies experience local recurrences or have unresectable disease making subsequent management often challenging and morbid. Although higher doses of radiation may offer improved local control, the ability for dose escalation of external beam radiation therapy is often limited by adjacent radiosensitive structures. Intraoperative radiation therapy allows for additional radiotherapy to be delivered directly to the tumor or areas at highest risk for local recurrence while minimizing toxicity to adjacent structures, offering potentially improved outcomes for patients with unresectable disease or those with a high risk of local recurrence.

Non-coding RNAs in radiotherapy resistance: Roles and therapeutic implications in gastrointestinal cancer.

Radiotherapy has become an indispensable and conventional means for patients with advanced solid tumors including gastrointestinal cancer. However, innate or acquired radiotherapy resistance remains a significant challenge and greatly limits the therapeutic effect, which results in cancer relapse and poor prognosis. Therefore, it is an urgent need to identify novel biomarkers and therapeutic targets for clarify the biological characteristics and mechanism of radiotherapy resistance. Recently, lots of studies have revealed that non-coding RNAs (ncRNAs) are the potential indicators and regulators of radiotherapy resistance via the mediation of various targets/pathways in different cancers. These findings may serve as a potential therapeutic strategy to overcome radiotherapy resistance. In this review, we will shed light on the recent findings regarding the functions and regulatory mechanisms of ncRNAs following radiotherapy, and comprehensively discuss their potential as biomarkers and therapeutic targets in radiotherapy resistance of gastrointestinal cancer.

Intrafractional accuracy and efficiency of a surface imaging system for deep inspiration breath hold during ablative gastrointestinal cancer treatment.

PURPOSE: Beam gating with deep inspiration breath hold (DIBH) usually depends on some external surrogate to infer internal target movement, and the exact internal movement is unknown. In this study, we tracked internal targets and characterized residual motion during DIBH treatment, guided by a surface imaging system, for gastrointestinal cancer. We also report statistics on treatment time. METHODS AND MATERIALS: We included 14 gastrointestinal cancer patients treated with surface imaging-guided DIBH volumetrically modulated arc therapy, each with at least one radiopaque marker implanted near or within the target. They were treated in 25, 15, or 10 fractions. Thirteen patients received treatment for pancreatic cancer, and one underwent separate treatments for two liver metastases. The surface imaging system monitored a three-dimensional surface with ± 3 mm translation and ± 3° rotation threshold. During delivery, a kilovolt image was automatically taken every 20° or 40° gantry rotation, and the internal marker was identified from the image. The displacement and residual motion of the markers were calculated. To analyze the treatment efficiency, the treatment time of each fraction was obtained from the imaging and treatment timestamps in the record and verify system. RESULTS: Although the external surface was monitored and limited to ± 3 mm and ± 3°, significant residual internal target movement was observed in some patients. The range of residual motion was 3-21 mm. The average displacement for this cohort was 0-3 mm. In 19% of the analyzed images, the magnitude of the instantaneous displacement was > 5 mm. The mean treatment time was 17 min with a standard deviation of 4 min. CONCLUSIONS: Precaution is needed when applying surface image guidance for gastrointestinal cancer treatment. Using it as a solo DIBH technique is discouraged when the correlation between internal anatomy and patient surface is limited. Real-time radiographic verification is critical for safe treatments.

A Critical Review of the Role of Local Therapy for Oligometastatic Gastrointestinal Cancer.

PURPOSE: The purpose of this critical review is to provide an overview of the role and outcomes associated with the use of local therapy for patients with oligometastatic gastrointestinal cancers. METHODS AND MATERIALS: A review of clinical data was performed to describe outcomes associated with the use of systemic therapy and/or locoregional therapies for patients with oligometastatic gastrointestinal cancers including esophagus, gastric, liver, biliary, pancreas, colorectal, and anal canal. RESULTS: This review describes outcomes associated with current first line systemic therapy and oligometastasis directed locoregional therapy for patients with gastrointestinal cancers. Available data suggest that for well-selected patients among each gastrointestinal disease subsite, the use of local therapy is associated with favorable disease control and possible survival benefit. CONCLUSIONS: These data emphasize the importance of multidisciplinary collaboration and consideration of radiation therapy for patients with oligometastatic gastrointestinal cancers to improve locoregional control and progression-free survival. Multiple trials are ongoing to determine whether metastasis-directed radiation therapy improves overall survival.

The Promise of Magnetic Resonance Imaging in Radiation Oncology Practice in the Management of Brain, Prostate, and GI Malignancies.

Magnetic resonance imaging (MRI) has a key role to play at multiple steps of the radiotherapy (RT) treatment planning and delivery process. Development of high-precision RT techniques such as intensity-modulated RT, stereotactic ablative RT, and particle beam therapy has enabled oncologists to escalate RT dose to the target while restricting doses to organs at risk (OAR). MRI plays a critical role in target volume delineation in various disease sites, thus ensuring that these high-precision techniques can be safely implemented. Accurate identification of gross disease has also enabled selective dose escalation as a means to widen the therapeutic index. Morphological and functional MRI sequences have also facilitated an understanding of temporal changes in target volumes and OAR during a course of RT, allowing for midtreatment volumetric and biological adaptation. The latest advancement in linear accelerator technology has led to the incorporation of an MRI scanner in the treatment unit. MRI-guided RT provides the opportunity for MRI-only workflow along with online adaptation for either target or OAR or both. MRI plays a key role in post-treatment response evaluation and is an important tool for guiding decision making. In this review, we briefly discuss the RT-related applications of MRI in the management of brain, prostate, and GI malignancies.

Ytrrium-90 transarterial radioembolization in patients with gastrointestinal malignancies

Transarterial radioembolization (TARE) with yttrium-90 (Y90) is a promising alternative strategy to treat liver tumors and liver metastasis from colorectal cancer (CRC), as it selectively delivers radioactive isotopes to the tumor via the hepatic artery, sparring surrounding liver tissue. The landscape of TARE indications is constantly evolving. This strategy is considered for patients with hepatocellular carcinoma (HCC) with liver-confined disease and preserved liver function in whom neither TACE nor systemic therapy is possible. In patients with liver metastases from CRC, TARE is advised when other chemotherapeutic options have failed. Recent phase III trials have not succeeded to prove benefit in overall survival; however, it has helped to better understand the patients that may benefit from TARE based on subgroup analysis. New strategies and treatment combinations are being investigated in ongoing clinical trials. The aim of this review is to summarize the clinical applications of TARE in patients with gastrointestinal malignancies.

The Evolving Role of Hypofractionated Radiotherapy in Older Adults with Gastrointestinal Cancers.

While radiotherapy treatment of gastrointestinal (GI) malignancies has historically involved 5-6 weeks of low dose fractions of radiation, hypofractionated radiation over 1-4 weeks has emerged as an efficacious alternative in treatment of many cancer types, including GI cancers. Hypofractionation is of particular relevance in the treatment of older adult patients, wherein the balance between cancer cure, toxicity, goals of care and convenience must be carefully weighed. The role of hypofractionated radiation in the definitive treatment of GI malignancies remains an active area of investigation in sites such as the esophagus, anus, and pancreas, an efficacious alternative for unresectable cases hepatocellular carcinoma and cholangiocarcinoma and standard of care for locally advanced rectal cancer. Meanwhile, hypofractionated radiation therapy represents an efficacious method of palliation for all GI cancers. In this review, we will discuss the application of hypofractionation in gastrointestinal malignancies by disease subsite, with a focus on caring for older adults.

Ytrrium-90 transarterial radioembolization in patients with gastrointestinal malignancies.

Transarterial radioembolization (TARE) with yttrium-90 (Y90) is a promising alternative strategy to treat liver tumors and liver metastasis from colorectal cancer (CRC), as it selectively delivers radioactive isotopes to the tumor via the hepatic artery, sparring surrounding liver tissue. The landscape of TARE indications is constantly evolving. This strategy is considered for patients with hepatocellular carcinoma (HCC) with liver-confined disease and preserved liver function in whom neither TACE nor systemic therapy is possible. In patients with liver metastases from CRC, TARE is advised when other chemotherapeutic options have failed. Recent phase III trials have not succeeded to prove benefit in overall survival; however, it has helped to better understand the patients that may benefit from TARE based on subgroup analysis. New strategies and treatment combinations are being investigated in ongoing clinical trials. The aim of this review is to summarize the clinical applications of TARE in patients with gastrointestinal malignancies.

Diagnostic timelines and self-reported symptoms of patients with lung and gastrointestinal cancers undergoing radiation therapy. Retrospective case control study.

BACKGROUND: Previous studies have found that patients with lung cancer report worse patient experience compared to other tumour groups. Reasons that may negatively impact patient experience include delays in diagnosis as well as inadequate symptom management. The purpose of this study was to compare the diagnostic timelines and symptom reports of patients with lung and gastrointestinal (GI) cancers. METHODS: This study included patients diagnosed with lung or GI cancers who attended a radiation oncology (RO) consultation and/or received radiation treatment between May and August 2019 at the Tom Baker Cancer Centre, Calgary, Alberta, Canada. Data collected included demographics, dates of diagnostic time points, and self-reported symptom scores across 3 time points. A descriptive analysis was completed, and the median number of days between time points was compared between tumour groups. RESULTS: Patients with lung cancer had longer diagnostic timelines compared to GI patients. The median number of days between the first investigative test and biopsy was 21 days longer for patients with lung cancer (p < 0.05). From RO consultation to the first treatment review appointment, 25% and 4% of lung and GI patients, respectively, reported worsening of symptoms. A greater proportion of lung patients reported worse symptom scores during treatment compared to GI patients. This varied by specific symptom. CONCLUSIONS: Patients with lung cancer experienced delays in receiving a diagnosis and worse symptom burden during radiation therapy in this study. We identified potential targets to improve patient experience.

Long-term clinical outcomes of lipiodol marking using standard gastroscopy for image-guided radiotherapy of upper gastrointestinal cancers.

BACKGROUND: Image-guided radiotherapy (IGRT) has significantly improved the precision in which radiotherapy is delivered in cancer treatment. Typically, IGRT uses bony landmarks and key anatomical structures to locate the tumor. Recent studies have demonstrated the feasibility of peri-tumor fiducials in enabling even more accurate delineation of target and normal tissue. The use of gold coils as fiducials in gastrointestinal tumors has been extensively studied. However, placement requires expertise and specialized endoscopic ultrasound equipment. This article reports the long-term outcomes of using a standard gastroscopy to inject liquid fiducials for the treatment of oesophageal and gastric tumors with IGRT. AIM: To assess the long-term outcomes of liquid fiducial-guided IGRT in a cohort of oesophageal and gastric cancer patients. METHODS: A retrospective cohort study of consecutive adults with Oesophagogastric cancers referred for liquid fiducial placement before definitive/neo-adjuvant or palliative IGRT between 2013 and 2021 at a tertiary hospital in Melbourne, Australia was conducted. Up to four liquid fiducials were inserted per patient, each injection consisting of 0.2-0.5mL of a 1:1 mixture of iodized oil (Lipiodol; Aspen Pharmacare) and n-butyl 2-cyanoacrylate (Histoacryl®; B. Braun). A 23-gauge injector (Cook Medical) was used for the injection. All procedures were performed by or under the supervision of a gastroenterologist. Liquid fiducial-based IGRT (LF-IGRT) consisted of computer-assisted direct matching of the fiducial region on cone-beam computerised tomography at the time of radiotherapy. Patients received standard-IGRT (S-IGRT) if fiducial visibility was insufficient, consisting of bone match as a surrogate for tumor position. Radiotherapy was delivered to 54Gy in 30 fractions for curative patients and up to 45Gy in 15 fractions for palliative treatments. RESULTS: 52 patients were referred for liquid fiducial placement within the study period. A total of 51 patients underwent liquid fiducial implantation. Of these a total of 31 patients received radiotherapy. Among these, the median age was 77.4 years with a range between 57.5 and 88.8, and 64.5% were male. Twenty-seven out of the 31 patients were able to have LF-IGRT while four had S-IGRT. There were no complications after endoscopic implantation of liquid fiducials in our cohort. The cohort overall survival (OS) post-radiotherapy was 19 mo (range 0 to 87 mo). Whilst the progression-free survival (PFS) post-radiotherapy was 13 mo (range 0 to 74 mo). For those treated with curative intent, the median OS was 22.0 mo (range 0 to 87 mo) with a PFS median of 14.0 mo (range 0 to 74 mo). Grade 3 complication rate post-radiotherapy was 29%. CONCLUSION: LF-IGRT is feasible in 87.1% of patients undergoing liquid fiducial placement through standard gastroscopy injection technique. Our cohort has an overall survival of 19 mo and PFS of 13 mo. Further studies are warranted to determine the long-term outcomes of liquid-fiducial based IGRT.

ESTRO ACROP guidelines for the delineation of lymph nodal areas in upper gastrointestinal malignancies.

The European SocieTy for Radiation and Oncology -Advisory Committee on Radiation Oncology Practice (ESTRO-ACROP) endorsed a project to provide guidelines (GL) for the identification and delineation of clinically negative lymph-nodal stations (LNs) involved in upper gastrointestinal clinical scenarios. The presented GL is focused on preoperative (or definitive) setting. The project aim is to improve the consistency of clinical target volume (CTV) delineation by providing: a description of the anatomical boundaries of the LNs; a radiological computed tomography-based atlas depicting the LNs areas; a free, web-based, interactive example case for independent training of radiation oncologists on LNs delineation according to the presented GL, by both qualitative and quantitative analysis (through the FALCON EduCase platform). This project was carried out with the intention to facilitate and improve uniformity of future upper gastrointestinal guidelines on nodal CTV delineation. We report methodology and results from the collaboration of a working group panel selected by the ESTRO-ACROP.

A Machine Learning Model Approach to Risk-Stratify Patients With Gastrointestinal Cancer for Hospitalization and Mortality Outcomes.

PURPOSE: Patients with gastrointestinal (GI) cancer frequently experience unplanned hospitalizations, but predictive tools to identify high-risk patients are lacking. We developed a machine learning model to identify high-risk patients. METHODS AND MATERIALS: In the study, 1341 consecutive patients undergoing GI (abdominal or pelvic) radiation treatment (RT) from March 2016 to July 2018 (derivation) and July 2018 to January 2019 (validation) were assessed for unplanned hospitalizations within 30 days of finishing RT. In the derivation cohort of 663 abdominal and 427 pelvic RT patients, a machine learning approach derived random forest, gradient boosted decision tree, and logistic regression models to predict 30-day unplanned hospitalizations. Model performance was assessed using area under the receiver operating characteristic curve (AUC) and prospectively validated in 161 abdominal and 90 pelvic RT patients using Mann-Whitney rank-sum test. Highest quintile of risk for hospitalization was defined as "high-risk" and the remainder "low-risk." Hospitalizations for high- versus low-risk patients were compared using Pearson's χ2 test and survival using Kaplan-Meier log-rank test. RESULTS: Overall, 13% and 11% of patients receiving abdominal and pelvic RT experienced 30-day unplanned hospitalization. In the derivation phase, gradient boosted decision tree cross-validation yielded AUC = 0.823 (abdominal patients) and random forest yielded AUC = 0.776 (pelvic patients). In the validation phase, these models yielded AUC = 0.749 and 0.764, respectively (P < .001 and P = .002). Validation models discriminated high- versus low-risk patients: in abdominal RT patients, frequency of hospitalization was 39% versus 9% in high- versus low-risk groups (P < .001) and 6-month survival was 67% versus 92% (P = .001). In pelvic RT patients, frequency of hospitalization was 33% versus 8% (P = .002) and survival was 86% versus 92% (P = .15) in high- versus low-risk patients. CONCLUSIONS: In patients with GI cancer undergoing RT as part of multimodality treatment, machine learning models for 30-day unplanned hospitalization discriminated high- versus low-risk patients. Future applications will test utility of models to prompt interventions to decrease hospitalizations and adverse outcomes.

An ionising radiation-induced specific transcriptional signature of inflammation-associated genes in whole blood from radiotherapy patients: a pilot study.

BACKGROUND: This communication reports the identification of a new panel of transcriptional changes in inflammation-associated genes observed in response to ionising radiation received by radiotherapy patients. METHODS: Peripheral blood samples were taken with ethical approval and informed consent from a total of 20 patients undergoing external beam radiotherapy for breast, lung, gastrointestinal or genitourinary tumours. Nanostring nCounter analysis of transcriptional changes was carried out in samples prior and 24 h post-delivery of the 1st radiotherapy fraction, just prior to the 5th or 6th fraction, and just before the last fraction. RESULTS: Statistical analysis with BRB-ArrayTools, GLM MANOVA and nSolver, revealed a radiation responsive panel of genes which varied by patient group (type of cancer) and with time since exposure (as an analogue for dose received), which may be useful as a biomarker of radiation response. CONCLUSION: Further validation in a wider group of patients is ongoing, together with work towards a full understanding of patient specific responses in support of personalised approaches to radiation medicine.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RT with passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Radiation and Immunotherapy in Upper Gastrointestinal Cancers: The Current State of Play.

Radiotherapy remains one of the contemporary cornerstones of cancer treatment in the neoadjuvant, curative, adjuvant and palliative settings, either in isolation or as a multimodal approach. Moreover, recent advances in targeted immune checkpoint therapy have firmly established immunotherapy as the fourth pillar in cancer therapy alongside surgery, chemotherapy and notably radiotherapy. There is emerging evidence to suggest both radioresistance and reduced efficacy of immune checkpoint blockade (ICB) are potentiated by the tumour microenvironment (TME) and in fact modulating aspects of this immunosuppressive milieu is instrumental to unlocking anti-tumour immunity. The response rates of Upper Gastrointestinal (UGI) malignancies to ICB remains modest at 10-15%, compared to melanoma at 20-40%. Harnessing the effects of radiotherapy through remodelling of the TME using ICB as a radiosensitisor is an avenue showing promise. Here we explore the rationale behind combining radiotherapy with ICB, as a symbiotic relationship in shifting the balance in favour of anti-tumour immunity. We discuss the effects of radiotherapy on immunogenic cell death, the concept of the abscopal effect, the importance of the cGAS STING pathway, and their relevance in the context of the tumour microenvironment. Furthermore, dosing and timing of radiotherapy and ICB is now being evaluated for its synergistic effects on host tumour immunity, and we review the ongoing efforts and current available literature for single agent and dual agent ICB in combination multimodal therapy for both locally advanced operable and metastatic disease of the upper gastrointestinal tract.

177Lu-PRRT in advanced gastrointestinal neuroendocrine tumors: 10-year follow-up of the IRST phase II prospective study.

PURPOSE: In March 2014, we reported the activity and safety of 177Lu-DOTA-octreotate peptide receptor radionuclide therapy (Lu-PRRT) at two different dosages (18.5 GBq and 27.5 GBq in 5 cycles) in patients with progressive metastatic gastrointestinal neuroendocrine tumors (GI-NETs). Disease control rate (DCR) and toxicity were addressed. Herein, we report the late toxicity, progression-free survival (PFS), and overall survival (OS) in the same cohort after a 10-year follow-up. METHODS: We conducted an open-label, disease-oriented prospective phase II trial. From March 2008 to June 2011, 43 patients received 3.7 GBq or 5.5 GBq of Lu-PRRT every 6 to 8 weeks, each cycle repeated 5 times. All patients showed 68Gallium-DOTA-peptide PET/Octreoscan® positivity (score 3-4 Rotterdam scale) in known lesions. Tumor burden was estimated radiologically. Time-to-event data (PFS and OS) were described using Kaplan-Meier curves and compared with the log-rank test. RESULTS: Forty-three patients (28 males and 15 females) were evaluable and were monitored for a median period of 118 months (range 12.6-139.6). Median PFS in patients receiving 18.5 GBq was 59.8 months (95% confidence interval [95% CI] 14.3-79.6), identical to that of patients treated with 27.5 GBq (59.8 months, 95% CI 23.4-82.0). Median OS was 71.0 months (95% CI 46.1-107.3) in the group who received 18.5 GBq and 97.6 months (95% CI 64.3-not reached) in the group treated with 27.5 GBq (P = 0.22). Patients with progression limited to lymph nodes showed significantly longer median PFS and OS than those with hepatic lesions (P = 0.02 for PFS and P = 0.04 for OS). Age over 65 years at the time of PRRT was also significant for OS. Of note, no late hematological or renal toxicity was observed in either group. CONCLUSIONS: The long-term follow-up of the IRST phase II study shows that Lu-PRRT is a safe and effective therapy for patients with advanced GI-NET, the most important prognostic factor being tumor burden, hepatic lesions, and age. We believe that Lu-PRRT should be offered to patients with early-stage disease.